Background: Patients infected with SARS-CoV-2 differ in the severity of disease. We hypothesized that characteristics of SARS-CoV-2 specific immunity correlate with disease severity. Methods: In this study, SARS-CoV-2 specific T-cells and antibodies were characterized in uninfected controls and patients with different COVID-19 related disease severity. SARS-CoV-2 specific T-cells were flow-cytometrically quantified after stimulation with SARS-CoV-2 peptide pools and analyzed for expression of cytokines (IFNγ, IL-2 and TNFα) and markers for activation, proliferation and functional anergy. SARS-CoV-2 specific IgG and IgA antibodies were quantified using ELISA. Moreover, global characteristics of lymphocyte subpopulations were compared between patient groups and uninfected controls Results: Despite severe lymphopenia affecting all major lymphocyte subpopulations, patients with severe disease mounted significantly higher levels of SARS-CoV-2 specific T-cells as compared to convalescent individuals. SARS-CoV-2 specific CD4 T-cells dominated over CD8 T-cells and closely correlated with the number of plasmablasts and SARS-CoV-2 specific IgA- and IgG-levels. Unlike in convalescents, SARS-CoV-2 specific T-cells in patients with severe disease showed marked alterations in phenotypical and functional properties, which also extended to CD4 and CD8 T-cells in general. Conclusion: Given the strong induction of specific immunity to control viral replication in patients with severe disease, the functionally altered characteristics may result from the need for contraction of specific and general immunity to counteract excessive immunopathology in the lung. Trial registration: n.a. Funding: The study was supported by institutional funds by M.S., and in part by grants of Saarland University (to M.S. and. R.B), the State of Saarland, and the Dr. Rolf M. Schwiete Stiftung to R.B.
David Schub, Verena Klemis, Sophie Schneitler, Janine Mihm, Philipp M. Lepper, Heinrike Wilkens, Robert Bals, Hermann Eichler, Barbara C. Gärtner, Sören L. Becker, Urban Sester, Martina Sester, Tina Schmidt
Background: Left atrial (LA) and left ventricular (LV) remodeling are associated with atrial fibrillation (AF). The prospective associations of impairment in cardiac mechanical function, as assessed by speckle-tracking echocardiography, with incident AF are less clear. Methods: In the Cardiovascular Health Study, a community-based cohort of older adults, participants free of AF with echocardiograms of adequate quality for speckle-tracking were included. We evaluated the associations of indices of cardiac mechanics (LA reservoir strain, LV longitudinal strain, and LV early diastolic strain rate) with incident AF. Results: Of 4,341 participants with strain imaging, participants with lower LA reservoir strain were older, had more cardiometabolic risk factors, and had lower renal function at baseline. Over median follow-up of 10 years, 497 (11.4%) participants developed AF. Compared with the highest quartile of LA reservoir strain, the lowest quartile of LA reservoir strain was associated with higher risk of AF after covariate adjustment, including LA volume and LV longitudinal strain (HR: 1.80, 95% CI: 1.31-2.45, P <0.001). The association of LA reservoir strain and AF was stronger in subgroups with higher blood pressure, NT-proBNP, and LA volumes. There were no associations of LV longitudinal strain and LV early diastolic strain rate with incident AF after adjustment for LA reservoir strain. Conclusion: Lower LA reservoir strain was associated with incident AF, independent of LV mechanics, and with stronger associations in high-risk subgroups. These findings suggest that mechanical dysfunction of the LA precedes the development of AF. Therapies targeting LA mechanical dysfunction may prevent progression to AF.
