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Randomized controlled trials have demonstrated responses to clinical parameters, but a significant proportion of allergy patients in real-life settings would have been excluded from such studies. Therefore, real-world research is needed, and there is a growing body of information on allergen immunotherapy's long-term effectiveness and safety. Real-world evidence can be a valuable instrument to better understand the patient's journey and the effectiveness and safety of therapies. For this purpose, a registry will be used for the first time in Italy to evaluate the impact of allergen immunotherapy on several outcomes, including quality of life and disease-related effects in the pediatric and adult allergic population with a socio-economic assessment and respect to real-world health. [ABSTRACT FROM AUTHOR]

Epithelial barrier damage plays a central role in the development and maintenance of allergic inflammation. Rises in the epithelial barrier permeability of airways alter tissue homeostasis and allow the penetration of allergens and other external agents. Different factors contribute to barrier impairment, such as eosinophilic infiltration and allergen protease action—eosinophilic cationic proteins' effects and allergens' proteolytic activity both contribute significantly to epithelial damage. In the airways, allergen proteases degrade the epithelial junctional proteins, allowing allergen penetration and its uptake by dendritic cells. This increase in allergen–immune system interaction induces the release of alarmins and the activation of type 2 inflammatory pathways, causing or worsening the main symptoms at the skin, bowel, and respiratory levels. We aim to highlight the molecular mechanisms underlying allergenic protease-induced epithelial barrier damage and the role of immune response in allergic asthma onset, maintenance, and progression. Moreover, we will explore potential clinical and radiological biomarkers of airway remodeling in allergic asthma patients. [ABSTRACT FROM AUTHOR]

Heterogeneity characterises inflammatory diseases and different phenotypes and endotypes have been identified. Both innate and adaptive immunity contribute to the immunopathological mechanism of these diseases and barrier damage plays a prominent role triggering type 2 inflammation through the alarmins system, such as anti-Thymic Stromal Lymphopoietin (TSLP). Treatment with anti-TSLP monoclonal antibodies showed efficacy in severe asthma and clinical trials for other eosinophilic diseases are ongoing. The aim of this perspective review is to analyse current advances and future applications of TSLP inhibition to control barrier damage. [ABSTRACT FROM AUTHOR]

Introduction: Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of B cells expressing B cell receptors (BCRs), often encoded by the VH1-69 variable gene, endowed with both rheumatoid factor (RF) and anti-HCV specificity. These cells display an atypical CD21low phenotype and functional exhaustion evidenced by unresponsiveness to BCR and Toll-like receptor 9 (TLR9) stimuli. Although antiviral therapy is effective on MC vasculitis, pathogenic B cell clones persist long thereafter and can cause virus-independent disease relapses. Methods: Clonal B cells from patients with HCV-associated type 2 MC or healthy donors were stimulated with CpG or heath-aggregated IgG (as surrogate immune complexes) alone or in combination; proliferation and differentiation were then evaluated by flow cytometry. Phosphorylation of AKT and of the p65 NF-kB subunit were measured by flow cytometry. TLR9 was quantified by qPCR and by intracellular flow cytometry, and MyD88 isoforms were analyzed using RT-PCR. Discussion: We found that dual triggering with autoantigen and CpG restored the capacity of exhausted VH1-69pos B cells to proliferate. The signaling mechanism for this BCR/TLR9 crosstalk remains elusive, since TLR9 mRNA and protein as well as MyD88 mRNA were normally expressed and CpG-induced phosphorylation of p65 NF-kB was intact in MC clonal B cells, whereas BCR-induced p65 NF-kB phosphorylation was impaired and PI3K/Akt signaling was intact. Our findings indicate that autoantigen and CpG of microbial or cellular origin may unite to foster persistence of pathogenic RF B cells in HCV-cured MC patients. BCR/TLR9 crosstalk might represent a more general mechanism enhancing systemic autoimmunity by the rescue of exhausted autoreactive CD21low B cells. [ABSTRACT FROM AUTHOR]

