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Background: Non-invasive mechanical ventilation (NIV) is effective for symptom relief and respiratory support in patients with respiratory insufficiency, severe comorbidities and no indication to intubation. Experience with NIV as the ceiling of treatment in severely compromised novel coronavirus disease (COVID-19) patients is lacking. Methods: We evaluated 159 patients with COVID-19-related acute respiratory syndrome (ARDS), 38 of whom with NIV as the ceiling of treatment, admitted to an ordinary ward and treated with continuous positive airway pressure (CPAP) and respiratory physiotherapy. Treatment failure and death were correlated with clinical and laboratory parameters in the whole cohort and in patients with NIV as the ceiling of treatment. Results: Patients who had NIV as the ceiling of treatment were elderly, with a low BMI and a high burden of comorbidities, showed clinical and laboratory signs of multi-organ insufficiency on admission and of rapidly deteriorating vital signs during the first week of treatment. NIV failure occurred overall in 77 (48%) patients, and 27/38 patients with NIV as the ceiling of treatment died. Congestive heart failure, chronic benign haematological diseases and inability/refusal to receive respiratory physiotherapy were independently associated to NIV failure and mortality. Need for increased positive end-expiratory pressures and low platelets were associated with NIV failure. Death was associated to cerebrovascular disease, need for CPAP cycles longer than 12h and, in the subgroup of patients with NIV as the ceiling of treatment, was heralded by vital sign deterioration within 48 h. Conclusions: NIV and physiotherapy are a viable treatment option for patients with severe COVID-19 and severe comorbidities.

Biological therapies are gaining relevance in the management of CRSwNP with few adverse events reported. Among these, dupilumab, an anti-IL4-Ra monoclonal antibody, is frequently associated with hypereosinophilia (HE) which usually remains silent and progressively resolves, although some cases of systemic involvement occurs. The aim of this paper is to describe our experience and propose a management flowchart for HE during therapy with dupilumab.Patients with CRSwNP who satisfied EPOS2020 criteria for biological therapies were included in this prospective study. Each case was discussed in a multidisciplinary meeting with subsequent prescription of dupilumab; all patients were candidates to follow-up bi-monthly for 6 months, while additional blood tests were scheduled in the event of HE.A total of 21 patients with a mean age of 48.4 years were enrolled. Of these, 15 of 21 presented an asthma comorbidity and 9 of 21 ASA sensitivity. Four patients (19%) developed HE with AEC 1.5 × 10During dupilumab therapy, HE may occur and should be considered benign when 3 × 10

Background Biologics are currently one of the main treatment options for a number of diseases. The IgG4 monoclonal antibody dupilumab targets the Interleukin-4 receptor alpha chain, thus preventing the biological effects of the cytokines IL-4 and IL-13, that are essential for the Th2 response. Several controlled trials showed that dupilumab is effective and safe in patients with atopic dermatitis (AD), severe asthma and chronic rhinosinusitis with nasal polyps (CRSwNP), thus resulting in approval by regulatory agencies. Aim of the study was to evaluate the efficacy and safety of dupilumab in adult patients with CRSwNP stratified by common overlapping comorbid conditions. Methods We performed a multicenter, observational, prospective study enrolling adult patients with severe CRSwNP who had started dupilumab treatment in the context of standard care from January 2021 to October 2021. Data were collected from twentynine Italian secondary care centers for allergy and clinical immunology, all of which were part of the Italian Society of Allergy, Asthma and Clinical Immunology (SIAAIC). A number of efficacy parameters were used. Patient data were compared using the Wilcoxon test for paired data. All statistical analyses were performed with SPSS version 20 (IBM, Armonk, NY, USA). Results In total, 82 patients with nasal polyposis were identified. A significant improvement was detected for all the applied efficacy parameters, i.e. 22-item Sino-Nasal Outcome Test (SNOT-22) and bilateral endoscopic nasal polyp score (NPS) scores for CRSwNP, Rhinitis Control Scoring System (RCSS) and Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) scores for allergic perennial rhinitis, Forced Expiratory Volume in the 1st second (FEV1) and Asthma Quality of Life Questionnaire (AQLQ) scores for asthma, Eczema Area and Severity Index (EASI) and Dermatology Life Quality Index (DLQI) scores for AD. A non-significant improvement was also obtained in the Urticaria Activity Score over 7 days (UAS7) for chronic spontaneous urticaria. Treatment with dupilumab was well tolerated. Conclusions These data suggest that dupilumab treatment in patients suffering from CRSwNP and associated comorbidities may be suitable. Such outcome, although confirmation by trials is warranted, suggests the possibility to treat different disorders with a single therapy, with favorable effects especially under the cost-effectiveness aspect.

Anti-Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) vaccination is the world’s most important strategy for stopping the pandemic. Vaccination challenges the body’s immune response and can be complicated by hypersensitivity reactions. The autonomic nervous system can modulate the inflammatory immune response, therefore constituting a potential marker to characterize individuals at high risk of hypersensitivity reactions. Autonomic nervous system functionality was assessed through measurement of the heart rate variability (HRV) in subjects with a history of severe allergic reactions and 12 control subjects. HRV parameters included the mean electrocardiograph RR interval and the standard deviation of all normal R–R intervals (SDNN). All measurements were performed immediately before the anti-SARS-CoV-2 vaccination. The median RR variability was lower in the study than in the control group: 687 ms (645–759) vs. 821 ms (759–902); p = 0.02. The SDNN was lower in the study group than in the control group: 32 ms (23–36) vs. 50 ms (43–55); p < 0.01. No correlation was found between age and the SDNN. Autonomic nervous system activity is unbalanced in people with a severe allergy background.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is a heterogeneous, multiorgan and potentially life-threatening drug-hypersensitivity reaction (DHR) that occurs several days or weeks after drug initiation or discontinuation. DHRs constitute an emerging issue for public health, due to population aging, growing multi-organ morbidity, and subsequent enhanced drug prescriptions. DRESS has more consistently been associated with anticonvulsants, allopurinol and antibiotics, such as sulphonamides and vancomycin, although new drugs are increasingly reported as culprit agents. Reactivation of latent infectious agents such as viruses (especially Herpesviridae) plays a key role in prompting and sustaining aberrant T-cell and eosinophil responses to drugs and pathogens, ultimately causing organ damage. However, the boundaries of the impact of viral agents in the pathophysiology of DRESS are still ill-defined. Along with growing awareness of the multifaceted aspects of immune perturbation caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) during the ongoing SARS-CoV-2-related disease (COVID-19) pandemic, novel interest has been sparked towards DRESS and the potential interactions among antiviral and anti-drug inflammatory responses. In this review, we summarised the most recent evidence on pathophysiological mechanisms, diagnostic approaches, and clinical management of DRESS with the aim of increasing awareness on this syndrome and possibly suggesting clues for future research in this field.

