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BackgroundPatients suffering from systemic autoimmune rheumatic disease (SARD) display poor antibody development after two doses of mRNA vaccinations leaving these patients with only limited humoral protection against severe SARS-CoV-2 disease courses. Of key interest is the effect of conventional synthetic (csDMARD) and biological/ targeted drugs (b/tsDMARDs) disease modifying antirheumatic drugs on the time of protection.ObjectivesTo compare antibody titer development in patients with vasculitis and connective tissue disease (CTD) with healthy controls 6 months after two mRNA vaccinations and after third immunization. To analyze factors, that affect the velocity of titer decline, well as qualitative humoral response.MethodsPatients with SARD were enrolled and matched for gender and age with healthy control subjects (HC) and the humoral response after 6 months to two doses of mRNA vaccine BNT162b2 in terms of SARS-COV-2 antibody titer was assessed. In addition to binding antibody units (BAU) we also analyzed neutralizing antibodies. Patients receiving B-cell depleting therapy and those with prior SARS-CoV-2 infection (via detection of nucleocapsid antibodies) were excluded. Differences between two groups were calculated with Wilcoxon signed-rank test.ResultsA total of 53 patients with SARD (42 patients suffering from connective tissue disease and 11 with vasculitis respectively) and 73 HC were analysed. Interestingly only patients receiving a combination therapy of different csDMARDs/ b/tsDMARDs demonstrated diminished antibody titers 6 months after two doses of mRNA vaccine (p-value p-value<0,001), whereas patients receiving only csDMARD as monotherapy displayed comparable antibody levels to healthy controls. This effect was equalized after a third booster vaccination (p-value=0,13). Concerning disease entities, patients with vasculitis seemed to have lower BAU than HC (p-value<0,05) and patients suffering from CTD. After third vaccination both patient groups had lower antibody levels than HC (vasculitis: p-value <0,0001;CTD: p-value p-value<0,01). Lower antibody levels before third vaccination correlated with lower antibodies after third immunization.ConclusionPatients with autoimmune rheumatic diseases undergoing combination therapy may be more vulnerable to SARS-CoV-2 infection, due to reduced antibody levels 6 months following two doses of mRNA vaccine. Our data strongly recommends antibody measurements in patients receiving combination therapy and individualized earlier booster vaccination.Figure 1.Anti-SARS-Cov-2 S antibody titers. A: Antibody titers measured 6 months after two doses of mRNA vaccination in patients with connective tissue disease, vasculitis and healthy controls. B, Antibody levels according to disease entity. AB: antibody;BAU: binding antibody unit;CTD: connective tissue disease;HC: healthy control;mono: disease modifying anti-rheumatic drug monotherapy;combination: combination therapy of disease modifying anti-rheumatic drugs;RBD: receptor binding domain;[Figure omitted. See PDF]Table 1.Demographic parameters and therapy of study participants.SARD (n=53)HC (n=73)Age, mean (standard deviation)53.55 (±14.04)51.27 (±14.07)Female45 (84.9%)47 (64.4%)Connective tissue disease42 (79%)Vasculitis11 (21%)csDMARD or b/tsDMARD monotherapy22 (41%)csDMARD and/or b/tsDMARD combination therapy13 (25%)No therapy18 (34%)Methotrexate8 (15%)Mycophenolate mofetil10 (19%)Hydroxychloroquine17 (32%)Azathioprine8 (15%)Belimumab3 (6%)Tocilizumab3 (6%)Glucocorticoid dose 1. vaccination, mean (standard deviation)2.8 (±10.8)Glucocorticoid dose 2. vaccination, mean (standard deviation)2.6 (±10.7)SARD: Systemic autoimmune rheumatic disease, HC: Healthy controls, csDMARD: conventional synthetic disease modifying antirheumatic drugs and b/tsDMARD: biological/ targeted drugs disease modifying antirheumatic drugsREFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsElisabeth Simader Speakers bureau: Lilly, Thomas Deimel: None declared, Felix Kartnig: None declared, Selma Tobudic: None declared, Helmuth Hasla her Grant/research support from: Glock Health, BlueSky Immunotherapies and Neutrolis, Thomas Maria Karonitsch: None declared, Daniel Mrak: None declared, Thomas Nothnagl: None declared, Thomas Perkmann: None declared, Helga Lechner-Radner: None declared, Judith Sautner: None declared, Florian Winkler: None declared, Heinz Burgmann Speakers bureau: speaker fees from Shionogi, Pfizer, MSD, Paid instructor for: advisory boards for Valneva, MSD, Gilead, Consultant of: consulting fees from MSD, Pfizer, Takeda, Gilead, Daniel Aletaha Speakers bureau: other from Abbvie, Amgen, Lilly, Merck, Novartis, Pfizer, Roche, Sandoz, Grant/research support from: grants from Abbvie, Amgen, Lilly, Novartis, Roche, SoBi, Sanofi, Stefan Winkler: None declared, Stephan Blüml Speakers bureau: personal fees from Abbvie, personal fees from Novartis, Peter Mandl Speakers bureau: reports speaker fees from AbbVie, Janssen and Novartis, Grant/research support from: research grants from AbbVie, BMS, Novartis, Janssen, MSD and UCB.
