Heterozygous Alterations of TNFRSF13B/TACI in Tonsillar Hypertrophy and Sarcoidosis

TNFRSF13B/TACI defects have been associated with CVID pathogenesis and/or phenotype, especially the development of benign lymphoproliferation and autoimmunity. Our purpose was to investigate the role of TNFRSF13B/TACI defects in the pathogenesis of two common lymphoproliferative disorders, namely, sarcoidosis and tonsillar hypertrophy (TH). 105 patients (71 with sarcoidosis and 34 with TH, including 19 without infectious causative and 15 due to Haemophilus influenzae) were analyzed for TNFRSF13B/TACI defects. Two out of 19 TH patients without infectious cause (10.5%) and 2 patients with sarcoidosis (2.8%) displayed rare TNFRSF13B/TACI defects (I87N, L69TfsX12, E36L, and R202H, resp.). Both mutations identified in TH patients have been assessed as deleterious for protein function, while the patient with the R202H mutation and sarcoidosis exhibited also sIgG4D. Our study further supports the notion that TNFRSF13B/TACI defects alone do not result in CVID but may be also found frequently in distinct clinical phenotypes, including benign lymphoproliferation and IgG subclass deficiencies

a retrospective multicenter study

Funding This study was supported in part by a grant from the French government through the « Programme Investissement d’Avenir» (I-SITE ULNE) managed by the Agence Nationale de la Recherche (coVAPid project). Prof. Ignacio Martin-Loeches has been supported by SFI (Science Foundation Ireland), Grant number 20/COV/0038. The funders of the study had no role in the study design, data collection, analysis or interpretation, writing of the report or deci sion to submit for publication.BACKGROUND: Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP. METHODS: Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox's proportional hazard models with adjustment on pre-specified confounders. RESULTS: Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17-1.31) at day 2, 0.95 (0.63-1.42) at day 7, 1.48 (1.01-2.16) at day 14 and 1.94 (1.09-3.46) at day 21. CONCLUSIONS: No significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up.publishersversionpublishe

