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Forsell, Mattias N. E.ORCID iD iconorcid.org/0000-0001-6904-742x
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Publications (10 of 48) Show all publications
Waltraud, S., Schmuckenschlager, A., Thunberg, T., Wigren, J., Fors Connolly, A.-M., Assinger, A., . . . Forsell, M. N. E. (2024). Direct and indirect effects of Puumala hantavirus on platelet function. Thrombosis Research, 233, 41-54
Open this publication in new window or tab >>Direct and indirect effects of Puumala hantavirus on platelet function
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2024 (English)In: Thrombosis Research, ISSN 0049-3848, E-ISSN 1879-2472, Vol. 233, p. 41-54Article in journal (Refereed) Published
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.

Keywords
Hemorrhagic fever with renal syndrome, Immunothrombosis, Infection, Platelet dysfunction, Puumala hantavirus, Thrombocytopenia
National Category
Hematology
Identifiers
urn:nbn:se:umu:diva-217532 (URN)10.1016/j.thromres.2023.11.017 (DOI)2-s2.0-85177814613 (Scopus ID)
Funder
Region Västerbotten, RV-967545Region Västerbotten, RV-734361Umeå UniversitySwedish Heart Lung Foundation, 20170334Swedish Research Council, 2020-06235The Kempe Foundations, SMK-1560
Available from: 2023-12-14 Created: 2023-12-14 Last updated: 2023-12-14Bibliographically approved
Rosenbaum, W., Bovinder Ylitalo, E., Castel, G., Sjödin, A., Larsson, P., Wigren Byström, J., . . . Tuiskunen-Bäck, A. (2024). Hybrid capture-based next-generation sequencing of new and old world Orthohantavirus strains and wild-type Puumala isolates from humans and bank voles. Journal of Clinical Virology, 172, Article ID 105672.
Open this publication in new window or tab >>Hybrid capture-based next-generation sequencing of new and old world Orthohantavirus strains and wild-type Puumala isolates from humans and bank voles
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2024 (English)In: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 172, article id 105672Article in journal (Refereed) Published
Abstract [en]

Orthohantaviruses, transmitted primarily by rodents, cause hemorrhagic fever with renal syndrome (HFRS) in Eurasia and hantavirus pulmonary syndrome in the Americas. These viruses, with documented human-to-human transmission, exhibit a wide case-fatality rate, 0.5–40 %, depending on the virus species, and no vaccine or effective treatment for severe Orthohantavirus infections exists. In Europe, the Puumala virus (PUUV), carried by the bank vole Myodes glareolus, causes a milder form of HFRS. Despite the reliance on serology and PCR for diagnosis, the three genomic segments of Swedish wild-type PUUV have yet to be completely sequenced.

We have developed a targeted hybrid-capture method aimed at comprehensive genomic sequencing of wild-type PUUV isolates and the identification of other Orthohantaviruses. Our custom-designed panel includes >11,200 probes covering the entire Orthohantavirus genus. Using this panel, we sequenced complete viral genomes from bank vole lung tissue, human plasma samples, and cell-cultured reference strains. Analysis revealed that Swedish PUUV isolates belong to the Northern Scandinavian lineage, with nucleotide diversity ranging from 2.8 % to 3.7 % among them. Notably, no significant genotypic differences were observed between the viral sequences from reservoirs and human cases except in the nonstructural protein.

