Effectiveness and safety of dupilumab in patients with chronic rhinosinusitis with nasal polyps and associated comorbidities: a multicentric prospective study in real life.

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.

The effect of allergen immunotherapy in the onset of new sensitizations: a meta-analysis.

BACKGROUND: Although the preventive efficacy of allergen immunotherapy (AIT) in the onset of new allergen sensitizations has been asserted by many reviews, position papers, and consensus conferences, the evidence available is from only 3 studies. The objective of this work was a systematic review to evaluate the preventive efficacy of AIT in the onset of new allergen sensitizations. The end-point was the risk difference (RD) in the onset of new allergen sensitizations between patients treated with AIT and pharmacotherapy. METHODS: Computerized bibliographic searches of MEDLINE, EMBASE, and the Cochrane Library (until November 30th, 2016) were done. Random-effects and fixed-effects model meta-analyses were performed. Randomized controlled trials or observational studies comparing children treated with AIT with house dust mite (HDM) to subjects who did not receive AIT, with a long-term observation period (at least 3 years including treatment and follow-up) have been included. RESULTS: Eight studies totaling 721 children (390 treated with AIT and 331 with pharmacotherapy) met the inclusion criteria. The risk of bias was high. Low evidence supports the conclusion that AIT prevents the onset of new allergen sensitizations, with 3 of 8 studies reporting a reduction in the onset of new sensitizations in patients treated with AIT vs pharmacotherapy. Our meta-analysis found no difference between AIT and pharmacotherapy, with high heterogeneity (RD, -0.10; 95% confidence interval [CI], -0.31 to 0.11; p = 0.32; I2 = 91.4%). CONCLUSION: The data of this systematic review do not support a preventive effect in the onset of new allergen sensitizations, in children treated with AIT in comparison with those treated with pharmacotherapy.

Efficacy of Grass Pollen Allergen Sublingual Immunotherapy Tablets for Seasonal Allergic Rhinoconjunctivitis: A Systematic Review and Meta-analysis.

IMPORTANCE: Randomized clinical trials (RCTs) and meta-analyses of sublingual immunotherapy (SLIT) for the treatment of seasonal allergic rhinoconjunctivitis (SARC) have shown a modest clinical benefit compared with placebo. Furthermore, indirect comparison by meta-analyses showed that subcutaneous immunotherapy is more effective than SLIT. Despite these data, SLIT has become the most prescribed treatment of SARC in Europe in recent years, and it was approved by the US Food and Drug Administration for the treatment of SARC to grass pollen in the United States on April 1, 2014. OBJECTIVE: To assess the efficacy and safety of the grass pollen sublingual tablets licensed as drugs in the treatment of patients with SARC to grass pollen. DATA SOURCES: Computerized bibliographic searches of MEDLINE, EMBASE, the Cochrane Library, and ClinicalTrials.gov (from inception to April 30, 2014) were supplemented with a manual search of reference lists. STUDY SELECTION: Randomized clinical trials were included if they compared the grass pollen SLIT tablets approved by regulatory authorities in the European Union and the United States for SARC with placebo. DATA EXTRACTION AND SYNTHESIS: Data on populations, interventions, and outcomes were extracted from each RCT according to the intent-to-treat method by 2 independent observers and were combined using the method by DerSimonian and Laird. MAIN OUTCOMES AND MEASURES: The primary end point was the difference in the symptom score and medication score between SLIT and placebo. We pooled data using random-effects meta-analysis, with standardized mean differences (SMDs) and 95% CIs reported. RESULTS: Data were available in 13 RCTs for the symptom score (4659 patients) and in 12 RCTs for the medication score (4558 patients). We found a small treatment benefit in the symptom score (SMD, -0.28; 95% CI, -0.37 to -0.19; P < .001) and in the medication score (SMD, -0.24; 95% CI, -0.31 to -0.17; P < .001). Adverse events were reported in 1384 of 2259 patients (61.3%) receiving SLIT and in 477 of 2279 patients (20.9%) receiving placebo. Seven patients in the SLIT group reported treatment-related adverse events requiring epinephrine. CONCLUSIONS AND RELEVANCE: Findings show a small benefit of the grass pollen sublingual tablets in reducing symptoms and in decreasing the use of symptomatic medication (antihistamines and corticosteroids) in patients with SARC. Considering the low magnitude of the benefit, the convenience and easy administration do not seem to be sufficient reasons for the choice of SLIT.

Assessment of a qualitative serological assay to screen for allergic sensitization in elderly subjects.