Background: Asthma, with several phenotypes and endotypes, is considered particularly suited for precision medicine. The identification of different non‐invasive biomarkers may facilitate diagnosis and treatment. Recently, Staphylococcus aureus and its enterotoxins (SE) have been found to have a role in inducing persistent type 2 airway inflammation in severe asthma, but also in such comorbidities as chronic rhinosinusitis with nasal polyposis (CRSwNP). Methods: The aim of this retrospective study was to evaluate the prevalence of SE‐IgE sensitization in a multicentric Italian cohort of severe asthmatic patients and correlate it with demographic and clinical characteristics. Results: A total of 249 patients were included in the analysis, out of which 25.3% were staphylococcal enterotoxin B (SEB)‐IgE positive. We found a meaningful association between SEB‐IgE and female gender, a positive association was also measured between CRS and CRSwNP. No significant association was found between SEB‐IgE sensitization and atopy, the occurrence of exacerbations and corticosteroid dosages. In the SEB‐IgE‐positive patient, blood eosinophil count does not appear to be correlated with the severity of the disease. Patients with SEB‐IgE sensitization are, on average, younger and with an earlier disease onset, thus confirming the possibility to consider SEB‐IgE sensitization as an independent risk factor for developing asthma. Conclusions: Our data confirm that the search for SE in the initial screening phase of these patients is helpful to better phenotype them, may predict the evolution of comorbidities and lead to a targeted therapeutic choice; in this point of view this represents a goal of precision medicine. [ABSTRACT FROM AUTHOR]

Inflammatory tissue damage plays a role in the onset, progression, and exacerbation of various chronic autoimmune and metabolic diseases such as autoimmune hepatitis. Here we present a case of autoimmune hepatitis with liver eosinophilic infiltrate in a severe eosinophilic asthma patient who failed conventional immunosuppressive treatment and showed improvement in gastrointestinal symptoms after anti-interleukin-5 receptor treatment. Our case highlights the potential role of eosinophils in initiating or worsening liver inflammation in autoimmune liver disease. The link between eosinophilic inflammation, barrier damage, and chronic autoimmune diseases should be considered in clinical practice. [ABSTRACT FROM AUTHOR]

Currently, asthma represents the most common chronic disorder in children, showing an increasingly consistent burden worldwide. Childhood asthma, similar to what happens in adults, is a diversified disease with a great variability of phenotypes, according to genetic predisposition of patients, age, severity of symptoms, grading of risk, and comorbidities, and cannot be considered a singular well-defined disorder, but rather a uniquely assorted disorder with variable presentations throughout childhood. Despite several developments occurring in recent years in pediatric asthma, above all, in the management of the disease, some essential areas, such as the improvement of pediatric asthma outcomes, remain a hot topic. Most treatments of the type 2 (T2) target phenotype of asthma, in which IL-4, IL-5, and IL-13 modulate the central signals of inflammatory reactions. Although, there may be an unresolved need to identify new biomarkers used as predictors to improve patient stratification using disease systems and to aid in the selection of treatments. Moreover, we are globally facing many dramatic challenges, including climate change and the SARS-CoV2 pandemic, which have a considerable impact on children and adolescent asthma. Preventive strategies, including allergen immunotherapy and microbiome evaluation, and targeted therapeutic strategies are strongly needed in this population. Finally, the impact of asthma on sleep disorders has been reviewed. [ABSTRACT FROM AUTHOR]

Prospective Italian real-world study of mepolizumab in severe eosinophilic asthma validates retrospective outcome reports Current asthma guidelines inform about evidence-based approaches to optimize patient outcomes. Notably, the severity of asthma experienced by patients in both studies was very similar, and additionally patients had similar annual exacerbation rates (3.48 vs. 4.09 exacerbations/year) and similar hospitalization rates (0.44/year vs. 0.39/year). [Extracted from the article]