Despite the high endemicity of PUUV in Northern Sweden, these are the first complete Swedish wild-type PUUV genomes and substantially increase our understanding of PUUV evolution and epidemiology. The panel's sensitivity enables genomic sequencing of human samples with viral RNA levels reflecting the natural progression of infection and underscores our panel's diagnostic value, and could help to uncover novel Orthohantavirus transmission routes.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
Targeted sequencing, Whole-genome sequencing, Puumala virus, Orthohantaviruses, Hemorrhagic fever with renal syndrome, Diagnostics
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-223355 (URN)10.1016/j.jcv.2024.105672 (DOI)38574565 (PubMedID)2-s2.0-85189510700 (Scopus ID)
Funder
Swedish Research Council, 2020-06235Lars Hierta Memorial Foundation, FO2021-0251O.E. och Edla Johanssons vetenskapliga stiftelseRegion Västerbotten, RV-970009Region Västerbotten, RV-982503Stiftelsen Seth M. Kempes Minnes Stipendiefond, SMK21-0039
Available from: 2024-04-15 Created: 2024-04-15 Last updated: 2024-04-16Bibliographically approved
Gröning, R., Walde, J., Ahlm, C., Forsell, M. N. E., Normark, J. & Rasmuson, J. (2024). Intravenous immunoglobulin therapy for COVID-19 in immunocompromised patients: A retrospective cohort study. International Journal of Infectious Diseases, 144, Article ID 107046.
Open this publication in new window or tab >>Intravenous immunoglobulin therapy for COVID-19 in immunocompromised patients: A retrospective cohort study
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2024 (English)In: International Journal of Infectious Diseases, ISSN 1201-9712, E-ISSN 1878-3511, Vol. 144, article id 107046Article in journal (Refereed) Published
Abstract [en]

Objectives: To investigate the effectiveness of intravenous immunoglobulin (IVIG) as treatment for COVID-19 in immunocompromised patients.

Methods: This retrospective study investigated outcomes for immunocompromised, vaccine non-responsive, patients that between September 2022 and April 2023 received IVIG as treatment for COVID-19 in the region of Västerbotten, Sweden. We analyzed clinical data, viral load, and anti-SARS-CoV-2 IgG binding and neutralization levels of patient serum samples and IVIG production batches. Primary and secondary outcomes were clinical cure and viral clearance, respectively.

Results: Sixteen patients were analyzed. After a median COVID-19 duration of 4 weeks, a median 60 g IVIG infusion increased SARS-CoV-2 binding and neutralizing antibody levels, with broad in vitro activity against tested variants. The treatment resulted in abrogation of viremia in all patients and general improvement in 15 survivors that all met the primary endpoint. Thirteen patients met the secondary endpoint at follow-up after a median of four months. Two subjects with persistent SARS-CoV-2 carriage relapsed but were successfully retreated with IVIG.

Conclusions: Antibodies in IVIG efficiently neutralized several SARS-CoV-2 variants. Treatment with IVIG was associated with clinical cure and viral clearance in immunocompromised patients. Our data suggests that IVIG could be a novel treatment alternative for COVID-19 for this patient category.

Place, publisher, year, edition, pages
Elsevier, 2024
Keywords
COVID-19, Humoral immunity, Immunocompromised, Intravenous immunoglobulin, SARS-CoV-2
National Category
Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-225264 (URN)10.1016/j.ijid.2024.107046 (DOI)38615825 (PubMedID)2-s2.0-85192717007 (Scopus ID)
Funder
Umeå UniversityKnut and Alice Wallenberg Foundation, VC-2022-0028Knut and Alice Wallenberg Foundation, VC-2020-0015Knut and Alice Wallenberg Foundation, DNR 2023-01154-01Swedish Research Council, 2020-06235Region Västerbotten, RV-938855Region Västerbotten, RV-939393Swedish Heart Lung Foundation, 20220325
Available from: 2024-06-10 Created: 2024-06-10 Last updated: 2024-06-10Bibliographically approved
Hellgren, F., Rosdahl, A., Cerveira, R. A., Lenart, K., Ols, S., Yongdae, G., . . . Loré, K. (2024). Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans. JCI Insight, 9(9), Article ID e175401.
Open this publication in new window or tab >>Modulation of innate immune response to mRNA vaccination after SARS-CoV-2 infection or sequential vaccination in humans
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2024 (English)In: JCI Insight, ISSN 2379-3708, Vol. 9, no 9, article id e175401Article in journal (Refereed) Published
Abstract [en]

mRNA vaccines are likely to become widely used for the prevention of infectious diseases in the future. Nevertheless, a notable gap exists in mechanistic data, particularly concerning the potential effects of sequential mRNA immunization or preexisting immunity on the early innate immune response triggered by vaccination. In this study, healthy adults, with or without documented prior SARS-CoV-2 infection, were vaccinated with the BNT162b2/Comirnaty mRNA vaccine. Prior infection conferred significantly stronger induction of proinflammatory and type I IFN-related gene signatures, serum cytokines, and monocyte expansion after the prime vaccination. The response to the second vaccination further increased the magnitude of the early innate response in both study groups. The third vaccination did not further increase vaccine-induced inflammation. In vitro stimulation of PBMCs with TLR ligands showed no difference in cytokine responses between groups, or before or after prime vaccination, indicating absence of a trained immunity effect. We observed that levels of preexisting antigen-specific CD4 T cells, antibody, and memory B cells correlated with elements of the early innate response to the first vaccination. Our data thereby indicate that preexisting memory formed by infection may augment the innate immune activation induced by mRNA vaccines.