Aberrant deployment of the immune response is a hallmark pathogenic feature of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related disease (COVID-19), possibly accounting for high morbidity and mortality, especially in patients with comorbidities, including immune-mediated disorders. Immunisation with SARS-COV-2 vaccines successfully instructs the immune system to limit viral spread into tissues, mitigate COVID-19 manifestations and prevent its most detrimental inflammatory complications in the general population. Patients with immune-mediated diseases have been excluded from vaccine registration trials, foreclosing the acquisition of specific efficacy and safety data. In this review, we aimed to summarise and critically discuss evidence from real-world studies addressing this issue to provide a comprehensive view of the impact of vaccination practices in patients with allergy, autoimmunity or immunodeficiency. We analysed clinical and laboratory data from 34 studies involving more than 13,000 subjects with various immune disorders who were vaccinated with mRNA- DNA- or inactivated viral particle-based vaccines. These data globally support the safe and effective use of SARS-CoV-2 vaccines in patients with immune-mediated diseases, although patient-tailored strategies to determine vaccination timing, vaccine choice and background therapy management are warranted to optimise vaccination outcomes. More data are needed regarding patients with primary immunodeficiencies.

Severe drug allergy affects patient hesitancy to new treatments, posing unprecedented challenges to anti-SARS-CoV-2 vaccination campaigns. We aimed to analyze the psychological profile of vaccinees with a history of severe allergy in comparison to subjects with a milder allergy history. Patients attending a dedicated vaccination setting were administered an anonymized questionnaire including clinical data and the State-Trait Anxiety Inventory (STAI) scale (score range 20–80). Patients were also asked whether being in a protected setting affected their attitude toward vaccination. Data are expressed as median (interquartile range). We enrolled 116 patients (78% women), of whom 79% had a history of drug anaphylaxis. The median state anxiety score was 36.5 (30–47.2), while the trait anxiety score was 37 (32–48). State anxiety was higher in those with severe than mild allergy [39 (32–50) vs. 30 (25–37); p < 0.001], with the highest score found in a patient with previous drug anaphylaxis (42.5 [32–51.7]). More than 50% of patients reported that being in a protected setting had lowered their anxiety. Severe allergy is associated with a higher burden of situational anxiety in the setting of vaccination without affecting patient constitutional (trait) levels of anxiety. Vaccination in dedicated facilities might overcome issues related to hesitancy and improve patients’ quality of life.

The prevalence of asthma in Italy is estimated to be around 4%; it affects approximately 2,000,000 citizens, and up to 80-90% of patients have mild-to-moderate asthma. Despite the clinical relevance of mild-to-moderate asthma, longitudinal observational data are very limited, including data on disease progression (worsening vs. improvement), the response to treatment, and prognosis. Studies are needed to develop long-term, observational, real-life research in large cohorts. The primary outcomes of this study will be based on prospective observation and the epidemiological evolution of mild and moderate asthma. Secondary outcomes will include patient-reported outcomes, treatments over time, disease-related functional and inflammatory patterns, and environmental and life-style influences.This study, called the Mild/Moderate Asthma Network of Italy (MANI), is a research initiative launched by the Italian Respiratory Society and the Italian Society of Allergology, Asthma and Clinical Immunology. MANI is a cluster-based, real world, cross-sectional, prospective, observational cohort study that includes 20,000 patients with mild-to-moderate asthma. (ClinicalTrials.gov Identifier: NCT04796844).Despite advances in asthma care, several research gaps remain to be addressed through clinical research. This study will add important new knowledge about long-term disease history, the transferability of clinical research results to daily practice, the efficacy of currently recommended strategies, and their impact on the burden and evolution of the disease.MANI:Mild/Moderate Asthma Network of ItalySANI:Severe Asthma Network ItalyGINA:Global Initiative for AsthmaSABA:short acting β2-agonistsICS:inhaled corticosteroidsCRF:Case Report Form.

Background Clinicians are increasingly recognizing severe asthma patients in whom biologics and other add-on therapies lead to dramatic improvement. Currently, there is no agreed-upon super-responder (SR) definition. Objective To survey severe asthma experts using a modified Delphi process, to develop an international consensus-based definition of a severe asthma SR. Methods The Delphi panel was composed of 81 participants (94% specialist pulmonologists or allergists) from 24 countries and consisted of three iterative online voting rounds. Consensus on individual items, whether acceptance or rejection, required at least 70% agreement by panel members. Results Consensus was achieved that the SR definition should be based on improvement across three or more domains assessed over 12 months. Major SR criteria included exacerbation elimination, a large improvement in asthma control (two or more times the minimal clinically important difference), and cessation of maintenance of oral steroids (or weaning to adrenal insufficiency). Minor SR criteria were composed of a 75% exacerbation reduction, having well-controlled asthma, and 500 mL or greater improvement in FEV1. The SR definition requires improvement in at least two major criteria. In the future, the SR definition should be expanded to incorporate quality of life measures, although current tools can be difficult to implement in a clinical setting and further research is needed. Conclusions This international consensus-based definition of severe asthma SRs is an important prerequisite for better understanding SR prevalence, predictive factors, and the mechanisms involved. Further research is needed to understand the patient's perspective and to measure quality of life more precisely in SRs.