We used a commercially available specific IgE qualitative serological assay to screen for allergic sensitization. Two hundred twenty-eight elderly subjects took part in the study. Skin-prick tests (SPTs) to a panel of relevant aeroallergens present in the study area were used as the diagnostic reference procedure (gold standard). Subjects with at least one positive SPT (≥3 mml n = 76) were considered to have developed an allergic sensitization. The qualitative assay correctly classified subjects as sensitized to an allergen or not sensitized in 257 of 288 cases (accuracy, 88.9%; 95% CI, 85.0-92.0%). The qualitative assay sensitivity was 70.0 (95% CI, 58.1-79.7) and specificity was 95.7 (95% CI, 92.1-98.0), positive predictive value (PPV) was 85.4 (95% CI, 85.1-93.4), negative predictive value (NPV) was 89.8 (95% CI, 85.1-93.4), positive likelihood ratio (LR(+)) was 16.5 (95% CI, 8.7-31.6), negative LR (LR(-)) was 0.31 (95% CI, 0.21-0.43), and the diagnostic odds ratio (DOR) was 52.2 (95% CI, 21.5-133.6). In the elderly subjects with respiratory symptoms, the qualitative assay correctly classified subjects as allergen sensitized or nonsensitized in 81 of 89 cases (accuracy, 91.0; 95% CI, 85.0-96.9). In this subgroup, the qualitative assay sensitivity was 94.6 (95% CI, 85.1-98.8), specificity was 84.8 (95% CI, 68.1-94.9), PPV was 91.3 (95% CI, 81.0-97.1), and NPV was 90.3 (95% CI, 74.2-97.9). LR(+) was 6.2 (95% CI, 3.0-14.2), LR(-) was 0.06 (95% CI, 0.02-0.17), and the DOR was 98.9 (95% CI, 18.0-621.4). The qualitative serological assay is a valuable tool for the diagnosis of allergic sensitization in a population of elderly subjects.

Chronic spontaneous urticaria: an autoimmune disease? A revision of the literature.

The cause of chronic spontaneous urticaria has been an enigma for decades, but the recognition of functional autoantibodies in some patients with the spontaneous chronic urticaria has opened up a new concept of autoimmune urticaria. Clinical and laboratory features are in keeping with an autoimmune aetiology for many patients with otherwise inexplicable disease, but there is still debate about the importance of functional autoantibodies in the disease pathogenesis, how to test them and the clinical implications for treatment and prognosis. This review will look at the evidence for there being an autoimmune subset of urticaria, the strengths and weaknesses of the available tests in current use.

Clinical course of rhinitis and changes in vivo and in vitro of allergic parameters in elderly patients: a long-term follow-up study.

Changes in rhinitis symptom severity tend to decrease with aging, but whether the decrease is associated with allergic skin test reactivity, serum total and specific IgE, and nasal eosinophils or determined only by aging is poorly understood. The aim of the study was to analyze sensitivity in vivo and in vitro some 15 years after primary testing, skin prick test (SPT), serum total and specific IgE, ratio sIgE/tIgE, and nasal eosinophils in order to evaluate changes due to age and changes due to the severity of rhinitis symptoms. One hundred and eight rhinitis patients who had been investigated in 1995 were re-interviewed and their current allergy re-assessed after a follow-up of 15 years. All patients were SPT with eight common allergens in the area of Palermo (Italy). Rhinitis symptoms tended, on average, to have become milder at the follow-up. All parameters examined showed a decreasing trend in older age groups over the period between the two investigations. Rhinitis symptoms tend to become milder and the allergic parameters both in vivo and in vitro usually decrease in the long run; however, the changes in rhinitis symptoms appear to be related to changes in the nasal eosinophils, independently of SPT and serum-specific IgE.

Efficacy of subcutaneous and sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a meta-analysis-based comparison.