Place, publisher, year, edition, pages
American Society For Clinical Investigation, 2024
National Category
Immunology in the medical area Infectious Medicine
Identifiers
urn:nbn:se:umu:diva-224930 (URN)10.1172/jci.insight.175401 (DOI)001226426900001 ()38716734 (PubMedID)2-s2.0-85192629165 (Scopus ID)
Funder
Knut and Alice Wallenberg Foundation, VC-2021-0017Swedish Research Council, 2019-01036Swedish Research Council, 2020-05929Swedish Research Council, 2023-02396Karolinska Institute
Available from: 2024-05-31 Created: 2024-05-31 Last updated: 2024-05-31Bibliographically approved
Granvik, C., Andersson, S., Andersson, L., Brorsson, C., Forsell, M. N. E., Ahlm, C., . . . Edin, A. (2024). Olfactory dysfunction as an early predictor for post-COVID condition at 1-year follow-up. Brain and Behavior, 14(6), Article ID e3574.
Open this publication in new window or tab >>Olfactory dysfunction as an early predictor for post-COVID condition at 1-year follow-up
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2024 (English)In: Brain and Behavior, E-ISSN 2162-3279, Vol. 14, no 6, article id e3574Article in journal (Refereed) Published
Abstract [en]

Background: Olfactory dysfunction together with neurological and cognitive symptoms are common after COVID-19. We aimed to study whether performance on olfactory and neuropsychological tests following infection predict post-COVID condition (PCC), persisting symptoms, and reduced health-related quality of life.

Methods: Both hospitalized (N = 10) and non-hospitalized individuals (N = 56) were enrolled in this prospective cohort study. Participants were evaluated 1–3 months after infection with an olfactory threshold test and neuropsychological tests, which was used as predictors of PCC. A questionnaire outlining persisting symptoms and the validated instrument EuroQol five-dimension five-level for health-related quality of life assessment were used as outcome data 1 year after infection (N = 59). Principal component analysis was used to identify relevant predictors for PCC at 1 year.

Results: Objectively assessed olfactory dysfunction at 1–3 months post infection, but not subjective olfactory symptoms, predicted post-COVID condition with reduced health-related quality of life (PCC+) at 1 year. The PCC+ group scored more often below the cut off for mild cognitive impairment on the Montreal Cognitive Assessment (61.5% vs. 21.7%) and higher on the Multidimensional Fatigue Inventory-20, compared to the group without PCC+.

Conclusion: Our results indicate that objectively assessed, olfactory dysfunction is a predictor for PCC+. These findings underscore the importance of objective olfactory testing. We propose that olfactory screening in the early post-acute phase of COVID-19 infection might identify individuals that are at higher risk of developing long-term health sequalae.

Place, publisher, year, edition, pages
John Wiley & Sons, 2024
Keywords
COVID-19, health-related quality of life, long covid, olfactory dysfunction, post-COVID condition (PCC)
National Category
Psychology (excluding Applied Psychology) Neurosciences
Identifiers
urn:nbn:se:umu:diva-226169 (URN)10.1002/brb3.3574 (DOI)38841730 (PubMedID)2-s2.0-85195270158 (Scopus ID)
Funder
Swedish Research Council, 2020-06235Swedish Research Council, 2016-06514Swedish Heart Lung Foundation, 20210078Swedish Heart Lung Foundation, 20200325Knut and Alice Wallenberg Foundation, VC-2020-0015Knut and Alice Wallenberg Foundation, FS2.1.6-849-20Knut and Alice Wallenberg Foundation, VLL 1925-2017Region Västerbotten, RV-939393Region Västerbotten, RV-938855
Available from: 2024-06-18 Created: 2024-06-18 Last updated: 2024-06-18Bibliographically approved
Carlund, O., Thörn, E., Osterman, P., Fors, M., Dernstedt, A., Forsell, M. N. E., . . . Hultdin, M. (2024). Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length. Clinical Epigenetics, 16(1), Article ID 68.
Open this publication in new window or tab >>Semimethylation is a feature of diffuse large B-cell lymphoma, and subgroups with poor prognosis are characterized by global hypomethylation and short telomere length
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2024 (English)In: Clinical Epigenetics, E-ISSN 1868-7083, Vol. 16, no 1, article id 68Article in journal (Refereed) Published
Abstract [en]

