First-in-human phase 2 trial with mite allergoids coupled to mannan in subcutaneous and sublingual immunotherapy.

BACKGROUND: Polymerized allergens conjugated to non-oxidized mannan (PM-allergoids) are novel vaccines targeting dendritic cells (DCs). Previous experimental data indicate that PM-allergoids are readily taken up by DCs and induce Treg cells. This first-in-human study was aimed to evaluate safety and to find the optimal dose of house dust mite PM-allergoid (PM-HDM) administered subcutaneously (SC) or sublingually (SL). METHODS: In a randomized, double-blind, double-dummy, placebo-controlled trial, 196 subjects received placebo or PM-HDM at 500, 1000, 3000, or 5000 mannan-conjugated therapeutic units (mTU)/mL in 9-arm groups for 4 months. All subjects received 5 SC doses (0.5 ml each) every 30 days plus 0.2 ml SL daily. The primary efficacy outcome was the improvement of titrated nasal provocation tests (NPT) with D. pteronyssinus at baseline and at the end of the study. All adverse events and reactions were recorded and assessed. Secondary outcomes were the combination of symptom and medication scores (CSMS) and serological markers. RESULTS: No moderate or severe adverse reactions were reported. Subjects improving the NPT after treatment ranged from 45% to 62% in active SC, 44% to 61% in active SL and 16% in placebo groups. Statistical differences between placebo and active groups were all significant above 500 mTU, being the highest with 3000 mTU SL (p = 0.004) and 5000 mTU SC (p = 0.011). CSMS improvement over placebo reached 70% (p < 0.001) in active 3000 mTU SC and 40% (p = 0.015) in 5000 mTU SL groups. CONCLUSIONS: PM-HDM immunotherapy was safe and successful in achieving primary and secondary clinical outcomes in SC and SL at either 3000 or 5000 mTU/ml.

Bacterial Mucosal Immunotherapy with MV130 Prevents Recurrent Wheezing in Children: A Randomized, Double-Blind, Placebo-controlled Clinical Trial.

Rationale: Recurrent wheezing in children represents a severe public health concern. Wheezing attacks (WA), mainly associated with viral infections, lack effective preventive therapies. Objectives: To evaluate the efficacy and safety of mucosal sublingual immunotherapy based on whole inactivated bacteria (MV130) in preventing WA in children. Methods: A Phase 3 randomized, double-blind, placebo-controlled, parallel-group trial including a cohort of 120 children <3 years old with ⩾3 WA during the previous year was conducted. Children with a positive skin test to common aeroallergens in the area where the clinical trial was performed were excluded from the trial. Subjects received MV130 or placebo daily for 6 months. The primary endpoint was the number of WA within 1 year after the first dose comparing MV130 and placebo. Measurements and Main Results: There was a significant lower number of WA in MV130 versus the placebo group, 3.0 (interquartile range [IQR], 2.0-4.0) versus 5.0 (IQR, 3.0-7.0) (P < 0.001). As secondary outcomes, a decrease in the duration of WA and a reduction in symptoms and medication scores in the MV130 versus placebo group were found. No adverse events were reported related to the active treatment. Conclusions: Mucosal bacterial immunotherapy with MV130 shows safety and clinical efficacy against recurrent WA in children.Clinical trial registered with www.clinicaltrials.gov (NCT01734811).

Validation of the food allergy independent measure and the EuroPrevall food allergy quality of life questionnaire for children 8-12 years translated into Spanish.

BACKGROUND: Different questionnaires have been developed to measure quality of life (QoL) in patients with food allergy. Our aim was to validate a Spanish translation of the Food Allergy Independent Measure (FAIM) and the EuroPrevall Food Allergy Quality of Life Questionnaire-Child Form (FAQLQ-CF) for children aged 8-12 years. METHODS: Sixty children with a diagnosis of IgE-mediated allergy to food completed the questionnaires. The internal consistency was evaluated with Cronbach's alpha. The correlation of FAQLQ-CF with FAIM was assessed to test construct validity. We compared both values with the diagnosis of anaphylaxis to evaluate discriminant validity. RESULTS: Cronbach's alpha was in the range of 0.654-0.863 for the four domains of FAQLQ-CF and 0.779 for FAIM. There were no criteria to remove questions from the questionnaires. Significant correlations could be found between FAQLQ-CF and the number of offending foods and the impact on social life (all r > 0.33, P < 0.01), and between FAIM and anaphylaxis. CONCLUSIONS: The Spanish translation of FAQLQ-CF showed acceptable internal consistency, good construct validity, and capacity to discriminate patients depending on the number of foods to avoid and the impact on social life. FAIM showed good discriminant capacity for anaphylaxis.