BACKGROUND: Subcutaneous (SCIT) and sublingual (SLIT) immunotherapy are the 2 most prescribed routes for administering allergen-specific immunotherapy. They were shown to be effective in control of symptoms and in reducing rescue medication use in patients with allergic diseases, but their effectiveness has to be balanced against side effects. In recent years, SLIT has been increasingly prescribed, instead of SCIT, because of improved safety and easy administration. OBJECTIVE: We assessed which route is the most effective in the treatment of patients with seasonal allergic rhinitis to grass pollen. METHODS: An indirect meta-analysis-based comparison between SCIT and SLIT was performed. Treatment efficacy was determined as the standardized mean difference (SMD) in symptom and medication scores obtained with active treatment, SCIT or SLIT, compared with placebo. Studies were included if they were double-blind randomized controlled trials comparing SCIT or SLIT with placebo. Thirty-six randomized controlled trials (3014 patients; 2768 controls) were analyzed. RESULTS: The overall effect size of SCIT for symptom score (SMD, -0.92; 95%CI, -1.26 to -0.58) was significantly higher than SLIT, both administered via drops (SMD, -0.25; 95% CI, -0.45 to -0.05) and tablets (SMD, -0.40; 95%CI, -0.54 to -0.27). Similar results were reported for medication score (SCIT: SMD, -0.58; 95% CI, -0.86 to -0.30. SLIT drops: SMD, -0.37; 95% CI, -0.74 to -0.00. SLIT tablets SMD, -0.30; 95% CI, -0.44 to -0.16). CONCLUSIONS: Our results provide indirect but solid evidence that SCIT is more effective than SLIT in controlling symptoms and in reducing the use of antiallergic medications in seasonal allergic rhinoconjuntivitis to grass pollen.

Prevalence of sensitization to Anisakis simplex among professionally exposed populations in Sicily.

Anisakis simplex (AS) is a cause of allergic sensitization and potential occupational risk is suggested in fishermen and workers assigned to fish processing and sale. A cross-sectional study was conducted in order to assess possible health effects of occupational exposure to AS in workers recruited from western Sicily fisheries sector. Social, demographic, and occupation-related data were collected. Serum total immunoglobulin E (IgE) and specific IgE levels to AS (threshold >0.35 kU/L) were determined by an fluoroimmunoassay technique. Ninety-four subjects with potential occupational exposure (fishmongers, fishermen, fish industry employees) were recruited. Specific AS IgEs were detected in 20.2% of the study population. AS IgE seroprevalence was elevated 6.7-fold (p = .03) among fishermen/sailors compared with fish industry workers. The study suggested the importance to adopt specific prevention strategies against exposure to AS in the occupational setting.

Differences and similarities between allergic and nonallergic rhinitis in a large sample of adult patients with rhinitis symptoms.

BACKGROUND: Allergic rhinitis (AR) and nonallergic rhinitis (NAR) may present with different clinical and laboratory characteristics. METHODS: A total of 1,511 consecutive patients, aged 18-81 years, diagnosed with rhinitis, 56% females and 44% males, underwent complete allergic evaluation including skin prick test, blood eosinophil counts, nasal eosinophil counts, peak nasal inspiratory flow (PNIF) measurement and evaluation of nasal symptoms using a visual analog scale (VAS). RESULTS: A total of 1,107 patients (73%)had AR, whereas 404 (27%) had NAR. Patients with NAR were older and predominantly female. A higher nasal eosinophils count was associated with AR and a lack of clinical response to antihistamines. AR patients had more sneezing and nasal pruritus, whereas NAR was characterized mainly by nasal obstruction and rhinorrhea. AR patients had more severe symptoms and recurrent conjunctivitis, whereas NAR patients had slightly more frequent episodes of recurring headaches as well as olfactory dysfunction. PNIF, blood eosinophil counts and VAS of nasal symptoms were higher in patients with AR. In a final logistic regression model, 10 variables were statistically different between AR and NAR: age [OR 0.97 (95% CI 0.96-0.98)], sneezing [OR 4.09 (95% CI 2.78-6.00)], nasal pruritus [OR 3.84 (95% CI 2.60-5.67)], mild symptoms [OR 0.21 (95% CI 0.09-0.49)], intermittent/severe nasal symptoms [OR 3.66 (95% CI 2.06-6.50)], VAS [OR 1.06 (95% CI 1.04-1.08)], clinical response to antihistamines [OR 22.59 (95% CI 13.79-37.00)], conjunctivitis [OR 4.49 (95% CI 2.86-7.05)], PNIF [OR 1.01 (95% CI 1.00-1.01)] and nasal eosinophil counts [OR 1.14 (95% CI 1.10-1.18)]. Receiver operating characteristic analysis showed high predictive accuracy for a model including these variables independently of the diagnosis of AR/NAR (cutoff <0.74). CONCLUSIONS: We showed that the several clinical and laboratory parameters reported above may help to reinforce or exclude the diagnosis of AR obtained with skin prick test.

Polymorphisms of cyclo-oxygenases and 5-lipo-oxygenase-activating protein are associated with chronic spontaneous urticaria and urinary leukotriene E4.