Background: Large B-cell lymphoma (LBCL) is the most common lymphoma and is known to be a biologically heterogeneous disease regarding genetic, phenotypic, and clinical features. Although the prognosis is good, one-third has a primary refractory or relapsing disease which underscores the importance of developing predictive biological markers capable of identifying high- and low-risk patients. DNA methylation (DNAm) and telomere maintenance alterations are hallmarks of cancer and aging. Both these alterations may contribute to the heterogeneity of the disease, and potentially influence the prognosis of LBCL.

Results: We studied the DNAm profiles (Infinium MethylationEPIC BeadChip) and relative telomere lengths (RTL) with qPCR of 93 LBCL cases: Diffuse large B-cell lymphoma not otherwise specified (DLBCL, n = 66), High-grade B-cell lymphoma (n = 7), Primary CNS lymphoma (n = 8), and transformation of indolent B-cell lymphoma (n = 12). There was a substantial methylation heterogeneity in DLBCL and other LBCL entities compared to normal cells and other B-cell neoplasms. LBCL cases had a particularly aberrant semimethylated pattern (0.15 ≤ β ≤ 0.8) with large intertumor variation and overall low hypermethylation (β > 0.8). DNAm patterns could not be used to distinguish between germinal center B-cell-like (GC) and non-GC DLBCL cases. In cases treated with R-CHOP-like regimens, a high percentage of global hypomethylation (β < 0.15) was in multivariable analysis associated with worse disease-specific survival (DSS) (HR 6.920, 95% CI 1.499–31.943) and progression-free survival (PFS) (HR 4.923, 95% CI 1.286–18.849) in DLBCL and with worse DSS (HR 5.147, 95% CI 1.239–21.388) in LBCL. These cases with a high percentage of global hypomethylation also had a higher degree of CpG island methylation, including islands in promoter-associated regions, than the cases with less hypomethylation. Additionally, telomere length was heterogenous in LBCL, with a subset of the DLBCL-GC cases accounting for the longest RTL. Short RTL was independently associated with worse DSS (HR 6.011, 95% CI 1.319–27.397) and PFS (HR 4.689, 95% CI 1.102–19.963) in LBCL treated with R-CHOP-like regimens.

Conclusion: We hypothesize that subclones with high global hypomethylation and hypermethylated CpG islands could have advantages in tumor progression, e.g. by inactivating tumor suppressor genes or promoting treatment resistance. Our findings suggest that cases with high global hypomethylation and thus poor prognosis could be candidates for alternative treatment regimens including hypomethylating drugs.

Place, publisher, year, edition, pages
BioMed Central (BMC), 2024
Keywords
Diffuse large-B cell lymphoma, DNA methylation, High-grade B-cell lymphoma, Predictive markers, Primary CNS lymphomas, Survival, Telomere length
National Category
Hematology Cancer and Oncology
Identifiers
urn:nbn:se:umu:diva-225340 (URN)10.1186/s13148-024-01680-4 (DOI)001228885200001 ()38773655 (PubMedID)2-s2.0-85193701494 (Scopus ID)
Funder
The Kempe FoundationsCancerforskningsfonden i NorrlandLions Cancerforskningsfond i Norr
Available from: 2024-06-03 Created: 2024-06-03 Last updated: 2024-06-04Bibliographically approved
Wigren, J., Vikström, L., Rosendal, E., Gröning, R., Gwon, Y.-D., Nilsson, E., . . . Forsell, M. N. E. (2023). At-home sampling to meet geographical challenges for serological assessment of SARS-CoV-2 exposure in a rural region of northern Sweden, March to May 2021: a retrospective cohort study. Eurosurveillance, 28(13), Article ID 2200432.
Open this publication in new window or tab >>At-home sampling to meet geographical challenges for serological assessment of SARS-CoV-2 exposure in a rural region of northern Sweden, March to May 2021: a retrospective cohort study
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2023 (English)In: Eurosurveillance, ISSN 1025-496X, E-ISSN 1560-7917, Vol. 28, no 13, article id 2200432Article in journal (Refereed) Published
Abstract [en]