Ravi B. Patel, Joseph A. Delaney, Mo Hu, Harnish Patel, Jeanette Y. Cheng, John Gottdiener, Jorge R. Kizer, Gregory M. Marcus, Mintu P. Turakhia, Rajat Deo, Susan R. Heckbert, Bruce M. Psaty, Sanjiv J. Shah
Background: Baseline expression of FCRL5, a marker of naïve and memory B cells, was shown to predict response to rituximab (RTX) in rheumatoid arthritis. This study investigated baseline expression of FCRL5 as a potential biomarker of clinical response to RTX in granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). Methods: A previously validated RT-qPCR-based platform was used to assess FCRL5 expression in patients with GPA/MPA (RAVE trial, NCT00104299). Results: Baseline FCRL5 expression was significantly higher in patients achieving complete response (CR) at 6, 12, and 18 months, independent of other clinical and serological variables, among those randomized to RTX but not CYC/AZA. Patients with baseline FCRL5 expression ≥ 0.01 expression units (termed FCRL5hi) exhibited significantly higher CR rates at 6, 12, and 18 months as compared to FCRL5low subjects (84% vs 57% p=0.016, 68% vs 40% p=0.02 and 68% vs 29% p=0.0009, respectively). Conclusion: Our data taken together suggest that FCRL5 is a biomarker of B cell lineage associated with increased achievement and maintenance of complete remission among patients treated with RTX and warrant further investigation in a prospective manner.
Kasia Owczarczyk, Matthew D. Cascino, Cecile Holweg, Gaik W. Tew, Ward Ortmann, Timothy W. Behrens, Thomas Schindler, Carol A. Langford, E. William St. Clair, Peter A. Merkel, Robert Spiera, Philip Seo, Cees G.M. Kallenberg, Ulrich Specks, Noha Lim, John H. Stone, Paul Brunetta, Marco Prunotto
BACKGROUND Genomic and experimental studies suggest a role for PITX2 in atrial fibrillation (AF). To assess if this association is relevant for recurrent AF in patients, we tested whether left atrial PITX2 affects recurrent AF after AF ablation.METHODS mRNA concentrations of PITX2 and its cardiac isoform, PITX2c, were quantified in left atrial appendages (LAAs) from patients undergoing thoracoscopic AF ablation, either in whole LAA tissue (n = 83) or in LAA cardiomyocytes (n = 52), and combined with clinical parameters to predict AF recurrence. Literature suggests that BMP10 is a PITX2-repressed, atrial-specific, secreted protein. BMP10 plasma concentrations were combined with 11 cardiovascular biomarkers and clinical parameters to predict recurrent AF after catheter ablation in 359 patients.RESULTS Reduced concentrations of cardiomyocyte PITX2, but not whole LAA tissue PITX2, were associated with AF recurrence after thoracoscopic AF ablation (16% decreased recurrence per 2–(ΔΔCt) increase in PITX2). RNA sequencing, quantitative PCR, and Western blotting confirmed that BMP10 is one of the most PITX2-repressed atrial genes. Left atrial size (HR per mm increase [95% CI], 1.055 [1.028, 1.082]); nonparoxysmal AF (HR 1.672 [1.206, 2.318]), and elevated BMP10 (HR 1.339 [CI 1.159, 1.546] per quartile increase) were predictive of recurrent AF. BMP10 outperformed 11 other cardiovascular biomarkers in predicting recurrent AF.CONCLUSIONS Reduced left atrial cardiomyocyte PITX2 and elevated plasma concentrations of the PITX2-repressed, secreted atrial protein BMP10 identify patients at risk of recurrent AF after ablation.TRIAL REGISTRATION ClinicalTrials.gov NCT01091389, NL50069.018.14, Dutch National Registry of Clinical Research Projects EK494-16.FUNDING British Heart Foundation, European Union (H2020), Leducq Foundation.