Objectives The biomarkers of an immunological dysregulation due to a chronic HBV infection are indeed understudied. If untreated, this condition may evolve into liver impairment co-occurring with extrahepatic involvements. Here, we aim to identify a new panel of biomarkers [including immunoglobulin G (IgG) subclasses, RF, and Free Light Chains (FLCs)] that may be useful and reliable for clinical evaluation of HBV-related cryoglobulinemia. Methods We retrospectively analysed clinical data from 44 HBV-positive patients. The patients were stratified (according to the presence/absence of mixed cryoglobulinemia) into two groups: 22 with cryoglobulins (CGs) and 22 without CGs. Samples from 20 healthy blood donors (HDs) were used as negative controls. Serum samples were tested for IgG subclasses, RF (-IgM, -IgG, and -IgA type), and FLCs. Results We detected a strikingly different distribution of serum IgG subclasses between HDs and HBV-positive patients, together with different RF isotypes; in addition, FLCs were significantly increased in HBV-positive patients compared with HDs, while no significant difference was shown between HBV-positive patients with/without mixed cryoglobulinemia. Conclusion The immune-inflammatory response triggered by HBV may be monitored by a peculiar profile of biomarkers. Our results open a new perspective in the precision medicine era; in these challenging times, they could also be employed to monitor the clinical course of those COVID-19 patients who are at high risk of HBV reactivation due to liver impairment and/or immunosuppressive therapies. [ABSTRACT FROM AUTHOR]

Summary: The objective of this study was to evaluate the predictive role of CD21low B cells as markers of new digital ulcers in systemic sclerosis patients. Peripheral blood B cell subpopulations and clinical assessments have been evaluated in 74 systemic sclerosis patients at baseline and after a 12‐month follow‐up. After a 12‐month follow‐up, 23 (31.1%) systemic sclerosis patients developed new digital ulcers. The median percentage of CD21low B cells was significantly higher in patients with than without new digital ulcers [10.1 (4.3–13.6) versus 4.8 (3.5–7.4); p < 0.01]. The 10% cut‐off shows good diagnostic accuracy [area under the curve (AUC) = 0.732, confidence interval (CI) = 0.587–0.878; P = 0.01]. Kaplan–Meier curves show a significantly reduced free survival from new digital ulcers in systemic sclerosis patients with CD21low B cells ≥ 10% (p < 0.0001). In multivariate analysis, CD21low B cells ≥ 10%, modified Rodnan skin score (mRSS) and systolic pulmonary arterial pressure (sPAP) are associated with the development of new digital ulcers. We hypothesize that CD21low B cells are a predictive marker of new digital ulcers in systemic sclerosis patients. [ABSTRACT FROM AUTHOR]

Hepatitis C virus (HCV) represents the major risk factor for mixed cryoglobulinemia (MC), a small-vessel vasculitis that may evolve into an overt B-cell non-Hodgkin's lymphoma. Here, we aimed to identify a biomarker signature for the early diagnosis of minimal residual disease (MRD). We assessed free light chains (FLCs), IgM k,and IgM λ heavy/light chain (HLC) pairs, and vascular endothelial growth factor (VEGF) in sera from 34 patients with MC vasculitis (32 HCV- and 2 HBV-related), treated with low-dose rituximab (RTX). FLCs and IgM HLCs were measured by turbidimetric assay; VEGF by an enzyme-linked immunosorbent assay. After RTX, the positive (complete + partial) clinical and laboratory responses were of 85.29% and 50%, respectively; in contrast, the mean levels of FLCs, IgM HLCs, and VEGF were substantially unaffected in most patients and still above the normal range. In those achieving a reduction of FLCs and IgM k and λ chains values within the range of normality, we found that post-treatment free λ chains and IgM k values correlated with clinical and laboratory response. Our results suggest that high levels of FLCs, IgM HLCs, and VEGF could represent the signature of "dormant" B cell clones' activity that could be very useful to identify MRD indicative of possible relapse or worsening outcome. [ABSTRACT FROM AUTHOR]

Sustained virological response (SVR) obtained with interferon (IFN) or with direct‐acting antivirals (DAAs) is commonly followed by response of hepatitis C virus (HCV)‐associated mixed cryoglobulinemia vasculitis (MCV), but relapse of MCV despite SVR has been reported in several patients after DAAs and rarely after IFN. Since relapses could have been overlooked in studies with IFN, we retrospectively compared the outcomes of MCV in SVR patients treated with DAAs (n = 70) or IFN (n = 39) followed‐up, respectively, for 30.5 (range 11‐51) or 48 months. Groups were comparable for demographics and clinics and response rates of MCV were similar (92% and 86%); however, DAA‐treated patients less efficiently reduced cryoglobulins (P =.006) and circulating B‐cell clones (P =.004), and had more frequently relapses of MCV (18% vs 3%, P =.028) and need for rituximab therapy (P =.01). Although largely inferior on an intention‐to‐treat basis, IFN may be superior to DAAs on clinico‐immunological outcomes possibly owing to its antiproliferative activity. [ABSTRACT FROM AUTHOR]