Background: The current SARS-CoV-2 pandemic has highlighted a need for easy and safe blood sampling in combination with accurate serological methodology. Venipuncture for testing is usually performed by trained staff at healthcare centres. Long travel distances to healthcare centres in rural regions may introduce a bias of testing towards relatively large communities with closer access. Rural regions are therefore often not represented in population-based data.

Aim: The aim of this retrospective cohort study was to develop and implement a strategy for at-home testing in a rural region of Sweden during spring 2021, and to evaluate its role to provide equal health care for its inhabitants.

Methods: We developed a sensitive method to measure antibodies to the S-protein of SARS-CoV-2 and optimised this assay for clinical use together with a strategy of at-home capillary blood sampling.

Results: We demonstrated that our ELISA gave comparable results after analysis of capillary blood or serum from SARS-CoV-2-experienced individuals. We demonstrated stability of the assay under conditions that reflected temperature and humidity during winter or summer. By assessment of capillary blood samples from 4,122 individuals, we could show both feasibility of the strategy and that implementation shifted the geographical spread of testing in favour of rural areas.

Conclusion: Implementation of at-home sampling enabled citizens living in remote rural areas access to centralised and sensitive laboratory antibody tests. The strategy for testing used here could therefore enable disease control authorities to get rapid access to information concerning immunity to infectious diseases, even across vast geographical distance.

Place, publisher, year, edition, pages
European Centre for Disease Control and Prevention (ECDC), 2023
Keywords
coronavirus disease (COVID-19), laboratory, surveillance, Sweden
National Category
Infectious Medicine Microbiology in the medical area
Identifiers
urn:nbn:se:umu:diva-206673 (URN)10.2807/1560-7917.ES.2023.28.13.2200432 (DOI)000971868200003 ()36995373 (PubMedID)2-s2.0-85151573640 (Scopus ID)
Available from: 2023-04-14 Created: 2023-04-14 Last updated: 2023-09-05Bibliographically approved
Lidström, T., Cumming, J., Gaur, R., Frängsmyr, L., Pateras, I., Mickert, M. J., . . . Öhlund, D. (2023). Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer. Cancer immunology research, 11(1), 72-92
Open this publication in new window or tab >>Extracellular galectin 4 drives immune evasion and promotes T-cell apoptosis in pancreatic cancer
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2023 (English)In: Cancer immunology research, ISSN 2326-6066, Vol. 11, no 1, p. 72-92Article in journal (Refereed) Published
Abstract [en]

Pancreatic ductal adenocarcinoma (PDAC) is characterized by rich deposits of extracellular matrix (ECM), affecting the pathophysiology of the disease. Here, we identified galectin 4 (gal 4) as a cancer cell produced protein deposited into the ECM of PDAC tumors and detected high circulating levels of gal 4 in PDAC patients. In orthotopic transplantation experiments we observed increased infiltration of T-cells and prolonged survival in immunocompetent mice transplanted with cancer cells with reduced expression of gal 4. Increased survival was not observed in immunodeficient RAG1-/- mice, demonstrating that the effect was mediated by the adaptive immune system. Furthermore, by performing single-cell RNA-sequencing we found that the myeloid compartment and cancer-associated fibroblast (CAF) subtypes were altered in the transplanted tumors. Reduced gal 4 expression was associated with higher proportion of myofibroblastic CAFs and reduced numbers of inflammatory CAFs. We also found higher proportions of M1 macrophages, T-cells and antigen presenting dendritic cells in tumors with reduced gal 4 expression. Using a co-culture system, we observed that extracellular gal 4 induced apoptosis in T-cells by binding N-glycosylation residues on CD3 epsilon/delta. Hence, we show that gal 4 is involved in immune evasion and identify gal 4 as a promising drug target for overcoming immunosuppression in PDAC. 