BackgroundRespiratory infections can be complicated by acute brain failure. We assessed delirium prevalence, predictors and outcomes in COVID-19 ED patients.MethodsThis was a retrospective observational study conducted at the San Raffaele ED (Italy). Patients age >18 years attending the ED between 26 February 2020 and 30 May 2020 and who had a positive molecular nasopharyngeal swab for SARS-CoV-2 were included. The Chart-Based Delirium Identification Instrument (CHART-DEL) was used to retrospectively assess delirium. Univariable and multivariable logistic regression analyses were used to evaluate delirium predictors. Univariable binary logistic regression analyses, linear regression analyses and Cox regression analyses were used to assess the association between delirium and clinical outcomes. Age-adjusted and sex-adjusted models were then run for the significant predictors of the univariable models.ResultsAmong the 826 included patients, 123 cases (14.9%) of delirium were retrospectively detected through the CHART-DEL method. Patients with delirium were older (76.9±13.15 vs 61.3±14.27 years, pConclusionsChart review frequently identified ED delirium in patients with COVID-19. Age, dementia, epilepsy and polypharmacy were significant predictors of ED delirium. Delirium was associated with an increased in-hospital mortality and with a reduced probability of being discharged home after hospitalisation. The findings of this single-centre retrospective study require validation in future studies.

Among 6146 hospital employees, 118 subjects with severe allergic background were identified through a screening questionnaire and stratified into 3 groups (Low-risk (LR), Intermediate (IR) and High-risk (HR) group), based on their allergic anamnesis. Data reports on hypersensitivity reactions (HypR) have been collected in both allergic and non-allergic subjects. Seventeen patients (14%) in the allergic population had a HypR after the first, the second or both doses. Skin manifestations were the most frequent ones. Allergic events were more frequent in HR (35%) than IR (10%; p=0.005) or LR (0%; p=0.074) subjects. No patient had anaphylaxis. All patients completed the vaccination schedule. 13 HypR occurred in patients without severe allergic background (13/6028, 0,2%) including one (1/6148, 0.016% of total population) WAO grade-4 anaphylaxis. Our data suggest that BNT162b2 mRNA Covid-19 vaccine is relatively safe also in patients with severe allergic background; however, some precautions are required for high-risk patients.

Objective. The purpose of the study was to describe the characteristics of patients experiencing hypersensitivity reactions (HRs) to iodinated contrast media (ICM) in a large Italian population and to investigate potential risks factors in order to obtain a risk stratification, helpful in the management of these patients. Methods. Data of 407 patients investigated in 9 Italian Allergy Centers for suspected HRs to ICM were analyzed and compared with a control group of 152 subjects that tolerated one or more ICM-enhanced examinations. The univariate and multivariate logistic regression model was used to evaluate associated factors. Results. The mean age of reactive patients was 61 years and 60% were female; 67% of patients reported immediate reactions and 35% experienced the reaction, more frequently with immediate onset, at the first examination in life. Iomeprol, iopromide and iodixanol were the most frequent culprit agents and 20% of patients showed a positive skin test result. Previous adverse reactions to ICM were reported by 15.6% of patients, whereas 35% of subjects experienced the reaction, more frequently immediate, after the first ICM-enhanced examination in their life. The multivariate analysis showed that male gender and age > 65 were associated with ICM reactions as protective factors [ORadja = 0.51; 95% CI: 0.33-0.77 and ORadja = 0.60; 95% CI: 0.39-0.92 respectively]. Cardio-vascular disease [ORadja = 2.06; 95% CI: 1.22-3.50)], respiratory allergy [ORadja = 2.30; 95% CI: 1.09-4.83)] and adverse drug reactions [ORadja = 1.99; 95% CI: 1.05-3.77)] were identified as risk factors for ICM reactions. Food allergy was not significantly associated with reactions [ORadja = 1.51; 5% CI: 0.41-5.56]. Conclusions. This is the largest study on Italian patients experiencing hypersensitivity reactions to ICM. Most results are in line with other studies, showing some association with factors that could influence the incidence of hypersensitivity reactions but not allowing an easy risk stratification.

BACKGROUND Heat-and-pepsin-sensitive plant food allergens (PR-10 and profilin) sometimes cause systemic reaction. OBJECTIVE To detect the risk factors for systemic reactions induced by labile food allergens. METHODS A retrospective multicenter study was performed on patients with a documented history of systemic allergic reaction to labile plant food allergens and on age-matched controls with a history of oral allergy syndrome (OAS) induced by the same foods. Offending foods, their amount, and state (solid or liquid), and potential cofactors (nonsteroidal anti-inflammatory drugs, protonic pump inhibitors, exercise, alcohol, and fasting) were considered. RESULTS We studied 89 patients and 81 controls. Sensitization to PR-10 or profilin, IgE to Bet v 1 and/or Bet v 2, and foods causing OAS were similar in the two groups. Twenty patients experienced >1 systemic allergic reaction. Tree nuts, Rosaceae, Apiaceae, and soymilk were the main offending foods. Seventeen (19%) patients were taking a PPI when the systemic reaction occurred (vs 5% in controls; P

