Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-γ Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

BackgroundSARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD).ObjectiveWith this study we aimed to shed new light on the pathogenesis of these two SARS-CoV-2-related clinical manifestations.MethodsWe investigated lymphocyte and dendritic cells subsets, chemokine/cytokine profiles and evaluated the neutrophil activity mediators, myeloperoxidase (MPO), and reactive oxygen species (ROS), in 10 children with COVID-19 and 9 with MIS-C at the time of hospital admission.ResultsPatients with MIS-C showed higher plasma levels of C reactive protein (CRP), MPO, IL-6, and of the pro-inflammatory chemokines CXCL8 and CCL2 than COVID-19 children. In addition, they displayed higher levels of the chemokines CXCL9 and CXCL10, mainly induced by IFN-gamma. By contrast, we detected IFN-alpha in plasma of children with COVID-19, but not in patients with MIS-C. This observation was consistent with the increase of ISG15 and IFIT1 mRNAs in cells of COVID-19 patients, while ISG15 and IFIT1 mRNA were detected in MIS-C at levels comparable to healthy controls. Moreover, quantification of the number of plasmacytoid dendritic cells (pDCs), which constitute the main source of IFN-alpha, showed profound depletion of this subset in MIS-C, but not in COVID-19.ConclusionsOur results show a pattern of immune response which is suggestive of type I interferon activation in COVID-19 children, probably related to a recent interaction with the virus, while in MIS-C the immune response is characterized by elevation of the inflammatory cytokines/chemokines IL-6, CCL2, and CXCL8 and of the chemokines CXCL9 and CXL10, which are markers of an active Th1 type immune response. We believe that these immunological events, together with neutrophil activation, might be crucial in inducing the multisystem and cardiovascular damage observed in MIS-C

Plasmacytoid Dendritic Cells Depletion and Elevation of IFN-\u3b3 Dependent Chemokines CXCL9 and CXCL10 in Children With Multisystem Inflammatory Syndrome

SARS-CoV-2 occurs in the majority of children as COVID-19, without symptoms or with a paucisymptomatic respiratory syndrome, but a small proportion of children develop the systemic Multi Inflammatory Syndrome (MIS-C), characterized by persistent fever and systemic hyperinflammation, with some clinical features resembling Kawasaki Disease (KD)

When a Nontuberculous Mycobacterial Infection Reveals an Error of Immunity: A Single Center's Experience

: We present an algorithm that may be applied in case of a diagnosis of pediatric nontuberculous mycobacterial disease to identify the patients who may require an immunologic assessment to discover a possible underlying immune system defect predisposing to their nontuberculous mycobacterial infections

ADA2 deficiency (DADA2) as an unrecognised cause of early onset polyarteritis nodosa and stroke: a multicentre national study

Objectives\u2002To analyse the prevalence of CECR1 mutations in patients diagnosed with early onset livedo reticularis and/or haemorrhagic/ischaemic strokes in the context of inflammation or polyarteritis nodosa (PAN). Forty-eight patients from 43 families were included in the study. Methods\u2002Direct sequencing of CECR1 was performed by Sanger analysis. Adenosine deaminase 2 (ADA2) enzymatic activity was analysed in monocyte isolated from patients and healthy controls incubated with adenosine and with or without an ADA1 inhibitor. Results Biallelic homozygous or compound heterozygous CECR1 mutations were detected in 15/48 patients. A heterozygous disease-associated mutation (p.G47V) was observed in two affected brothers. The mean age of onset of the genetically positive patients was 24months (6months to 7 years). Ten patients displayed one or more cerebral strokes during their disease course. Low immunoglobulin levels were detected in six patients. Thalidomide and anti-TNF (tumour necrosis factor) blockers were the most effective drugs. Patients without CECR1 mutations had a later age at disease onset, a lower prevalence of neurological and skin manifestations; one of these patients displayed all the clinical features of adenosine deaminase 2deficiency (DADA2) and a defective enzymatic activity suggesting the presence of a missed mutation or a synthesis defect. Conclusions\u2002DADA2 accounts for paediatric patients diagnosed with PAN-like disease and strokes and might explain an unrecognised condition in patients followed by adult rheumatologist. Timely diagnosis and treatment with anti-TNF agents are crucial for the prevention of severe complications of the disease. Functional assay to measure ADA2 activity should complement genetic testing in patients with non-confirming genotypes