Place, publisher, year, edition, pages
American Association for Cancer Research, 2023
Keywords
Galectin 4, pancreatic cancer, immunosuppression, extracellular matrix, drug target
National Category
Cancer and Oncology
Research subject
Immunology; Medicine; Oncology
Identifiers
urn:nbn:se:umu:diva-201042 (URN)10.1158/2326-6066.CIR-21-1088 (DOI)36478037 (PubMedID)2-s2.0-85145492684 (Scopus ID)
Funder
The Swedish Foundation for International Cooperation in Research and Higher Education (STINT), PT2015-6432Swedish Cancer Society, AMP17-877, LP18-2202, LP20-2257, LP 21-2298Swedish Research Council, 2017-01531The Kempe Foundations, JCK-1301, SMK-1765Swedish Society of Medicine, SLS-890521, SLS-786661, SLS-691681, SLS-591551Västerbotten County Council, RV-930167, VLL-643451, VLL-832001Sjöberg FoundationKnut and Alice Wallenberg FoundationMarianne and Marcus Wallenberg Foundation, MMW 2020.0189Swedish Cancer Society, CAN 2017/332, CAN 2017/827, 20 1339 PjFSwedish Cancer Society, AMP-18-919Knut and Alice Wallenberg Foundation
Note

Originally included in thesis in manuscript form. 

Available from: 2022-11-16 Created: 2022-11-16 Last updated: 2023-10-18Bibliographically approved
Ahmad, I., Edin, A., Granvik, C., Kumm Persson, L., Tevell, S., Månsson, E., . . . Normark, J. (2023). High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19. Frontiers In Public Health, 11, Article ID 1104267.
Open this publication in new window or tab >>High prevalence of persistent symptoms and reduced health-related quality of life 6 months after COVID-19
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2023 (English)In: Frontiers In Public Health, ISSN 2296-2565, Vol. 11, article id 1104267Article in journal (Refereed) Published
Abstract [en]

Background: The long-term sequelae after COVID-19 constitute a challenge to public health and increased knowledge is needed. We investigated the prevalence of self-reported persistent symptoms and reduced health-related quality of life (HRQoL) in relation to functional exercise capacity, 6 months after infection, and explored risk factors for COVID-19 sequalae. Methods: This was a prospective, multicenter, cohort study including 434 patients. At 6 months, physical exercise capacity was assessed by a 1-minute sit-to-stand test (1MSTST) and persistent symptoms were reported and HRQoL was evaluated through the EuroQol 5-level 5-dimension (EQ-5D-5L) questionnaire. Patients with both persistent symptoms and reduced HRQoL were classified into a new definition of post-acute COVID syndrome, PACS+. Risk factors for developing persistent symptoms, reduced HRQoL and PACS+ were identified by multivariable Poisson regression. Results: Persistent symptoms were experienced by 79% of hospitalized, and 59% of non-hospitalized patients at 6 months. Hospitalized patients had a higher prevalence of self-assessed reduced overall health (28 vs. 12%) and PACS+ (31 vs. 11%). PACS+ was associated with reduced exercise capacity but not with abnormal pulse/desaturation during 1MSTST. Hospitalization was the most important independent risk factor for developing persistent symptoms, reduced overall health and PACS+. Conclusion: Persistent symptoms and reduced HRQoL are common among COVID-19 survivors, but abnormal pulse and peripheral saturation during exercise could not distinguish patients with PACS+. Patients with severe infection requiring hospitalization were more likely to develop PACS+, hence these patients should be prioritized for clinical follow-up after COVID-19.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
COVID-19, EQ-5D, long-COVID, PACS, Post COVID-19 condition (PCC), post-acute COVID syndrome (PACS), SARS-CoV-2
National Category
Public Health, Global Health, Social Medicine and Epidemiology
Identifiers
urn:nbn:se:umu:diva-205360 (URN)10.3389/fpubh.2023.1104267 (DOI)000937266000001 ()36817925 (PubMedID)2-s2.0-85148359690 (Scopus ID)
Funder
Nyckelfonden, OLL-938628Nyckelfonden, OLL-961416Region Västmanland, 20201009Swedish Research Council, 2020-06235Swedish Heart Lung Foundation, 20200325Swedish Heart Lung Foundation, 20210078Knut and Alice Wallenberg Foundation, VC-2020-0015Umeå UniversityRegion Västerbotten, RV-938855Region Värmland, LIVFOU-939646
Available from: 2023-03-29 Created: 2023-03-29 Last updated: 2023-10-30
Gröning, R., Dernstedt, A., Ahlm, C., Normark, J., Sundström, P. & Forsell, M. N. E. (2023). Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption. Frontiers in Immunology, 14, Article ID 1219560.
Open this publication in new window or tab >>Immune response to SARS-CoV-2 mRNA vaccination in multiple sclerosis patients after rituximab treatment interruption
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1219560Article in journal (Refereed) Published
Abstract [en]