β-Lactams which include penicillins, cephalosporins, carbapenems, and monobactams are the most common antibiotic classes reported to cause allergic reactions to drugs. This review is mainly about published studies assessing the cross-reactivity among β-lactams in penicillin- or cephalosporin-allergic subjects by carrying out diagnostic tests with alternative β-lactams and, if appropriate, graded challenges. Several studies demonstrated that cross-reactivity connected with the β-lactam ring, causing positive responses to allergy tests with all β-lactams, is infrequent in subjects with an IgE-mediated allergy and anecdotal in those with a T-cell-mediated allergy. Identities or similarities of β-lactam side-chain structures are mainly responsible for cross-reactivity among these antibiotics. For example, in aminopenicillin-allergic subjects, cross-reactivity with aminocephalosporins could possibly be over 30%. On the other hand, in a few prospective studies of penicillin-allergic individuals, less than 1% of cases show a cross-reactivity between penicillins and both aztreonam and carbapenems. Particular patterns of allergy-test positivity observed in some studies that assessed cross-reactivity among β-lactams seem to indicate that prior exposures may be responsible for coexisting sensitivities. Therefore, pre-treatment skin tests with the related β-lactams are suggested before administering them via graded challenges to β-lactam-allergic patients who need alternative β-lactams. [ABSTRACT FROM AUTHOR]

Introduction. The poor long-term adherence is known to affect the efficacy of allergen immunotherapy (AIT). In the case of injection AIT (SCIT), one of the main determinants is the inconvenience for patients to undergo prolonged build-up phases. Thus, simplifying the time schedule of the induction protocol could be effective in increasing the adherence to SCIT. Methods. We backtracked the SCIT renewal orders, thanks to the cooperation of the manufacturing company, and we compared the long-term adherence of 152 patients, who were prescribed with an abbreviated build-up schedule (4 injections, allergoid) with that of 302 patients treated with the same product, but with the traditional build-up protocol (7 injections). Results. According to the patient-named refills, those patients on the abbreviated build-up were significantly more compliant at the 2nd and 3rd year of treatment compared to the other group (p = 0.0001). The drop-out rate after one year was also significantly lower between the two groups (p = 0.0001). In the abbreviated group, as expected, reimbursed patients showed significantly better adherence compared with patients with no reimbursement at all (p < 0.05). Conclusions. Abbreviating the build-up phase by reducing the number of injections significantly improves patients' adherence to SCIT. [ABSTRACT FROM AUTHOR]

Background & Aims: Hepatitis C virus (HCV)‐related mixed cryoglobulinaemia vasculitis (MCV) is characterized by the expansion of rheumatoid factor‐producing B‐cell clones. The aim of this study was to assess whether B‐cell clones may persist in these patients after the clearance of the virus with antiviral therapy, and whether their persistence influences clinical outcomes. Methods: Forty‐five HCV‐cured MCV patients were followed up for a median of 18.5 (range 9‐38) months after the clearance of HCV. Circulating B‐cell clones were detected using flow cytometry either by the skewing of kappa/lambda ratio or by the expression of a VH1‐69‐encoded idiotype. Results: The clinical response of vasculitis was 78% complete, 18% partial and 4% null. However, cryoglobulins remained detectable in 42% of patients for more than 12 months. Circulating B‐cell clones were detected in 18 of 45 patients, and in 17 of them persisted through the follow‐up; nine of the latter patients cleared cryoglobulins and had complete response of vasculitis. Several months later, two of these patients had relapse of MCV. Conclusions: B‐cell clones persist in MCV patients long after HCV infection has been cleared but halt the production of pathogenic antibody. These 'dormant' cells may be reactivated by events that perturb B‐cell homeostasis and can give rise to the relapse of cryoglobulinaemic vasculitis. [ABSTRACT FROM AUTHOR]