Jasmeet S. Reyat, Winnie Chua, Victor R. Cardoso, Anika Witten, Peter M. Kastner, S. Nashitha Kabir, Moritz F. Sinner, Robin Wesselink, Andrew P. Holmes, Davor Pavlovic, Monika Stoll, Stefan Kääb, Georgios V. Gkoutos, Joris R. de Groot, Paulus Kirchhof, Larissa Fabritz
Background: Control of the tuberculosis (TB) pandemic remains hindered, in part, by a lack of simple and accurate measures of treatment efficacy. Current gold standard markers rely on sputum-based assays that are slow and challenging to implement. Previous work identified urinary N1, N12-diacetylspermine (DiAcSpm), neopterin, hydroxykynurenine, N-acetylhexosamine, ureidopropionic acid, sialic acid, and m/z 241.0903 as potential biomarkers of active pulmonary TB (ATB). Here, we evaluated their ability to serve as biomarkers of TB treatment response and mycobacterial load. Methods: We analyzed urine samples prospectively collected from two cohorts with ATB: 34 participants from African countries treated with first line TB therapy (HRZE) and followed for one year, and 35 participants from Haiti treated with either HRZE or an experimental drug followed for 14 days. Blinded samples were analyzed by untargeted high-performance liquid chromatography-coupled-time of flight-mass spectrometry. Results: Urinary levels of all seven molecules exhibited significant decreases by week 26 of successful treatment (p=0.01-p<0.0001), and positive correlations with sputum mycobacterial load (p<0.0001). Urinary levels of DiAcSpm exhibited significant decreases in participants treated with HRZE as early as 14 days (p<0.0001) but were unchanged in participants receiving ineffective therapy (p=0.14). Conclusion: Reductions in urinary DiAcSpm, neopterin, hydroxykynurenine, N-acetylhexosamine, ureidopropionic acid, sialic acid, and m/z 241.0903 correlated with successful anti-TB treatment and sputum mycobacterial load. Levels of DiAcSpm exhibited reductions capable of differentiating treatment success from failure as early as two weeks after the initiation of chemotherapy, commending its further development as a potentially simple, non-invasive biomarker of treatment response and bacterial load. Funding: This work was supported by the Clinical and Translational Science Center at Weill Cornell College of Medicine (NIH/NCATS 1 UL1 TR002384-02 and KL2TR000458), the Department of Defense (PR170782), the National Institute of Allergy and Infectious Disease grants (NIAID T32AI007613-16, K24 AI098627 and K23 AI131913), the NIH Fogarty International Center grants (R24 TW007988 and TW010062), the National Institute of Health grant (R01 GM135926 ), the Abby and Howard P. Milstein Program in Chemical Biology and Translational Medicine, and the Tuberculosis Research Units Networks (TBRU-N, AI111143).
Qianjing Xia, Myung Hee Lee, Kathleen F. Walsh, Kathrine McAulay, James M. Bean, Daniel W. Fitzgerald, Kathryn M. Dupnik, Warren D. Johnson, Jean W. Pape, Kyu Y. Rhee, Flonza Isa
Background Tuberculosis (TB) kills more people than any other infection and new diagnostic tests to identify active cases are urgently required. We aimed to discover and verify novel markers for TB in non-depleted plasma. Methods We applied an optimised quantitative proteomics discovery methodology based on multidimensional and orthogonal liquid chromatographic separation hyphenated with high-resolution mass spectrometry (q3D LC-MS) to study non-depleted plasma of 11 patients with active TB compared to 10 healthy control donors. Prioritised candidates were verified in an independent UK-based (n=118) and a South African cohorts (n=203). Results We generated the most comprehensive TB plasma proteome to date, profiling 5022 proteins spanning 11 orders-of-magnitude concentration range with diverse biochemical and molecular properties. We further analysed the predominantly low molecular weight sub-proteome; identifying 46 proteins with significantly increased and 90 with decreased abundance (peptide FDR ≤1%, q-value ≤0.05). Biological network analysis showed regulation of new pathways involving lipid and organophosphate ester transport. Verification was performed for novel candidate biomarkers (CFHR5, ILF2) in two independent cohorts. These proteins were elevated in both TB and other respiratory diseases (ORD). Receiver-operating-characteristics analyses using a 5-protein panel (CFHR5, LRG1, CRP, LBP and SAA1) exhibited discriminatory power in distinguishing between TB and ORD (AUC =0.81). Conclusions We report the most comprehensive TB plasma proteome to date, identifying numerous novel markers with verification in two independent cohorts, which led to a 5-protein biosignature with potential to improve TB diagnosis. With further development, these biomarkers have potential as a diagnostic triage test. Funding Colombia: Colciencias. UK: Medical Research Council, Innovate UK, National Institute for Health Research, Academy of Medical Sciences. Peru: Program for Advanced Research Capacities for AIDS. South Africa: Wellcome Centre for Infectious Diseases Research.