Expression and mutational status of TACI in sarcoidosis

OBJECTIVE The pathogenesis of sarcoidosis is presumed to be dictated by enhanced T cell immunity deregulation, however studies have suggested that patients with sarcoidosis exhibit an augmented humoral immune response manifested by increased amount of circulating immunoglobulins and the presence of autoantibodies. However the pathogenetic involvement of B cells in the development of sarcoidosis is poorly investigated. B cell homeostasis is largely influenced by B cell Activating Factor (BAFF) that acts through BAFF receptor (BAFFR) and Transmembrane Activator and Calcium-modulator and cyclophilin ligand interactor (TACI). The goal of this study was to determine the subpopulation distribution of peripheral blood B cells, the levels of TACI and BAFFR expression in B cells and immunoglobulins levels in patients with sarcoidosis.SAMPLES Seventy one sarcoidosis patients and an equivalent number of control subjects were enrolled in the study.METHODS The expression levels of the TACI and BAFFR receptors, through monoclonal antibodies anti-CD267 (clone: 1a1, BioLegend) and anti-CD268 (clone: 11C1, BioLegend) respectively, and the immunophenotyping of peripheral blood cells were estimated by flow cytometry. The detection of V220A, P251L variants of TNFRSF13B/TACI, was performed by PCR-RFLP protocol. The concentration of immunoglobins was determined by immunonephelometry. Statistical analyses were performed by the non-parametric Mann-Whitney and the Spearman correlation tests, using the SPSS (v10.0) software. RESULTS Absolute numbers and percentages of class-switched (CD19+CD27+IgD-) and unswitched (CD19+CD27+IgD+) memory B cells were significantly decreased while frequency of naive (CD19+CD27-IgD+) B cells was significantly increased. TACI and BAFFR expression did not differ between patients and controls, while a significant reduction of T and B lymphocyte count was found and was not related to medical treatment.CONCLUSION Our findings suggest disturbed homeostasis in peripheral B cells in patients with sarcoidosis. Further functional studies addressing TACI and BAFFR signalling pathway are needed in order to elucidate their role in the pathogenesis of sarcoidosis.ΣΚΟΠΟΣ Η παθογένεια της σαρκοείδωσης θεωρείται ότι καθορίζεται από την απορρύθμιση της Τ κυτταρικής ανοσίας. Παρόλα αυτά, μελέτες έχουν δείξει ότι ασθενείς με σαρκοείδωση παρουσιάζουν αυξημένη χυμική ανοσιακή απάντηση η οποία χαρακτηρίζεται από αυξημένο αριθμό κυκλοφορούντων ανοσοσφαιρινών και αυτόαντισωμάτων. Ωστόσο, η συμμετοχή των Β-κυττάρων στην παθογένεια της σαρκοείδωσης δεν έχει διερευνηθεί επαρκώς. Η ομοιόσταση των Β-κυττάρων επηρεάζεται σε μεγάλο βαθμό από τον παράγοντα ενεργοποίησης των Β-κυττάρων (BAFF) ο οποίος δρά μέσω του υποδοχέα BAFF (BAFFR) και του διαμεμβρανικού ενεργοποιητή και ρυθμιστή ασβεστίου και του αλληλεπιδρών με τον συνδέτη κυκλοφιλίνης (TACI). Σκοπός της μελέτης ήταν ο καθορισμός της κατανομής των υποπληθυσμών των περιφερικών Β-κυττάρων στο αίμα, ο καθορισμός της έκφρασης των TACI και BAFFR στα Β-κύτταρα, καθώς και των επιπέδων των ανοσοσφαιρινών σε ασθενείς με σαρκοείδωση.ΥΛΙΚΟ Εβδομήντα ένας ασθενείς με σαρκοείδωση και αντίστοιχος αριθμός υγιών εθελοντών συμπεριλήφθηκαν στην μελέτη. Συλλέχθηκε περιφερικό αίμα κατά την ένταξή τους στη μελέτη. Από όλα τα άτομα της μελέτης απομονώθηκε γενετικό υλικό καθώς και ορός.ΜΕΘΟΔΟΙ Η έκφραση των υποδοχέων TACI και BAFFR, μέσω των μονοκλωνικών αντισωμάτων αντι-CD267 (Abcam, κλώνος:1α1) και αντι-CD268 (Clone:11C1, BioLegend), καθώς και ο ανοσοφαινοτυπικός χαρακτηρισμός των κυττάρων του περιφερικού αίματος πραγματοποιήθηκε με κυτταρομετρία ροής. Η ανίχνευση των παραλλαγών V220A, P251L του γονιδίου TNFRSF13B/TACI έγινε με πρωτόκολλο PCR-RFLP. Ο προσδιορισμός της συγκέντρωσης των ανοσοσφαιρινών έγινε με ανοσονεφελομετρία. Η αναζήτηση συσχετίσεων έγινε με τη χρήση μονοπαραγοντικής λογιστικής παλινδρόμησης. Η σύγκριση των συνεχών μεταβλητών έγινε με μη παραμετρική δοκιμασία U των Mann-Whitney και τον συντελεστή συσχέτισης r κατά Spearman, με τη χρήση του λογισμικού προγράμματος SPSS (v10.0). ΑΠΟΤΕΛΕΣΜΑΤΑ Οι απόλυτοι αριθμοί και τα ποσοστά των μνημονικών Β-κυττάρων που έχουν (CD19+CD27+IgD-) ή δεν έχουν μετέλθει ισοτυπική μεταστροφή (CD19+CD27+IgD+) βρέθηκαν να είναι σημαντικά μειωμένοι, ενώ η συχνότητα των παρθένων (CD19+CD27-IgD+) Β-κυττάρων βρέθηκε να είναι σημαντικά αυξημένη. Η έκφραση του TACI και του BAFFR δεν παρουσίασε διαφορά ανάμεσα στους ασθενείς και στους υγιείς εθελοντές ενώ παρατηρήθηκε μια σημαντική μείωση στον απόλυτο αριθμό των Τ και Β-κυττάρων η οποία δεν σχετιζόταν με την θεραπευτική αγωγή.ΣΥΜΠΕΡΑΣΜΑΤΑ Τα αποτελέσματά μας υποδηλώνουν διαταραγμένη ομοιόσταση των περιφερικών B-κυττάρων σε ασθενείς με σαρκοείδωση. Αναγκαίες κρίνονται περαιτέρω λειτουργικές μελέτες πάνω στο σηματοδοτικό μονοπάτι των TACI και BAFFR, έτσι ώστε να αποσαφηνιστεί ο ρόλος τους στην παθογένεια της σαρκοείδωσης