Background: Histamine Intolerance (HIT) is a multifaceted pseudoallergic disorder possibly due to defective histamine metabolism. Diamine oxidase (DAO) contributes to histamine degradation and can be measured in the serum. The role of DAO measurement in the diagnostic work-up of HIT still remains unclear, and conflicting results have been reported in the literature. Therefore, we aimed to evaluate the possible clinical usefulness and consistency of DAO value ranges as provided by the assay manufacturer and verify whether they could predict the response to treatment. Methods: We retrospectively analyzed 192 outpatients with HIT symptoms and measured serum DAO values at baseline. Patients were prescribed either with low-histamine diet and/or enzymatic supplementation according to symptom severity and re-evaluated six to eight months later. Patients were stratified into three groups according to DAO levels: 10 U/mL. HIT severity was assessed on a scale of 1 to 5 before and after treatment. Results: A total of 146 patients completed the study. Gastrointestinal and cutaneous symptoms, often associated with headache, were more frequent in subjects with DAO < 10 U/mL. Symptom severity and DAO ranges were correlated. Patients with intermediate DAO levels (3–10 U/mL) showed a more complex clinical phenotype but also a more significant improvement in symptom severity (score reduction 50%, interquartile range (IQR) = 33–60%) when compared to patients with low DAO (40%, IQR = 20–60%; p = 0.045) or high DAO (33%, IQR = 0–50%; p < 0.001). Complex clinical phenotypes were also more frequent in patients with intermediate DAO levels. Conclusions: HIT is characterized by typical symptoms and low levels of DAO activity. Symptom severity was associated with the degree of DAO deficiency. Patients with DAO values between 3 and 10 U/mL show the best response to treatment (low-histamine diet and/or DAO supplementation). DAO value could arguably be considered as a predictor of clinical response to treatment. Prospective studies are needed to confirm these data.

We read with interest the article from Simpson et al on the efficacy of dupilumab—an anti-IL-4 receptor alfa monoclonal antibody—in a patient with multi-organ IgG4-related disease (IgG4-RD) involving the retroperitoneum and, apparently, the prostate and the parotid glands.1 According to the case presentation, the patient refused immunosuppressive agents due to the risk of adverse events, and treating physicians decided to start him on 40 mg oral prednisone. Subcutaneous dupilumab was added based on multiple concomitant poorly controlled atopic manifestations including asthma, dermatitis and periorbital angioedema. Prednisone was tapered over 2 months and then withdrawn. Dupilumab was administered subcutaneously at initial dose of 600 mg, followed by 300 mg injections every other week for 12 months. Three months later, amelioration of all manifestations was observed, and after 12 months on dupilumab, retroperitoneal fibrosis was dramatically improved. Sensible decrease in …

Background: Altered innate and adaptive immune response is a hallmark of the pathogenesis of systemic lupus erythematosus (SLE). Autoimmune manifestations are a major cause of morbidity and damage accrual and constitute the main target of treatment in patients with SLE. Exposure to medications for purposes of immune suppression or treatment of complications might also synergise with an aberrant immune response and facilitate infections as well as hypersensitivity to non-harmful antigens. Epidemiological data about allergy in SLE are scanty. Objectives: To describe clinical and epidemiological features of allergy and asthma in SLE. Methods: One-hundred-thirty-five patients with SLE (classified according to the American College of Rheumatology, ACR, 1990 revised criteria) were enrolled. Retrospective data collection included autoimmune manifestations during the course of SLE and history of asthma. In addition, we recorded timing, clinical features, culprit(s) of the first three hypersensitivity reactions (HyR, together with concomitant infections, SLEDAI-2K and prednisone dose at time of each reaction. Damage accrual was quantitated by employing the SLE International Collaborating Clinics/ACR damage index (SDI). Results: A history of one or more HyR was found in 40.7% of patients. Immediate-type HyR were most significantly represented (83.6% of cases) and four cases were anaphylaxis (lifelong incidence rate of 67.04/105 persons-years). Respiratory allergy (allergic rhinitis or asthma) occurred in 19 patients (34.5%). Twenty-one out of 55 (38.3%) patients with allergy had ≥2 manifestations, five (9.1%) had ≥3 manifestations. Drugs were the most frequent culprits, accounting for 81.8% of HyR. Early-onset SLE (before the age of 21) associated with a higher risk of becoming allergic during SLE course compared with late-onset SLE (LR=8.01; p=0.005; HR=2.28, 95%CI=1.27-4.11). Patients with allergy onset after SLE (52.7% of cases) developed a second HyR more frequently and earlier (LR=11.49; p=0.001; HR=5.19, 95%CI=1.87-14.42). SLE with vasculitic manifestations also was a risk factor for developing HyR (LR=4.00; p=0.045; HR=2.13, 95%CI=1.00-4.55). Patients with allergy post-lupus had a SLEDAI-2K>4 and a prednisone dose>5mg/day in 51.7%, 41.7%, 50% of cases and in 37.9%, 50% and 50% of cases at first, second and third HyR respectively. Concomitant infections were detected in 20.7, 25% and 0% of cases respectively. Patients with ≥2 HyR had faster damage accrual compared to patients with ≤1 manifestations (median SDI/year=0.04, IQR=0.00-0.11 vs 0.00, IQR=0.00-0.06; p = 0.048). Conclusion: Patients with SLE have a high prevalence of allergy, which might contribute to its protean phenotype SLE deflects allergy incidence trajectories towards an increased risk. Allergy, in turn, associates with increased SLE activity, medication burden and infectious complications and might affect the risk of long-term damage accrual. References [1] Sequeira JF, et al., Lupus, 1993 [2] Hsiao YP, et al., Int. J. Environ. Res. Public Health2014 [3] Goldman JA, et al., Arthritis Rheum1976 [4] Pope J, et al. J Rheumatol, 2002 [5] Morton S, et al. Ann Rheum Dis, 1998 [6] Danza Aet al, Lupus, 2013 [7] Touma Z, et al., Curr Opin Rheumatol, 2013 [8] Sin E, et al., Autoimmun Reviews, 2016 [9] Wozniacka A, et al., Mediators Inflamm, 2003 Disclosure of Interests: None declared

