Non-specific oral and cutaneous manifestations of coronavirus disease 2019 in children

Background: Coronavirus Disease 2019 (COVID-19) seems to affect children only marginally, as a result, there is less knowledge of its manifestations in childhood. The purpose of this retrospective cross-sectional study was to investigate the oral and cutaneous manifestations in children affected by COVID-19. Material and Methods: All the medical records of children with COVID-19 admitted to the Pediatric Clinic-ASST Spedali Civili of Brescia from March to April 2020 were reviewed. The following data were recorded: Age, temperature, clinical presentation, oral mucosa lesions, taste alteration and cutaneous lesions. Results: The medical records of twenty-seven pediatric patients (mean age 4,2 years + 1,7) were analyzed. The clinical presentation of the disease mainly included elevated body temperature and cough. The following oral lesions were recorded: Oral pseudomembranous candidiasis (7.4 %), geographic tongue (3.7%), coated tongue (7.4 %) and hyperaemic pharynx (37 %). Taste alteration was reported by 3 patients. Six patients presented cutaneous flat papular lesions. Conclusions: As for our paediatric sample, COVID-19 resulted to be associated with non-specific oral and cutaneous manifestations

CVID-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses.

Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt's lymphoma cells and analyzed for their impacts on BAFFR function. Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID

NFKB1 regulates human NK cell maturation and effector functions

12siopenopenLougaris, Vassilios; Patrizi, Ornella; Baronio, Manuela; Tabellini, Giovanna; Tampella, Giacomo; Damiati, Eufemia; Frede, Natalie; van der Meer, Jos W.M.; Fliegauf, Manfred; Grimbacher, Bodo; Parolini, Silvia; Plebani, AlessandroLougaris, Vassilios; Patrizi, Ornella; Baronio, Manuela; Tabellini, Giovanna; Tampella, Giacomo; Damiati, Eufemia; Frede, Natalie; van der Meer, Jos W. M.; Fliegauf, Manfred; Grimbacher, Bodo; Parolini, Silvia; Plebani, Alessandr

Activated phosphoinositide 3-dinase delta syndrome (APDS): An update

Activated phosphoinositide 3-kinase delta syndrome (APDS) is a recently described form of inborn error of immunity (IEI) caused by heterozygous mutations in PIK3CD or PIK3R1 genes, respectively, encoding leukocyte-restricted catalytic p110\u3b4 subunit and the ubiquitously expressed regulatory p85 \u3b1 subunit of the phosphoinositide 3-kinase \u3b4 (PI3K\u3b4). The first described patients with respiratory infections, hypogammaglobulinemia with normal to elevated IgM serum levels, lymphopenia, and lymphoproliferation. Since the original description, it is becoming evident that the onset of disease may be somewhat variable over time, both in terms of age at presentation and in terms of clinical and immunological complications. In many cases, patients are referred to various specialists such as hematologists, rheumatologists, gastroenterologists, and others, before an immunological evaluation is performed, leading to delay in diagnosis, which negatively affects their prognosis. The significant heterogeneity in the clinical and immunological features affecting APDS patients requires awareness among clinicians since good results with p110\u3b4 inhibitors have been reported, certainly ameliorating these patients\u2019 quality of life and prognosis

Reduced NK cell activity and abnormal expression of CCR7 and CXCR1 by NK cells analysis in patients with DOCK8 deficiency

DOCK8-deficiency is an autosomal recessive primary immunodeficiency that is characterized by multiple abnormalities of the immune system, including a defect of NK cell cytotoxicity which could not be restored after IL2 stimulation. Nevertheless, unanswered questions remain regarding how the absence of DOCK8 leads to predisposition for malignancy, viral, fungal, and bacterial infections. To address these questions we have analyzed NK cell phenotype and functions in patients with DOCK8 deficiency. We observed that NK cells derived from five DOCK8-deficient patients displayed dramatically reduced cytotoxicity which was partially restored after IL-2 stimulation. Analysis of activating and inhibitory NK receptors, including KIRs molecules, chemokine receptors and activation markers on gated CD56+cells by cytofluorimetric analysis showed a substantial defect of CCR7 expression by CD56bright NK cells. Noteworthy, we have also detected the expression of NKG2C and of the chemokine receptor CXCR1 on CD56dull NK cells in DOCK8-deficient cells. Because CCR7 expression by NK cells can be induced after cell culture with IL18 we stimulated NK cells from DOCK-8 deficient patients with IL18. Despite unstimulated CD56bright NK cells from DOCK8 patients showed reduced CCR7 expression, we could not detect any increase of CCR7 on CD56 dull and bright NK cells of DOCK8-deficient patients, whereas CCR7 expression on NK cells derived from healthy donors significantly increased from 5% to 17%.Taken together our results suggest that NK cells of DOCK-8 deficient patients show reduced cytotoxicity and abnormal expression of the chemokine receptors CXCR1 and CCR7 suggesting an abnormal recruitment of these cells to secondary lymphoid organs