Keywords: asthma; basophil; eosinophils; interleukins EN asthma basophil eosinophils interleukins 1569 1571 3 05/17/21 20210501 NES 210501 Interleukin-5 (IL-5) is one of the main cytokine involved in the pathogenesis of eosinophilic asthma (EA) and exerts pleiotropic activities on various target cells expressing its receptor, including eosinophils and basophils. Basophil activation and serum IL-5 levels as possible monitor biomarkers in severe eosinophilic asthma patients treated with anti-IL-5 drugs Allergy Asthma Clin Immunol. 2020; 22 (16): 27. 9 Siegmund R, Vogelsang H, Machnik A, Herrmann D. Surface membrane antigen alteration on blood basophils in patients with hymenoptera venom allergy under immunotherapy. [Extracted from the article]

Purpose: To quantify the health related quality of life in primary immunodeficiency patients. Materials and Methods: We used generic health status and general psychological health questionnaires to determine the range of issues that needed to be considered in examining the burden of common variable immunodeficiency (CVID). Results: The health status of patients with CVID was lower than that observed in normal subjects. Overall, Role-Physical and General Health scales correlated with a poorer clinical status. Surprisingly, the duration of disease did not influence health status. Being female, older, General Health Questionnaire-positive and alexithymic proved to be major risk factors associated with a poor health status. Patients with chronic lung disease and chronic diarrhea had the lowest values on the Medical Outcome Study, Short Form SF-36 (SF-36) scales. Disease severity perception was associated with the General Health Questionnaire and alexithymia status. Limitations in daily activities as a result of lower physical health were the major problems facing common variable immunodeficiency patients. Conclusion: Our data underlined the importance of conducting a periodical health related quality of life assessment on patients with primary antibody deficiencies and, moreover, stressed the necessity of providing psychological support to at risk patients. [ABSTRACT FROM AUTHOR]

Precision medicine refers to the tailoring of therapeutic strategies to the individual characteristics of each patient; thus, it could be a new approach for the management of severe asthma that considers individual variability in genes, environmental exposure, and lifestyle. Precision medicine would also assist physicians in choosing the right treatment, the best timing of administration, consequently trying to maximize drug efficacy, and, possibly, reducing adverse events. Metabolomics is the systematic study of low molecular weight (bio)chemicals in a given biological system and offers a powerful approach to biomarker discovery and elucidating disease mechanisms. In this point of view, metabolomics could play a key role in targeting precision medicine. [ABSTRACT FROM AUTHOR]

The author looks at late relapses of hepatitis C virus-cured mixed cryoglobulinaemia (MC) linked with infection or cancer. Five patients with type II MC who had persistence or late relapse of vasculitis were described. The demographic and clinical attributes of four patients with relapse of MC vasculitis despite sustained virologic response were summarized. Lymphoma was excluded by negative bone marrow biopsy and positron emission tomography/computed tomography scan.

Hepatitis C virus (HCV) causes mixed cryoglobulinemia (MC) by driving clonal expansion of IgM+CD27+ B cells. These cells display both the features of anergy induced by continual engagement of the B-cell receptor (BCR), such as high expression of phosphorylated extracellular signal–regulated kinase (pERK) and reduced lifespan, and of virus-specific exhaustion, such as CD21low phenotype and a defective response to ligation of BCR and Toll-like receptor 9 (TLR9). MC usually regresses after eradication of HCV with interferon, whose immunomodulatory activity might contribute to this effect. We investigated the phenotypic and functional changes in clonal B cells of MC patients with sustained virologic responses to direct-acting antivirals (DAAs), which lack immunomodulatory properties. We found that high pERK expression and accelerated apoptosis revert within 4 weeks after beginning therapy, whereas clonal B cells unresponsive to TLR9 stimulation persist for at least 24 weeks, although they may partially rescue normal CD21 expression. Thus, similar to mouse models, features of anergy in MC B cells rapidly revert after disengagement from HCV, whereas virus-specific exhaustion imparts a durable inhibitory imprint on cell function. Treatment of HCV+ MC with DAAs provides a valuable tool for untangling the molecular mechanisms of anergy and exhaustion in human B cells. [ABSTRACT FROM AUTHOR]