Diana J. Garay-Baquero, Cory H. White, Naomi F. Walker, Marc Tebruegge, Hannah F. Schiff, Cesar Ugarte-Gil, Stephen Morris-Jones, Ben G. Marshall, Antigoni Manousopoulou, John H. Adamson, Andres F. Vallejo, Magdalena K. Bielecka, Robert J. Wilkinson, Liku B. Tezera, Christopher H. Woelk, Spiros D. Garbis, Paul Elkington
Background: The complement system plays a key role in host defense but is activated by ischemia-reperfusion injury (IRI). Primary graft dysfunction (PGD) is a form of acute lung injury occurring predominantly due to IRI, which worsens survival after lung transplantation (LTx). Local complement activation is associated with acute lung injury, but whether it is more reflective of allograft injury compared to systemic activation remains unclear. We proposed that local complement activation would help identify those who develop PGD post-LTx. We also aimed to identify which complement activation pathways are associated with PGD. Methods: We performed a multicenter cohort study at the University of Pennsylvania and Washington University. Bronchoalveolar lavage (BAL) and plasma specimens were obtained from recipients within 24 h post-LTx. PGD was scored based on the consensus definition. Complement activation products and components of each arm of the complement cascade were measured using ELISA. Results: In both cohorts, sC4d and sC5b-9 levels were increased in BAL of subjects with PGD compared to those without PGD. Subjects with PGD also had higher C1q, C2, C4, and C4b, compared to subjects without PGD, suggesting classical and lectin pathway involvement. Ba levels were higher in subjects with PGD, suggesting alternative pathway activation. Among lectin pathway-specific components, MBL and FCN-3 had a moderate-to-strong correlation with the terminal complement complex in the BAL but not in the plasma. Conclusion: Complement activation fragments are detected in the BAL within 24 h post-LTx. Components of all three pathways are locally increased in subjects with PGD. Our findings create a precedent for investigating complement-targeted therapeutics to mitigate PGD. Funding: This research was supported by the National Institutes of Health (NIH), American Lung Association, Children’s Discovery Institute, the Robert Wood Johnson Foundation, the Cystic Fibrosis Foundation, the Barnes-Jewish Hospital Foundation, The Danish Hearth Foundation], The Danish Research Foundation of Independent Research, The Svend Andersen Research Foundation and the Novo Nordisk Research Foundation.
Hrishikesh S. Kulkarni, Kristy Ramphal, Lina Ma, Melanie Brown, Michelle L. Oyster, Kaitlyn Speckhart, Tsuyoshi Takahashi, Derek E. Byers, Mary K. Porteous, Laurel Kalman, Ramsey R. Hachem, Melanie Rushefski, Ja'Nia McPhatter, Marlene Cano, Daniel Kreisel, Masina Scavuzzo, Brigitte Mittler, Edward Cantu, Katrine Pilely, Peter Garred, Jason D. Christie, John Atkinson, Andrew E. Gelman, Joshua M. Diamond
Background: Elevated levels of inflammatory cytokines have been associated with poor outcomes among COVID-19 patients. It is unknown, however, how these levels compare to those observed in critically ill patients with ARDS or sepsis due to other causes. Methods: We used a luminex assay to determine expression of 76 cytokines from plasma of hospitalized COVID-19 patients and banked plasma samples from ARDS and sepsis patients. Our analysis focused on detecting statistical differences in levels of 6 cytokines associated with cytokine storm (IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFα) between patients with moderate COVID-19, severe COVID-19, and ARDS or sepsis. Results: 15 hospitalized COVID-19 patients, 9 of whom were critically ill, were compared to critically ill patients with ARDS (n = 12) or sepsis (n = 16). There were no statistically significant differences in baseline levels of IL-1b, IL-1RA, IL-6, IL-8, IL-18, and TNFα between patients with COVID-19 and critically ill controls with ARDS or sepsis. Conclusions: Levels of inflammatory cytokines were not higher in severe COVID-19 patients than in moderate COVID-19 or critically ill patients with ARDS or sepsis in this small cohort. Broad use of immunosuppressive therapies in ARDS has failed in numerous Phase 3 studies; use of these therapies in unselected patients with COVID-19 may be unwarranted. Funding: A.J.R.: Stanford ICU Biobank NHLBI K23 HL125663. C.A.B.: Burroughs Wellcome Fund Investigators in the Pathogenesis of Infectious Diseases #1016687; NIH/NIAID U19AI057229-16 (PI MM Davis); Stanford Maternal Child Health Research Institute; Chan Zuckerberg Biohub.