We read with interest the recent report by Geisen et al ,1 who describe the immunogenicity and safety profile of two mRNA-based anti-SARS-CoV-2 vaccines in a cohort of 26 patients with chronic arthritides, psoriasis and other inflammatory diseases, compared with 42 healthy controls. The majority of subjects were health professionals, which makes the 14-day post-vaccinal observations provided by the authors particularly informative for high-risk settings, such as hospitals. Extensive data about the impact of anti-SARS-CoV-2 vaccines in patients with immune-mediated disorders are eagerly awaited, since people living with these diseases were excluded from registration trials,2–4 despite constituting a risk group for severe SARS-CoV-2-realated disease (COVID-19)5–7 and, potentially, for adverse immune-mediated post-vaccinal events.8–11 To contribute in filling this knowledge gap, we studied 55 consecutive patients (54 health professionals) with rheumatic diseases and primary immunodeficiencies, for a median (IQR) of 66 (42–75) days from the first and 45 (20–52) days from the second dose of the BNT162b2 vaccine2 (detailed methods: online supplemental material 1). Thirty-eight patients (69%) had one or more comorbidities, including allergy in 22 cases (table 1).### Supplementary data [annrheumdis-2021-220539supp001.pdf] View this table: Table 1 Clinical features of the study cohort At time of vaccination, 42/55 patients had been in remission for 20 (5–29) months. The median disease duration was 11 (5–18) years. Fifty-one patients (93%) were taking one or more immunosuppressive/immunomodulating drugs beside other treatments (online supplemental tables 1 and 2).### Supplementary data [annrheumdis-2021-220539supp002.pdf] ### Supplementary data [annrheumdis-2021-220539supp003.pdf] No patient had evidence of …

Background:Systemic lupus erythematosus (SLE) is a multi-organ immune-mediated disease characterised by autoimmunity. Dysfunction in immune tolerance towards allergens and protection from infections has less been studied. Human leukocyte antigen (HLA) genotype affects the risk of developing SLE. Little is known on the role of HLA in shaping SLE phenotype.Objectives:To test for potential associations among active SLE, occurrence of infections and hypersensitivity reactions (HyR) at a clinical level and assess whether these events segregate with patients’ HLA-DRB1 typing.Methods:224 patients with SLE were prospectively followed up over the course of 1267 consecutive visits with a median interval of five months between each visit. HyR occurring within one month before or after each visit and occurrence of at least one infection leading to antimicrobial treatment and/or absence from work in the interval between each visit were recorded. Disease activity was estimated through the systemic lupus erythematosus disease activity index 2000 (SLEDAI-2K). Remission was surrogated by the Lupus Low Disease Activity State (LLDAS). Demographics and general disease features including a previous history of allergy were retrospectively assessed. HLA-DRB1 genotype was obtained from 188 patients. Data are expressed as median [interquartile range], unless otherwise specified.Results:Incidence rates for HyR and infections were 80/1000 person-years and 45/100 person-years. Culprit agents for HyR were drugs in 61% of cases, inhalants, food or other allergens in the remainder 42%. Most frequent sites for infections were the airways (55%), skin and mucosae (16%), the genital and/or urinary tracts (14%) and the gastrointestinal tract (7%). LLDAS was inversely associated with HyR (χ2=20.912; p2=8.234; p=0.005). patients with a recent HyR had a shorter disease duration (9 [2-15] vs 13 [8-22] years; p=0.006) and higher SLEDAI-2K scores (4 [3.5-11] vs 3 [2-4]; p2=15.509; p2=4.944; p=0.035). Among patients with at least four prospective visits, HLA-DRB1*11:01 carriers reported a recent infection more frequently (25% [13-40%] vs 14% [0-29%]; p=0.044) and HLA-DRB1*07:01 carriers less frequently (0% [0-17%] vs 18% [11-33%]; p=0.026) compared to patients with other HLA-DRB1 genotypes.Conclusion:These data suggest that immune dysfunction in SLE not only affects tolerance to self antigens but also antimicrobial and allergic responses and that genetically determined HLA-restricted mechanisms of antigen presentation might influence the shape of this dysfunctional immune response in patients with SLE.References:[1]Teruel M et al. Curr Opin Rheumatol, 2016[2]Sequeira JF et al., Lupus, 1993[3]Danza A et al, Lupus, 2013[4]Park H et al., Allergy Asthma Immunol Res, 2012[5]Quiralte J et al., J Allergy Clin Immunol, 1999Disclosure of Interests:Giuseppe Alvise Ramirez: None declared, Andrea Sorce: None declared, Benedetta Allegra Mazzi: None declared, Luca Moroni: None declared, Emanuel Della Torre: None declared, Giselda Colombo: None declared, Mona-Rita Yacoub: None declared, Enrica Bozzolo: None declared, Lorenzo Dagna Grant/research support from: The Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) received unresctricted research/educational grants from Abbvie, Bristol-Myers Squibb, Celgene, Janssen, Merk Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI., Consultant of: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI., Angelo Manfredi: None declared