Peripheral B cell depletion via anti-CD20 treatment is a highly effective disease-modifying treatment for reducing new relapses in multiple sclerosis (MS) patients. A drawback of rituximab (RTX) and other anti-CD20 antibodies is a poor immune response to vaccination. While this can be mitigated by treatment interruption of at least six months prior to vaccination, the timing to resume treatment while maintaining subsequent vaccine responses remains undetermined. Here, we characterized SARS-CoV-2 S-directed antibody and B cell responses throughout three BNT162b2 mRNA vaccine doses in RTX-treated MS patients, with the first two doses given during treatment interruption. We examined B-cell mediated immune responses in blood samples from patients with RTX-treated MS throughout three BNT162b2 vaccine doses, compared to an age- and sex-matched healthy control group. The first vaccine dose was given 1.3 years (median) after the last RTX infusion, the second dose one month after the first, and the third dose four weeks after treatment re-initiation. We analyzed SARS-CoV-2 S-directed antibody levels using enzyme-linked immunosorbent assay (ELISA), and the neutralization capacity of patient serum against SARS-CoV-2 S-pseudotyped lentivirus using luciferase reporter assay. In addition, we assessed switched memory (CD19+CD20+CD27+IgD-), unswitched memory (CD19+CD20+CD27+IgD+), naïve (CD19+CD20+CD27-IgD+), and double negative (DN, CD19+CD20+CD27-IgD-) B cell frequencies, as well as their SARS-CoV-2 S-specific (CoV+) and Decay Accelerating Factor-negative (DAF-) subpopulations, using flow cytometry. After two vaccine doses, S-binding antibody levels and neutralization capacity in SARS-CoV-2-naïve MS patients were comparable to vaccinated healthy controls, albeit with greater variation. Higher antibody response levels and CoV+-DN B cell frequencies after the second vaccine dose were predictive of a boost effect after the third dose, even after re-initiation of rituximab treatment. MS patients also exhibited lower frequencies of DAF- memory B cells, a suggested proxy for germinal centre activity, than control individuals. S-binding antibody levels in RTX-treated MS patients after two vaccine doses could help determine which individuals would need to move up their next vaccine booster dose or postpone their next RTX infusion. Our findings also offer first indications on the potential importance of antigenic stimulation of DN B cells and long-term impairment of germinal centre activity in rituximab-treated MS patients.

Place, publisher, year, edition, pages
Frontiers Media S.A., 2023
Keywords
B cell immunology, COVID-19, multiple sclerosis, rituximab, vaccination
National Category
Infectious Medicine Immunology in the medical area
Identifiers
urn:nbn:se:umu:diva-212992 (URN)10.3389/fimmu.2023.1219560 (DOI)37575257 (PubMedID)2-s2.0-85167514064 (Scopus ID)
Funder
Region Västerbotten, RV-969133Swedish Research Council, 2020-0625Swedish Research Council, 2021-04665Knut and Alice Wallenberg Foundation, VA-2021-0018Knut and Alice Wallenberg Foundation, VA-2022-0008Science for Life Laboratory, SciLifeLab
Available from: 2023-08-18 Created: 2023-08-18 Last updated: 2024-01-17Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-6904-742x

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