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Background: Venovenous extracorporeal membrane oxygenation (ECMO) is a cornerstone in the management of severe acute respiratory distress syndrome (ARDS) and causes hemostatic system activation and inflammation. COVID-19 is known to cause thromboinflammation. Elucidation of the underlying pathomechanisms is of great importance. Aim(s): To evaluate markers of NET formation in COVID-19 and non-COVID- 19 associated ARDS and ECMO and to explore the role of different NET parameters as markers of inflammation and coagulopathy. Method(s): We studied 31 adult COVID-19 patients and 23 adult non-COVID- 19 patients with severe ARDS requiring ECMO and 47 sex-and age-matched healthy controls. Blood was collected at time point A (ECMO day 0-4) and at time point B (ECMO day 7-17). Citrullinated histone H3 (citH3), cell-free DNA (cfDNA), and plasma myeloperoxidase DNA (mpoDNA), as well as d-Dimer, were evaluated. Values are given as median (25th, 75th percentile). Statistical testing was performed using unpaired t-tests of logarithmized parameters. Result(s): COVID-19 and non-COVID- 19 patients exhibited significantly higher levels of citH3, cfDNA, and mpoDNA than healthy controls (Table 1). Levels of citH3 decreased significantly from time point A to B in COVID-19 patients. No comparable effect was identified for cfDNA and mpoDNA (Table 1). In non-COVID- 19 patients, no differences in levels of citH3, cfDNA, and mpoDNA were found between timepoints A and B (Table 1). d-Dimer increased from time point A to timepoint B in both groups (Table 1). Conclusion(s): NET formation is comparably increased in patients on ECMO because of COVID-19 and non-COVID- 19 ARDS. Markers of NET formation could add information on immunothrombosis and the complex interplay of coagulation and inflammation in the context of ECMO.
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Background: Vaccination efficiency has been demonstrated to be reduced in patients with systemic autoimmune rheumatic disease (SARD) compared with the general population. Objectives: To assess the humoral response to mRNA vaccine in patients with (SARD) and the effect of immunosuppressive medication in a matched cohort study. Methods: Patients with SARD were enrolled and matched 1:1 for gender and age with healthy control subjects (HC). Differences in the humoral response to two doses of mRNA vaccine BNT162b2 in terms of seroconversion rate and SARS-COV-2 antibody titer between the two groups and impact of treatment within SARD patients was assessed using Fisher's exact test, Student's t-test, Mann-Whitney test and Kruskal-Wallis test, adjusting for multiple testing. Results: We enrolled 82 patients with SARD and 82 matched HC (Table 1). Among patients the seroconversion rate was signifcantly lower after the 1st dose (65% compared to 100% in HC, p<0.0001) but levelled up after the 2nd dose (94% vs. 100%). While the difference in seroconversion rate was independent of treatment regime (no disease modifying anti-rheumatic drug (DMARD), DMARD monother-apy, DMARD combination therapy), the seroconversion rate of SARD patients on mono-or combination DMARD therapy was also signifcantly lower as compared to those receiving no DMARD therapy (56% for monotherapy and 57% for combination therapy compared to 77% for no DMARD therapy, p=0.002 and p=0.004 respectively;Figure 1A). Seroconversion rate after the 2nd dose was signifcantly lower for patients on combination DMARD therapy compared to all other groups (81% compared to 95% for monotherapy, and 100% for both no DMARD therapy and HC respectively, all p<0.0001);also antibody titers after the 2nd dose were lower when comparing patients on combination DMARD therapy to all other groups (49 binding antibody units (BAU)/ml versus 1673 BAU/ml in HC, p<0.0001;2500 BAU/ml in those on no DMARD therapy, p<0.0001;and 687 BAU/ml in those on DMARD monotherapy, p=0.0072;Figure 1B). Considering effects of individual compounds, mycophenolate mofetil in mono-or combination therapy led to lower antibody titers after the 2nd dose as compared to HC or patients receiving no DMARDs (2 BAU/ml versus 1673 BAU/ml and 2500 BAU/ml respectively, both p<0.0001). Conclusion: Patients with SARD showed a good response after the 2nd vaccination with the mRNA vaccine. However, the choice of immunosuppressive regimen has a marked effect on both seroconversion rate and overall antibody titer.