Background:Eosinophilic granulomatosis with polyangiitis (EGPA), previously known as Churg-Strauss syndrome, is a systemic disease characterized by late onset asthma associated with small- and/or medium-size vessel vasculitis, besides eosinophil-mediated cytotoxic organ damage. About 20-30% of patients with EGPA displays allergic manifestations related with inhalant sensitization, while prevalence of food and drug allergy is unknown in this context. Moreover, some authors in the past hypothesized in favor of a possible role of allergen-specific immunotherapy (ASIT) as a trigger of disease.Objectives:Aim of the present study is to establish the prevalence of each category allergen sensitization and to determine whether atopy or specific immunotherapy could influence clinical expression of the disease.Methods:Our study consisted in a retrospective demographic and clinical data collection regarding EGPA history (including age at diagnosis, organ and tissue involvement, autoantibody profile) and the presence of allergic comorbidities or previous drug hypersensitivity reactions. Patients without either proven allergic reactions or positive tests have been excluded.Results:Fifty-three (53) patients with definitive diagnosis of EGPA have been included in the analysis among which 25 (47.2%) with chronic respiratory allergy or previous acute allergic reaction. Among allergic patients 15 (60%) resulted sensitized towards inhalants and among them 13 (86.7%) displayed multiple sensitization. Drug allergy affected 13 patients (52%), food 4 (16%). Among 15 patients with respiratory allergy, 13 were eligible to allergen-specific immunotherapy (ASIT). Seven (7) subjects underwent ASIT prior EGPA diagnosis with an average time-to-EGPA of 16.2 years. No statistically significant difference was found in terms of sex, age at diagnosis, positivity for or specificity of anti-neutrophil cytoplasm antibodies (ANCA), eosinophil count at onset, pattern of clinical manifestations comparing allergic vs. non-allergic, ASIT vs. non-ASIT, ASIT vs. allergic, ASIT vs. eligible.Conclusion:Among patients with EGPA allergies are highly prevalent, particularly towards inhalants and drugs. In the great majority of patients multiple sensitization profile is found. Atopy doesn’t seem to be associated with specific patterns of disease presentation. The absence of correlation between inhalant ASIT exposure and variation in mode and time of EGPA onset doesn’t support the hypothesis of a its potential role in triggering the disease.References:[1]Berti A et al. Severe/uncontrolled asthma and overall survival in atopic patients with eosinophilic granulomatosis with polyangiitis. Respiratory Medicine 2018; DOI: 10.1016/j.rmed.2018.07.017[2]Cottin V et al. Respiratory manifestations of eosinophilic granulomatosis with polyangiitis (Churg–Strauss). European Respiratory Journal 2016; DOI: 10.1183/13993003.00097-2016Disclosure of Interests:Luca Moroni: None declared, adriana cariddi: None declared, Silvia Sartorelli: None declared, Emanuel Della Torre: None declared, Tommaso Germanò: None declared, Giuseppe Alvise Ramirez: None declared, Enrica Bozzolo: None declared, Mona-Rita Yacoub: None declared, Lorenzo Dagna Grant/research support from: The Unit of Immunology, Rheumatology, Allergy and Rare Diseases (UnIRAR) received unresctricted research/educational grants from Abbvie, Bristol-Myers Squibb, Celgene, Janssen, Merk Sharp & Dohme, Mundipharma Pharmaceuticals, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI., Consultant of: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI.

Background Food hypersensitivity is characterized by a wide range of symptoms. The relationship between symptoms and food is more frequently suspected than objectively proven. Basophil activation test (BAT) is based on the evaluation of activation markers on blood basophils in vitro stimulated with drugs or allergens. The aim of the study was to evaluate the usefulness of BAT when introduced in the routine work-up of suspected food hypersensitivity. Methods BAT was requested in subjects with food adverse reactions when a discrepancy existed among history and skin prick test (SPT) and/or specific IgE. Data from 150 subjects were analysed using CD63 as basophil activation marker. Thirty controls were evaluated for cut-offs. Immunoblots was performed with the sera of representative subjects positive for BAT and negative for SPT and sIgE. Results 1,024 BAT were carried out, the agreement (positive/positive and negative/negative) was 78.5% for BAT vs. SPT and 78.3% for BAT vs. IgE. Atopic patients, but not atopic controls, more frequently had a positive BAT than non-atopic patients (P

Introduction: Diamine oxidase (DAO) catabolizes and inactivates histamine, a key player in a wide range of invalidating conditions, such as migraine and chronic spontaneous urticaria (CSU). The highest expression of DAO occurs in the gastrointestinal tract, possibly to control the burden of histamine intake from food. Methods: Here, we tested the hypothesis that a 30-day oral supplementation with DAO (1 capsule b.i.d., 15 min before a meal) could reduce the severity of CSU as estimated by the 7-Day Urticaria Activity Score (UAS-7). The study was designed as a double-blind, placebo-controlled, crossover investigation of 22 patients with CSU incompletely controlled by first-line antihistamine therapy. Results: Twenty patients completed the study. Supplemental therapy with DAO caused a 3.8 ± 1.2 point mean ± SEM UAS-7 score reduction in patients with low serum DAO levels at time 0 (p = 0.041 compared to placebo). The degree of UAS-7 improvement was inversely correlated with the levels of basal DAO (p = 0.019). Patients receiving DAO supplementation were able to slightly reduce their daily antihistamine dose (p = 0.049). Conclusion: These data suggest that DAO may be involved in the pathogenic cascade of CSU and that DAO supplementation could be effective for symptom relief in patients with low DAO levels in serum.

Background Omalizumab therapy is effective and safe in patients with chronic spontaneous urticaria (CSU) resistant to nonsedating histamine 1 (H 1 ) antihistamines (nsAHs). Objective To evaluate the efficacy and safety of omalizumab in elderly (aged ≥65 years) patients with nonsedating H 1 -antihistamine–refractory CSU in a real-life setting. Methods Patients with nonsedating H 1 -antihistamine–refractory CSU (n = 322) treated with omalizumab administered every 4 weeks in doses of 300 mg for 24 weeks were divided into 2 groups according to age at omalizumab treatment onset: 15 to 64 years and 65 years or older. Treatment response was assessed using a 7-day urticaria activity score (UAS7). Adverse effects of omalizumab therapy were recorded. Results Among patients, 32 (9.9%) were 65 years or older. At baseline, CSU characteristics were generally similar among the groups, although the presence of angioedema was statistically significantly lower in patients younger than 65 years. Any differences in weekly itch severity score, hive score, and UAS7 between the 2 age groups were not significant at weeks 4, 12, and 24, with the exception of the hive score at 24 weeks and the UAS7 at week 24. No significant between-group differences were seen in the proportion of patients with a UAS7 of 6 or lower and with a UAS7 score of 0 at weeks 4, 12, 24, and 40. The proportion of patients with at least one adverse event reported as suspected to be caused by study drug was 10% in the younger group vs 6.3% in the older group ( P = .53). Conclusion Our study found that omalizumab is a well-tolerated and effective therapy for elderly patients with nonsedating H 1 -antihistamine–refractory CSU.