Primary atopic disorders and chronic skin disease

open13noPrimary atopic disorders (PADs) are monogenic diseases characterized by allergy or atopy-related symptoms as fundamental features. In patients with PADs, primary immune deficiency and immune dysregulation symptoms are usually coexist. Chronic skin disease, manifesting with erythroderma, severe atopic dermatitis or eczema, and urticaria, is one of the main features observed in PADs, such as hyper-IgE syndromes, Omenn syndrome, Wiskott-Aldrich syndrome, IPEX-linked syndrome, skin barrier disorders, as well as some autoinflammatory diseases. The recognition of PADs in the context of an allergic phenotype is crucial to ensure prompt diagnosis and appropriate treatment. This article provides an overview of the main PADs with skin involvement.openCinicola B.L.; Corrente S.; Castagnoli R.; Lougaris V.; Giardino G.; Leonardi L.; Volpi S.; La Torre F.; Federici S.; Soresina A.; Cancrini C.; Marseglia G.L.; Cardinale F.Cinicola, B. L.; Corrente, S.; Castagnoli, R.; Lougaris, V.; Giardino, G.; Leonardi, L.; Volpi, S.; La Torre, F.; Federici, S.; Soresina, A.; Cancrini, C.; Marseglia, G. L.; Cardinale, F

Inherited defects in the complement system

open13noThe complement system plays an essential role in both innate and adaptive immune responses. Any dysregulation in this system can disturb normal host defense and alter inflammatory response leading to both infections and autoimmune diseases. The complement system can be activated through three different pathways. Inherited complement deficiencies have been described for all complement components and their regulators. Despite being rare diseases, complement deficiencies are often severe, with a frequent onset during childhood. We provide an overview of clinical disorders related to these disorders and describe current diagnostic strategies required for their comprehensive characterization and management.openLeonardi L.; La Torre F.; Soresina A.; Federici S.; Cancrini C.; Castagnoli R.; Cinicola B.L.; Corrente S.; Giardino G.; Lougaris V.; Volpi S.; Marseglia G.L.; Cardinale F.Leonardi, L.; La Torre, F.; Soresina, A.; Federici, S.; Cancrini, C.; Castagnoli, R.; Cinicola, B. L.; Corrente, S.; Giardino, G.; Lougaris, V.; Volpi, S.; Marseglia, G. L.; Cardinale, F

Interim analysis:Open-label extension study of leniolisib for patients with APDS

Background: Activated phosphoinositide 3-kinase delta (PI3Kδ) syndrome (APDS; or p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency) is an inborn error of immunity caused by PI3Kδ hyperactivity. Resultant immune deficiency and dysregulation lead to recurrent sinopulmonary infections, herpes viremia, autoimmunity, and lymphoproliferation. Objective: Leniolisib, a selective PI3Kδ inhibitor, demonstrated favorable impact on immune cell subsets and lymphoproliferation over placebo in patients with APDS over 12 weeks. Here, we report results from an interim analysis of an ongoing open-label, single-arm extension study. Methods: Patients with APDS aged 12 years or older who completed NCT02435173 or had previous exposure to PI3Kδ inhibitors were eligible. The primary end point was safety, assessed via investigator-reported adverse events (AEs) and clinical/laboratory evaluations. Secondary and exploratory end points included health-related quality of life, inflammatory markers, frequency of infections, and lymphoproliferation. Results: Between September 2016 and August 2021, 37 patients (median age, 20 years; 42.3% female) were enrolled. Of these 37 patients, 26, 9, and 2 patients had previously received leniolisib, placebo, or other PI3Kδ inhibitors, respectively. At the data cutoff date (December 13, 2021), median leniolisib exposure was 102 weeks. Overall, 32 patients (87%) experienced an AE. Most AEs were grades 1 to 3; none were grade 4. One patient with severe baseline comorbidities experienced a grade 5 AE, determined as unrelated to leniolisib treatment. While on leniolisib, patients had reduced annualized infection rates (P =.004), and reductions in immunoglobulin replacement therapy occurred in 10 of 27 patients. Other observations include reduced lymphadenopathy and splenomegaly, improved cytopenias, and normalized lymphocyte subsets. Conclusions: Leniolisib was well tolerated and maintained durable outcomes with up to 5 years of exposure in 37 patients with APDS. ClinicalTrials.gov identifier: NCT02859727.</p