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Background: Little is known about the duration of humoral antibody levels after two SARS-CoV-2 mRNA vaccinations in patients with immunosuppression. During this ongoing global epidemic, it is of essential interest to gather information about the time of protection after initial immunization in the vulnerable patients receiving either conventional synthetic disease modifying antirheumatic drugs (csDMARD) or biological/targeted drugs (b/tsDMARDs). Objectives: In this study we compared the antibody level development after vaccination and after six months in patients with infammatory arthritis, infammatory bowel disease (IBD) and healthy controls. Furthermore, we assessed factors affecting the quality and quantity of the humoral response. Methods: We enrolled 85 healthy controls (HC), 75 patients with rheumatoid arthritis and spondyloarthritis and 41 patients suffering from IBD. Patients treated with B-cell depleting therapies were excluded from this study. Binding antibody units were measured after vaccination and 6 or more months. Neutralizing antibodies were measured after 6 months. Multivariate regression analyses analyzing factors associated with low titers after 6 months was performed. Results: We found that patients with infammatory arthritis or IBD showed reduced anti-SARS-CoV-2 S titers compared to HC. When we stratifed for therapies, we found that patients receiving conventional synthetic disease modifying antirheumatic dugs (csDMARDs) had comparable anti-SARS-CoV-2 S titers to HC. In contrast, patients receiving biological or targeted synthetic (b/tsDMARDs) showed reduced anti-SARS-CoV-2 Igs as well as neutralizing antibody titers compared with healthy controls (HC) or patients receiving conventional synthetic (cs)DMARDs. We further show that anti-SARS-CoV-2 titers declined more rapidly in patients receiving b/tsDMARDs compared to HC, leading to a 50 percent reduction in vaccination-associated protection time in patients receiving b/tsD-MARDs when compared to those receiving csDMARDs or even HC. In multi-variate regression analyses, we found that in addition to the type of treatment, also age as well as corticosteroid use were associated with reduced anti-SARS-CoV-2 S titers. Conclusion: Patients under ongoing b/tsDMARDs therapy exposed an accelerated waning of anti-SARS-CoV-2 S titers and therefore decreased immunity and protection against severe Covid-19 infections over time. These results may lead to more personalized approaches for further vaccination strategies in this group of immunosuppressed patients.
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Background : Pulmonary thrombus formation is a hallmark of COVID-19. A dysregulated immune response culminating in thromboinflammation has been described, but the pathomechanisms remain unclear. Aims : To evaluate the role of extracellular vesicles (EV) and citrullinated histone H3 (citH3) as markers of coagulopathy and inflammation. Methods : We studied 41 adult COVID-19 patients with a positive result on a reverse-transcriptase polymerase-chain-reaction assay and 37 sex-and age-matched healthy controls. Number and surface characteristics of EV and citH3 levels were determined in plasma upon admission by flowcytometry and immunoassay, respectively. Values are given as median (25 th , 75 th percentile) and differences by geometric mean ratios (GMR [95% CI]) or mean differences (ΔsMean [95% CI]). Results : 20 patients had severe and 21 mild disease. Patients exhibited significantly higher numbers of total EV, and of EV derived from platelets, endothelial cells, leukocytes, or neutrophils than controls (Table 1). EV from alveolar-macrophages and alveolar-epithelial-cells were detectable in plasma and were significantly higher in patients. ICAM-1 positive EV levels were higher in patients while no difference between TF-positive and ACE-positive EV was seen between the two groups. Levels of EV did not differ between patients with severe and mild COVID-19. citH3 levels were higher in patients than in controls [1.42 (0.6, 3.37) vs 0.31 (0.14, 0.6), GMR 4.44 (2.57, 7.66);P < 0.001], and were significantly lower in patients with mild disease compared to those with severe disease. Conclusions : EV and citH3 are associated with COVID-19. They provide information regarding pathophysiology and could be explored as markers of the disease.
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Personal protective equipment and adherence to disinfection protocols are essential to prevent nosocomial severe acute respiratory syndrome coronavirus (SARS-CoV-2) transmission. Here, we evaluated infection control measures in a prospective longitudinal single-center study at the Vienna General Hospital, the biggest tertiary care center in Austria, with a structurally planned low SARS-CoV-2 exposure. SARS-CoV-2-specific antibodies were assessed by Abbott ARCHITECT chemiluminescent assay (CLIA) in 599 health care workers (HCWs) at the start of the SARS-CoV-2 epidemic in early April and two months later. Neutralization assay confirmed CLIA-positive samples. A structured questionnaire was completed at both visits assessing demographic parameters, family situation, travel history, occupational coronavirus disease 2019 (COVID-19) exposure, and personal protective equipment handling. At the first visit, 6 of 599 participants (1%) tested positive for SARS-CoV-2-specific antibodies. The seroprevalence increased to 1.5% (8/553) at the second visit and did not differ depending on the working environment. Unprotected SARS-CoV-2 exposure (p = 0.003), positively tested family members (p = 0.04), and travel history (p = 0.09) were more frequently reported by positively tested HCWs. Odds for COVID-19 related symptoms were highest for congestion or runny nose (p = 0.002) and altered taste or smell (p < 0.001). In conclusion, prevention strategies proved feasible in reducing the risk of transmission of SARS-CoV-2 from patients and among HCWs in a low incidence hospital, not exceeding the one described in the general population.