Despite being the second least represented granulocyte subpopulation in the circulating blood, eosinophils are receiving a growing interest from the scientific community, due to their complex pathophysiological role in a broad range of local and systemic inflammatory diseases as well as in cancer and thrombosis. Eosinophils are crucial for the control of parasitic infections, but increasing evidence suggests that they are also involved in vital defensive tasks against bacterial and viral pathogens including HIV. On the other side of the coin, eosinophil potential to provide a strong defensive response against invading microbes through the release of a large array of compounds can prove toxic to the host tissues and dysregulate haemostasis. Increasing knowledge of eosinophil biological behaviour is leading to major changes in established paradigms for the classification and diagnosis of several allergic and autoimmune diseases and has paved the way to a “golden age” of eosinophil-targeted agents. In this review, we provide a comprehensive update on the pathophysiological role of eosinophils in host defence, inflammation, and cancer and discuss potential clinical implications in light of recent therapeutic advances.

Summary: Background. Histamine release (HR) test has previously been shown to predict the presence of endogenous histamine-releasing factors in chronic spontaneous urticaria (CSU). Objectives and methods. Twenty CSU patients unresponsive to antihistamine treatment were enrolled in order to evaluate the correlations between HR test results and demographic features, quality of life, disease activity, clinical course, and autologous serum and plasma skin tests (ASST and APST). Results. All patients with positive HR test (9/9, 100%) had a more severe disease activity at onset (urticaria activity score, UAS > 2) when compared to negative HR test patients (5/11; p = 0.04). Quality of life questionnaire's results were not substantially different between HR positive and negative subgroups at baseline (p > 0.05), and results of HR test and ASST/APST did not co-segregate (p > 0.05). After 12 months, patients with a positive HR test had a significant reduction of disease activity (p = 0.003) whereas patients with a negative HR test did not (p > 0.05), leading to disease remission and antihistamine treatment withdrawal in 67% (6/9) of positive HR test patients versus 18% (2/11) of negative HR test patients (p = 0.027). Conclusions. Positive HR test may predict spontaneous CSU remission at 12 months.

The most common allergic diseases, and especially the respiratory disorders such as rhinitis and asthma, are closely related to the allergic inflammation elicited by the causative allergen. This makes inflammation the main target of anti-allergic therapies. Among the available treatments, allergen specific immunotherapy (AIT) has a patent effect on allergic inflammation, which persists also after its discontinuation, and is the only therapy able to modify the natural history of allergy. The traditional, subcutaneous route of administration was demonstrated to modify the allergen presentation by dendritic cells (DCs) that in turn correct the phenotype of allergen-specific T cells, switching from the Th2-type response, typical of allergic inflammation and characterized by the production of IL-4, IL-5, IL-13, IL-17, and IL-32 cytokines to a Th1-type response. This immune deviation is related to an increased IFN-gamma and IL-2 production as well as to the anergy of Th2 or to tolerance, the latter being related to the generation of allergen-specific T regulatory (Treg) cells, which produce cytokines such as IL-10 and TGF-beta. Anti-inflammatory mechanisms observed during sublingual AIT with high allergen doses proved to be similar to subcutaneous immunotherapy. Data obtained from biopsies clearly indicate that the pathophysiology of the oral mucosa, with particular importance for mucosal DCs, plays a crucial role in inducing tolerance to the administered allergen.

During the 80' and the 90's, the role of pulmonary rehabilitation (PR) was still not clearly demonstrated. The following development of PR was mainly due to the increasing number of clinical studies providing proofs of its effectiveness, and convincing physicians, institutions, and regulatory agencies about its additional value to conventional pharmacological therapies. In the later years, PR has become an evidence-based non pharmacological treatment, designed for patients suffering from chronic obstructive lung disease (COPD). In the pulmonary rehabilitation programs (PRPs), exercise is essential for improving muscular tone and thus reducing disability. This later is due to chronic breathlessness, fatigue, and impairment of daily activities, that cause a reduction in functional performance and quality of life (QoL) in COPD patients. PRPs include also educational, psychosocial and nutritional interventions, so that it becomes a multifaceted approach. Despite the existing consciousness that PR results in improvement of exercise tolerance, dyspnea, and QoL, it is under prescribed by most health professionals, and only about 2% of COPD patients undergo PRPs. An appropriate consideration of the PR is essential to ensure optimal management of COPD, in particular when patients have respiratory symptoms that lead to a decrease in physical activity.

The present document is the result of a consensus reached by a panel of experts from European and nonEuropean countries on Occupational Rhinitis (OR), a disease of emerging relevance, which has received little attention in comparison to occupational asthma. The document covers the main items of OR including epidemiology, diagnosis, management, socio-economic impact, preventive strategies and medicolegal issues. An operational definition and classification of OR tailored to that of occupational asthma, as well as a diagnostic algorithm based on steps allowing different levels of diagnostic evidence, are proposed. The needs for future research are pointed out. Key messages are issued for each item.