The mechanisms of chronic spontaneous urticaria (CSU) continue to be unknown. Our working hypothesis is that polymorphisms of cyclo-oxygenases and 5-lipo-oxygenase-activating protein may be involved in the pathways leading to CSU. We examined five candidate polymorphisms of cyclo-oxygenases 1 and 2 and of 5-lipo-oxygenase-activating protein in 109 controls and in 94 CSU patients from Northern Italy. We also examined the levels of urinary leukotriene E4 (LTE4) before and after challenge with ASA. A multiple regression model was found to show that COX-2 5'UTR T/G, COX-2 Exon 10 T/C, and FLAP -336 G/A polymorphisms were significantly associated with CSU, with the minor allele more represented in CSU group. Similar results were obtained as regards the specific association with ASA-tolerated CSU and ASA-exacerbated CSU. Evaluating a polygenic model, reflecting the sum of the concomitant alleles associated with CSU (i.e. COX-2 5'UTR G allele, COX-2 Exon 10 C allele, and FLAP -336 G/A allele), the proportion of CSU patients increased progressively with the increasing number of unfavourable alleles. Finally, in a linear regression model after adjustment for disease status COX-1 22 T carriership remained a significant predictor of post-challenge high urinary LTE4 levels. Our results support the hypothesis that polymorphisms of cyclo-oxygenases and 5-lipo-oxygenase-activating protein may be associated with CSU.

Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: a systematic review and meta-analysis.

BACKGROUND: The benefit of sublingual immunotherapy (SLIT) with grass allergens for seasonal allergic rhinitis has been extensively studied, but data on efficacy are still equivocal. OBJECTIVE: To assess the effectiveness of SLIT with grass allergens in the reduction of symptoms and medication in patients with seasonal allergic rhinitis to grass pollen. METHODS: Computerized bibliographic searches of MEDLINE (1995-2010) were supplemented by hand searches of reference lists. Studies were included if they were double-blind randomized controlled trials (RCTs) comparing SLIT to placebo and if they included patients with history of allergy to grass pollen treated with natural grass pollen extracts. Nineteen RCTs with 2971 patients were analyzed. The outcomes assessed were symptom and medication scores. RESULTS: Using a random-effects model, SLIT with grass allergens significantly reduces both symptoms (standardized mean difference, -0.32; 95% CI, -0.44 to -0.21) and medication use (standardized mean difference, -0.33; 95% CI, -0.50 to -0.16) compared with placebo. The treatment is more efficacious in adults than in children. Prolonging duration of preseasonal treatment for more than 12 weeks improves the treatment efficacy. CONCLUSION: This meta-analysis found that SLIT with grass allergens is effective in patients with seasonal allergic rhinitis compared with placebo. The benefit is clinically modest, and criteria are needed to identify patients most likely to benefit from SLIT.

Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy.

BACKGROUND: To date, no predictive tests for the clinical response to allergen-specific immunotherapy (ASI) are available. Therefore an in vivo or in vitro test would be of great value. OBJECTIVE: We sought to evaluate pretreatment parameters used in diagnosing allergic rhinitis and determining serum specific IgE (s-IgE) levels, serum total IgE (t-IgE) levels, and blood eosinophil counts and to identify whether can be used to predict clinical improvement in monosensitized patients with allergic rhinitis with or without asthma treated with immunotherapy. METHODS: We analyzed 279 patients who had undergone 4 years of ASI administered either by means of the subcutaneous immunotherapy (76 patients) or sublingual immunotherapy (203 patients) routes. Serum t-IgE and s-IgE levels, blood eosinophil counts, and serum s-IgE/t-IgE ratios were calculated and tested for correlation with clinical response to ASI. Receiver operating characteristic curves were determined. Predicted probabilities and predictive areas under the curve were calculated. RESULTS: The clinical response to ASI was effective in 145 (52.0%) of 279 total patients, 42 (55.2%) of 76 patients treated with subcutaneous immunotherapy, and 103 (50.7%) of 203 patients treated with sublingual immunotherapy. A significant correlation was found between the serum s-IgE/t-IgE ratio and the clinical response to ASI, with high ratios (>16.2) associated with an effective response. The sensitivity and specificity of the area under the curve of the ratio were higher than those of serum s-IgE and t-IgE alone. CONCLUSION: The calculation of the serum s-IgE/t-IgE ratio for predicting the clinical response to ASI offers an advantage over measuring t-IgE and s-IgE levels in monosensitized patients for the following allergens: grass, Parietaria judaica, Olea europea, and house dust mite.

Leukotriene receptor antagonists in monotherapy or in combination with antihistamines in the treatment of chronic urticaria: a systematic review.