Brief Review: Ergospirometry in Patients with Obstructive Sleep Apnea Syndrome

This brief review summarizes the available literature on the intersection of obstructive sleep apnea syndrome (OSAS) and ergospirometry. Ergospirometry provides an assessment of integrative exercise responses involving pulmonary, cardiovascular, neuropsychological, and skeletal muscle systems, which are not adequately reflected through the measurement of individual organ system functions. Sleep disorders, including OSAS, often exacerbate problems in the operation of the autonomic nervous system, heart function, lung mechanics, anxiety, and muscle metabolism. Patients with OSAS have low aerobic capacity due to dysfunction of these systems, which often affect quality of sleep. Further research is necessary to elucidate the precise mechanisms through which ergospirometry can be useful in the assessment and early identification of patients with OSAS

Supervised Versus Unsupervised Pulmonary Rehabilitation in Patients with Pulmonary Embolism: A Valuable Alternative in COVID Era

The aim of our study was to assess the effect of 8 weeks of pulmonary rehabilitation (PR) in patients with pulmonary embolism (PE) during unsupervised PR (unSPRgroup) versus supervised PR (SPRgroup) on cardiopulmonary exercise testing (CPET) parameters, sleep quality, quality of life and cardiac biomarkers (NT-pro-BNP). Fourteen patients with PE (unSPRgroup, n = 7, vs. SPRgroup, n = 7) were included in our study (age, 50.7 ± 15.1 years; BMI, 30.0 ± 3.3 kg/m2). We recorded anthropometric characteristics and questionnaires (Quality of life (SF-36) and Pittsburg sleep quality index (PSQI)), we performed blood sampling for NT-pro-BNP measurement and underwent CPET until exhausting before and after the PR program. All patients were subjected to transthoracic echocardiography prior to PR. The SPRgroup differed in mean arterial pressure at rest before and after the PR program (87.6 ± 3.3 vs. 95.0 ± 5.5, respectively, p = 0.010). Patients showed increased levels of leg fatigue (rated after CPET) before and after PR (p = 0.043 for SPRgroup, p = 0.047 for unSPRgroup) while the two groups differed between each other (p = 0.006 for post PR score). Both groups showed increased levels in SF-36 scores (general health; p = 0.032 for SPRgroup, p = 0.010 for unSPRgroup; physical health; p = 0.009 for SPRgroup, p = 0.022 for unSPRgroup) and reduced levels in PSQI (cannot get to sleep within 30-min; p = 0.046 for SPRgroup, p = 0.007 for unSPRgroup; keep up enough enthusiasm to get things done; p = 0.005 for SPRgroup, p = 0.010 for unSPRgroup) following the PR program. The ΝT-pro-BNP was not significantly different before and after PR or between groups. PR may present a safe intervention in patients with PE. The PR results are similar in SPRgroup and unSPRgroup

Relationship between corticosteroid use and incidence of ventilator-associated pneumonia in COVID-19 patients: a retrospective multicenter study

International audienceAbstract Background Ventilator-associated pneumonia (VAP) is common in patients with severe SARS-CoV-2 pneumonia. The aim of this ancillary analysis of the coVAPid multicenter observational retrospective study is to assess the relationship between adjuvant corticosteroid use and the incidence of VAP. Methods Planned ancillary analysis of a multicenter retrospective European cohort in 36 ICUs. Adult patients receiving invasive mechanical ventilation for more than 48 h for SARS-CoV-2 pneumonia were consecutively included between February and May 2020. VAP diagnosis required strict definition with clinical, radiological and quantitative microbiological confirmation. We assessed the association of VAP with corticosteroid treatment using univariate and multivariate cause-specific Cox’s proportional hazard models with adjustment on pre-specified confounders. Results Among the 545 included patients, 191 (35%) received corticosteroids. The proportional hazard assumption for the effect of corticosteroids on the incidence of VAP could not be accepted, indicating that this effect varied during ICU stay. We found a non-significant lower risk of VAP for corticosteroid-treated patients during the first days in the ICU and an increased risk for longer ICU stay. By modeling the effect of corticosteroids with time-dependent coefficients, the association between corticosteroids and the incidence of VAP was not significant (overall effect p = 0.082), with time-dependent hazard ratios (95% confidence interval) of 0.47 (0.17–1.31) at day 2, 0.95 (0.63–1.42) at day 7, 1.48 (1.01–2.16) at day 14 and 1.94 (1.09–3.46) at day 21. Conclusions No significant association was found between adjuvant corticosteroid treatment and the incidence of VAP, although a time-varying effect of corticosteroids was identified along the 28-day follow-up