Subjects with occupational asthma (OA) are often left with permanent sequelae after removal from exposure, and assessing their impairment/disability should utilise various tools. The aim of the present study was to examine whether: 1) assessment of inflammation in induced sputum is relevant to impairment; and 2) use of questionnaires on quality of life and psychological factors can be useful for the evaluation of disability. In total, 40 subjects were prospectively assessed for permanent impairment/disability due to OA 2 yrs after cessation of exposure. Impairment was assessed as follows: 1) need for asthma medication; 2) asthma severity; 3) airway calibre and responsiveness; and 4) degree of inflammation in induced sputum. Disability was assessed according to quality of life and psychological distress. There was a significant improvement in airway responsiveness and inflammation from diagnosis to the present assessment. Sputum eosinophils > or =2% and neutrophils >60% were present in eight (20%) and 12 (30%) out of all subjects, respectively, one or the other feature being the only abnormalities in 15% of subjects. Quality of life was moderately affected and there was a prevalence of depression and anxiety close to 50%. In the assessment of subjects with occupational asthma, information on airway inflammation and psychological impacts are relevant to the assessment of impairment/disability, although these findings need further investigation.

Food hypersensitivity is characterized by a wide range of symptoms. The relationship between symptoms and food is more frequently suspected than objectively proven. Basophil activation test (BAT) is based on the evaluation of activation markers on blood basophils in vitro stimulated with drugs or allergens. The aim of the study was to evaluate the usefulness of BAT when introduced in the routine work-up of suspected food hypersensitivity.BAT was requested in subjects with food adverse reactions when a discrepancy existed among history and skin prick test (SPT) and/or specific IgE. Data from 150 subjects were analysed using CD63 as basophil activation marker. Thirty controls were evaluated for cut-offs. Immunoblots was performed with the sera of representative subjects positive for BAT and negative for SPT and sIgE.1,024 BAT were carried out, the agreement (positive/positive and negative/negative) was 78.5% for BAT vs. SPT and 78.3% for BAT vs. IgE. Atopic patients, but not atopic controls, more frequently had a positive BAT than non-atopic patients (P 0.0001). Among subjects with positive BAT, those with negative sIgE had lower total IgE, P = 0.001. Nearly 23.3% of all subjects had positive BAT (for at least one tested food) and both negative sIgE and SPT. Immunoblots revealed the presence of sIgE for the tested foods in representative patients with positive BAT, negative SPT and sIgE.Introduction of BAT in routine of food hypersensitivity, limited to subjects with a discrepancy between history and traditional tests, might be useful particularly when total IgE are low. © 2015 International Clinical Cytometry Society.

Table S1. Allergy characterization of the study population.

Food allergy has an increasing prevalence in the general population and in Italy concerns 8 % of people with allergies. The spectrum of its clinical manifestations ranges from mild symptoms up to potentially fatal anaphylactic shock. A number of patients can be diagnosed easily by the use of first- and second-level procedures (history, skin tests and allergen specific IgE). Patients with complex presentation, such as multiple sensitizations and pollen-food syndromes, frequently require a third-level approach including molecular diagnostics, which enables the design of a component-resolved sensitization profile for each patient. The use of such techniques involves specialists' and experts' skills on the issue to appropriately meet the diagnostic and therapeutic needs of patients. Particularly, educational programs for allergists on the use and interpretation of molecular diagnostics are needed.

Buckwheat allergy is considered a rare food allergy outside of Asia. In Europe, buckwheat has been described mainly as a hidden allergen. Data on the prevalence of buckwheat hypersensitivity in non-Asian countries is very poor. The aim of this multicenter study was to evaluate the prevalence of buckwheat sensitization and its association with other sensitizations among patients referred to allergy clinics in different geographic areas of Italy. All patients referred to 18 Italian allergy clinics from February through April 2011 were included in the study and evaluated for sensitization to buckwheat and other allergens depending on their clinical history. A total of 1,954 patients were included in the study and 61.3 percent of them were atopic. Mean prevalence of buckwheat sensitization was 3.6 percent with significant difference between Northern (4.5 percent), Central (2.2 percent) and Southern (2.8 percent) regions. This is, to our knowledge, the largest epidemiological survey on buckwheat allergy reported outside of Asia. Buckwheat is an emerging allergen in Italy, being more frequently associated to sensitization in Northern regions.

Allergen immunotherapy (AIT) has the exclusive ability to modify the natural history of allergy and to maintain its clinical efficacy also after stopping the treatment. This occurs because of the AIT mechanism of action, mainly consisting in a specific induction of tolerance to the causative allergen. Such tolerance takes place as a result of a complex interaction of innate and adaptive immunity processes, that involve inflammatory cells, cytokines and chemokines. The first response to allergens is provided by the antigen-presenting cells, and particularly by dendritic cells (Dcs) that, following activation, acquire chemokine receptors (CCRs), useful for migration to lymphoid organs, where adaptive immune response is induced. DCs act by presenting the antigen(s) to effectors T cells (T helper CD4 + and T suppressor CD8 +) derived from naïve T cells. The development of different cell subtypes from naïve T cells (Th0) may follow various pathways and depends on both individual genetic background (atopic/non atopic) and environmental factors. The T cell response in atopic subjects is influenced by the Th2 polarization promoting the production of cytokines such as IL-4 and IL- 5. On the contrary, the expression of CD80 may determine a Th1 cytokines production, and ICOS-L supports the Tregulatory cells activation that significantly reduce allergic inflammation. The suppressive effect of Treg is due to the expression of high level of the transcription factor Foxp3 on their surface, to the production of IL-10 and TGF-ß and to the expression of membrane molecules as CTL-4 PD-1 and BTLA. Recent advances highlighted a role also for Th9 and Th17 lymphocytes. Such immunologic modification leads to the long noted events in studies on mechanisms of action, such as the decrease of specific IgE and the increase of specific IgG1 and IgG4, and ultimately on the inhibition of inflammatory cells such as mast cells, basophils and eosinophils and on the control of clinical symptoms.