In vitro and in vivo clinical and experimental data have suggested that leukotrienes play a key role in inflammatory reactions of the skin. Antileukotriene drugs, ie, leukotriene receptor antagonists and synthesis inhibitors, are a class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma and in rhinitis with asthma. We searched MEDLINE database and carried out a manual search on journals specializing in allergy and dermatology for the use of antileukotriene drugs in urticaria. Montelukast might be effective in chronic urticaria associated with aspirin (ASA) or food additive hypersensitivity or with autoreactivity to intradermal serum injection (ASST) when taken with an antihistamine but not in mild or moderate chronic idiopathic urticaria [urticaria without any possible secondary causes (ie, food additive or ASA and other NSAID hypersensitivity, or ASST)]. Evidence for the effectiveness of zafirlukast and the 5-lipoxygenase inhibitor, zileuton, in chronic urticaria is mainly anecdotal. In addition, there is anecdotal evidence of effectiveness of antileukotrienes in primary cold urticaria, delayed pressure urticaria and dermographism. No evidence exists for other physical urticarias, including cholinergic, solar and aquagenic urticarias, vibratory angioedema, and exercise-induced anaphylaxis.

The characteristics of different diagnostic tests in adult mild asthmatic patients: comparison with patients with asthma-like symptoms by gastro-oesophageal reflux.

BACKGROUND: Diagnosing asthma cannot be always easy. It is important to consider the validity of the diagnostic tests, and/or how much more commonly they are positive in patients with asthma compared to healthy subjects and, particularly, to patients with asthma-like symptoms. OBJECTIVE: To evaluate the validity of diagnostic tests for asthma, in terms of sensitivity, specificity, positive and negative predictive values, in patients with bronchial asthma compared to patients affected by gastro-oesophageal reflux disease (GERD) with asthma-like symptoms, and healthy control subjects without asthma and gastro-oesophageal reflux (GER). DESIGN: Single-center, cross-sectional, observational study. PATIENTS: We studied 60 patients with mild asthma, 30 patients with GERD and asthma-like symptoms and 25 healthy control subjects. MEASUREMENTS: We measured provocative concentration of methacholine causing a 20% fall in the forced expiratory volume in 1s (MCh PC(20)/FEV(1)), the amplitude percent mean of peak expiratory flow (A%M of PEF), derived from twice-daily readings for >2 weeks, the FEV(1)/forced vital capacity (FEV(1)/FVC) ratio, the eosinophil count in blood and in induced sputum and the serum eosinophil cationic protein (ECP) levels. RESULTS: FEV(1)/FVC ratio, A%M of PEF, blood eosinophils counts and serum ECP levels were less sensitive and specific when the reference population was composed of patients with asthma-like symptoms by GER. While, MCh PC(20)/FEV(1) and induced sputum eosinophils count were the most sensitive (both 90%) and specific (89% and 92%, respectively) tests. CONCLUSION: Our findings demonstrate that MCh PC(20)/FEV(1) and the induced sputum eosinophil count are the most useful objective tests in patients with mild asthma. All patients with asthma presented both an MCh PC(20)/FEV(1) <1500 microg and eosinophils count in the induced sputum >1%.

Food-additive-induced urticaria: a survey of 838 patients with recurrent chronic idiopathic urticaria.

BACKGROUND: Recurrent chronic idiopathic urticaria (RCIU) is a common skin condition that affects 0.1-3% of the population in the USA and Europe and accounts for nearly 75% of all 'ordinary' chronic urticaria (CU) cases. METHODS: We studied 838 consecutive patients with RCIU referred to hospital between 1998 and 2003. Patients with known causes of CU were excluded. Clinical history, physical examination, and symptom diaries were evaluated during two periods, a diet-free period (1 week) and a food-additive-free diet (FAFD) period (4 weeks), respectively, and two double-blind placebo-controlled (DBPC) challenges of six food additives were administered. The first DBPC challenge included a mixture of the six food additives (DBPCmixed) given to all patients. The second DBPC challenge comprised the single food additives, administered at increasing doses (DBPCsingle) to patients with a positive DBPCmixed test and 105 patients with a negative DBPCmixed test, as a control. RESULTS: The DBPCmixed challenge was positive in 116 patients. None of the 105 control patients had a positive DBPCsingle test. Only 31 DBPCsingle tests were positive in patients with positive DBPCmixed challenge. Twenty-four of the 116 patients showing a positive DBPCmixed challenge also had a positive DBPCsingle result. CONCLUSIONS: Our results confirmed that food additive hypersensitivity reactions occurred in few RCIU patients using DBPCsingle challenge. The combination of the results of FAFD and DBPCmixed challenge seems to be of considerable practical interest for allergists, internists and dermatologists, rather than the data of clinical history and the results of DBPCsingle challenge, in patients with RCIU.