Vascular risk factors in glaucoma: The results of a national survey

Graefe's Archive for Clinical and Experimental Ophthalmology Volume 245, Issue 6, 1 June 2007, Pages 795-802 Vascular risk factors in glaucoma: The results of a national survey (Article) Orzalesi, N.a , Rossetti, L.a, Omboni, S.b, Sborgia, C.c, Vetrugno, M.c, Cantatore, F.c, Campos, E.d, Baldi, A.d, Quaranta, L.e, Serra, A.f, Zucca, I.f, Mura, M.f, Malocci, M.f, Uva, M.g, Longo, A.g, Lombardo, A.g, Scorcia, G.h, Moschettini, R.h, Gallenga, P.E.i, Mastropasqua, L.i, Ciancaglini, M.i, Carpineto, P.i, Lobefalo, L.i, Perri, P.j, Paduano, B.j, Alfieri, G.k, Menchini, U.k, Campana, F.k, Giansanti, F.k, Delle Noci, N.l, Balducci, F.l, Calabria, G.m, Saccà, S.m, Sanna, G.m, Camicione, P.m, Mastromarino, A.m, Balestrazzi, E.n, Di Staso, S.n, Ferreri, G.o, D’Andrea, A.o, Orzalesi, N.p, Rossetti, L.p, Fogagnolo, P.p, Mazzolani, F.p, Brancato, R.q, Carassa, R.q, Bettin, P.q, Fiori, M.q, Guerra, R.r, Martini, E.r, Scarale, G.r, Campi, L.r, Bonavolontà, G.s, Rinaldi, E.s, Di Meo, A.s, Fusco, R.s, Dorigo, M.T.t, Doro, D.t, Grgic, V.t, Lodato, G.u, Morreale Bubella, D.u, Signorelli, F.u, Gandolfi, S.v, Trimarchi, F.w, Milano, G.w, Fiore, C.x, De Carolis, A.x, Sbordone, G.x, Nardi, M.y, Bartolomei, M.P.y, Figus, M.y, Guidi, G.y, Scullica, L.z, Salgarello, T.z, Colotto, A.z, Bucci, M.G.aa, Cerulli, L.aa, Manni, G.L.aa, Centofanti, M.aa, Parravano, M.aa, Scuderi, G.aa, Nucci, C.aa, Carta, F.ab, Pinna, A.ab, Caporossi, A.ac, Frezzotti, P.ac, Grignolo, F.ad, Brogliatti, B.ad, Rolle, T.ad, Ravalico, G.ae, Vattovani, O.ae, Tritto, D.ae, Canziani, T.ae, Marchini, G.af, Marraffa, M.af, OPTIME Study Group (Osservatorio sulla Patologia glaucomatosa, Indagine Medico Epidemiologica)ag, CONPROSO (Collegio Nazionale dei Professori Ordinari di Scienze Oftalmologiche)ah Hide additional authors a Department of Medicine, Surgery and Odontology, University of Milan, San Paolo Hospital, Milan, Italy b Docleader Srl, Somma Lombardo, VA, Italy c University of Bari, Italy View additional affiliations View references (52) Abstract Background The role of vascular risk factors in glaucoma is still being debated. To assess the importance of vascular risk factors in patients with primary open-angle glaucoma (POAG), data from the medical history of 2,879 POAG patients and 973 age-matched controls were collected and analyzed. Methods Design: observational survey. Setting: 35 Italian academic centers. Study population: POAG patients and age-matched controls. In order to reduce bias consecutive patients were included. Observation procedures: data concerning vascular risk factors were collected for all patients with a detailed questionnaire. A complete ophthalmological examination with assessment of intraocular pressure (IOP), visual field, optic disc, and systemic blood pressure was performed. Main outcome measures: the ESH-ESC (European Society of Hypertension-European Society of Cardiology) guidelines were used to calculate the level of cardiovascular risk. Crude and adjusted estimates of the odds ratios (OR) were calculated for all cardiovascular risk factors in POAG and controls. Results The study included 2,879 POAG patients and 973 controls. POAG cases had a significantly higher systolic and diastolic blood pressure (p=0.001) and systolic perfusion pressure (p=0.02) as compared with controls. Also mean IOP was significantly higher in the POAG group (p=0.01), while diastolic perfusion pressure was not significantly different in the two groups. Myopia was more prevalent in the POAG group (23 vs 18%, p=0.005) as well as a positive family history for glaucoma (26 vs 12%, p= 0.004). POAG patients tended to have a higher cardiovascular risk than controls: 63% of glaucoma cases vs 55% of controls (OR: 1.38, p=0.005) had a “high” or “very high” cardiovascular risk. Conclusions The level of cardiovascular risk was significantly higher in glaucoma patients than in controls. © Springer-Verlag 2006

Tolerability of vortioxetine compared to selective serotonin reuptake inhibitors in older adults with major depressive disorder (VESPA): a randomised, assessor-blinded and statistician-blinded, multicentre, superiority trialResearch in context

Summary: Background: Major depressive disorder (MDD) is prevalent and disabling among older adults. Standing on its tolerability profile, vortioxetine might be a promising alternative to selective serotonin reuptake inhibitors (SSRIs) in such a vulnerable population. Methods: We conducted a randomised, assessor- and statistician-blinded, superiority trial including older adults with MDD. The study was conducted between 02/02/2019 and 02/22/2023 in 11 Italian Psychiatric Services. Participants were randomised to vortioxetine or one of the SSRIs, selected according to common practice. Treatment discontinuation due to adverse events after six months was the primary outcome, for which we aimed to detect a 12% difference in favour of vortioxetine. The study was registered in the online repository clinicaltrials.gov (NCT03779789). Findings: The intention-to-treat population included 179 individuals randomised to vortioxetine and 178 to SSRIs. Mean age was 73.7 years (standard deviation 6.1), and 264 participants (69%) were female. Of those on vortioxetine, 78 (44%) discontinued the treatment due to adverse events at six months, compared to 59 (33%) of those on SSRIs (odds ratio 1.56; 95% confidence interval 1.01–2.39). Adjusted and per-protocol analyses confirmed point estimates in favour of SSRIs, but without a significant difference. With the exception of the unadjusted survival analysis showing SSRIs to outperform vortioxetine, secondary outcomes provided results consistent with a lack of substantial safety and tolerability differences between the two arms. Overall, no significant differences emerged in terms of response rates, depressive symptoms and quality of life, while SSRIs outperformed vortioxetine in terms of cognitive performance. Interpretation: As opposed to what was previously hypothesised, vortioxetine did not show a better tolerability profile compared to SSRIs in older adults with MDD in this study. Additionally, hypothetical advantages of vortioxetine on depression-related cognitive symptoms might be questioned. The study's statistical power and highly pragmatic design allow for generalisability to real-world practice. Funding: The study was funded by the Italian Medicines Agency within the “2016 Call for Independent Drug Research”