Jennifer G. Wilson, Laura J. Simpson, Anne-Maud Ferreira, Arjun Rustagi, Jonasel A. Roque, Adijat Asuni, Thanmayi Ranganath, Philip M. Grant, Aruna K. Subramanian, Yael Rosenberg-Hasson, Holden Maecker, Susan Holmes, Joseph E. Levitt, Catherine Blish, Angela J. Rogers
BACKGROUND. Metabolically healthy obesity (MHO) and metabolically healthy overweight (MH-OW) have been suggested to be an important and emerging phenotype with an increased risk of cardiovascular disease (CVD). However, whether MHO and MH-OW are associated with all-cause mortality remains inconsistent. METHODS. The association of MHO and MH-OW and all-cause mortality was determined in China community-based prospective cohort study (Kailuan Study) including 93,272 adults at baseline. Data were analyzed from 2006 to 2017. Participants were categorized into six mutually exclusive groups according to the body mass index (BMI) and metabolic syndrome (MetS) status. The primary outcome is all-cause death, whereas accidental deaths were excluded. RESULTS. During a median follow-up of 11.04 years (interquartile range: 10.74-11.22 years), 8,977 deaths occurred. Compared to healthy participants with normal BMI (MH-NW), MH-OW had lowest risk of all-cause mortality (multivariate-adjusted hazard ratio [aHR]: 0.926; 95% confidence interval [CI]: 0.861 to 0.997), whereas there was no increased or decreased risk for MHO (aHR: 1.009; 95% CI: 0.886 to 1.148). Stratified analyses and sensitivity analyses further validated that nonsignificant association between MHO and all-cause mortality. CONCLUSIONS. Overweight and obesity do not predicate increased risk of all-cause mortality in metabolic healthy Chinese individuals.
Qiuyue Tian, Anxin Wang, Yingting Zuo, Shuohua Chen, Haifeng Hou, Wei Wang, Shouling Wu, Youxin Wang
Background: Our objective is to investigate whether primary Sjogren’s syndrome (pSS) is associated with multiple system atrophy (MSA). Methods: We performed a retrospective cohort study assessing rates of (a) MSA in a cohort of patients with pSS, and (b) and rates of pSS in a cohort of patients with MSA. These data were, compared to rates in respective control groups. We additionally reviewed the neuropathologic findings in two patients with pSS, cerebellar degeneration, parkinsonism, and autonomic dysfunction. Results: Our cohort of 308 pSS patients had a greater incidence of MSA compared with four large population-based studies and had had a significantly higher prevalence of at least probable MSA (1% vs. 0%, p = 0.02) compared to 776 patients in a control cohort of patients with other autoimmune disorders. Our cohort of 26 autopsy-proven MSA patients had a significantly higher prevalence of pSS compared with a cohort of 115 patients with other autopsy-proven neurodegenerative disorders (8% vs. 0%, p = 0.03). The two patients we described with pSS and progressive neurodegenerative disease showed classic MSA pathology at autopsy. Conclusion: Our findings provide evidence for an association between MSA and pSS that is specific to both pSS, among autoimmune disorders, and MSA, among neurodegenerative disorders. The two cases we describe of autopsy-proven MSA support that MSA pathology can explains neurologic disease in a subset of pSS patients. These findings together support the hypothesis that systemic autoimmune disease plays role in neurodegeneration. Study funding: The Michigan Brain Bank is supported in part through an NIH grant P30AG053760.
Kyle S. Conway, Sandra Camelo-Piragua, Amanda O. Fisher-Hubbard, William Perry, Vikram G. Shakkottai, Sriram Venneti
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