Heterogeneity of pollen food allergy syndrome in seven Southern European countries: The @IT.2020 multicenter study.

BACKGROUND: Pollen food allergy syndrome (PFAS) is a frequently underdiagnosed disease due to diverse triggers, clinical presentations, and test results. This is especially relevant in geographic areas with a broad spectrum of pollen sensitization, such as Southern Europe. OBJECTIVES: To elucidate similarities and differences of PFAS in nine Southern European centers and identify associated characteristics and unique markers of PFAS. METHODS: As part of the @IT.2020 Multicenter Study, 815 patients with seasonal allergic rhinitis (SAR), aged 10-60 years, were recruited in seven countries. They completed questionnaires regarding SAR, comorbidities, family history, and PFAS, and underwent skin prick testing (SPT) and serum IgE testing. RESULTS: Of the 815 patients, 167 (20.5%) reported PFAS reactions. Most commonly, eliciting foods were kiwi (58, 34.7%), peach (43, 25.7%), and melon (26, 15.6%). Reported reactions were mostly local (216/319, 67.7%), occurring within 5 min of contact with elicitors (209/319, 65.5%). Associated characteristics included positive IgE to at least one panallergen (profilin, PR-10, or nsLTP) (p = 0.007), maternal PFAS (OR: 3.716, p = 0.026), and asthma (OR: 1.752, p = 0.073). Between centers, heterogeneity in prevalence (Marseille: 7.5% vs. Rome: 41.4%, p < 0.001) and of clinical characteristics was apparent. Cypress played a limited role, with only 1/22 SPT mono-sensitized patients reporting a food reaction (p < 0.073). CONCLUSIONS: PFAS is a frequent comorbidity in Southern European SAR patients. Significant heterogeneity of clinical characteristics in PFAS patients among the centers was observed and may be related to the different pollen sensitization patterns in each geographic area. IgE to panallergen(s), maternal PFAS, and asthma could be PFAS-associated characteristics.

Lurbinectedin versus pegylated liposomal doxorubicin or topotecan in patients with platinum-resistant ovarian cancer: A multicenter, randomized, controlled, open-label phase 3 study (CORAIL).

OBJECTIVE: The randomized phase 3 CORAIL trial evaluated whether lurbinectedin improved progression-free survival (PFS) compared to pegylated liposomal doxorubicin (PLD) or topotecan in patients with platinum-resistant ovarian cancer. METHODS: Patients were randomly assigned (1:1) to lurbinectedin 3.2 mg/m2 1-h i.v. infusion q3wk (experimental arm), versus PLD 50 mg/m2 1-h i.v. infusion q4wk or topotecan 1.50 mg/m2 30-min i.v. infusion Days 1-5 q3wk (control arm). Stratification factors were PS (0 vs. ≥1), prior PFI (1-3 months vs. >3 months), and prior chemotherapy lines (1-2 vs. 3). The primary endpoint was PFS by Independent Review Committee in all randomized patients. This study was registered with ClinicalTrials.gov, NCT02421588. RESULTS: 442 patients were randomized: 221 in lurbinectedin arm and 221 in control arm (127 PLD and 94 topotecan). With a median follow-up of 25.6 months, median PFS was 3.5 months (95% CI, 2.1-3.7) in the lurbinectedin arm and 3.6 months (95% CI, 2.7-3.8) in the control arm (stratified log-rank p = 0.6294; HR = 1.057). Grade ≥ 3 treatment-related adverse events (AEs) were most frequent in the control arm: 64.8% vs. 47.9% (p = 0.0005), mainly due to hematological toxicities. The most common grade ≥ 3 AEs were: fatigue (7.3% of patients) and nausea (5.9%) with lurbinectedin; mucosal inflammation (8.5%) and fatigue (8.0%) in the control arm. CONCLUSIONS: The primary endpoint of improvement in PFS was not met. Lurbinectedin showed similar antitumor efficacy and was better tolerated than current standard of care in patients with platinum-resistant ovarian cancer.

Defining challenge-proven coexistent nut and sesame seed allergy: A prospective multicenter European study.

BACKGROUND: Peanut, tree nut, and sesame allergies are responsible for most life-threatening food-induced allergic reactions. Rates of coexistent allergy between these foods have been from mostly retrospective studies that include only a limited number of tree nuts or were not based on oral food challenges. OBJECTIVE: The Pronuts study is a multicenter European study (London, Geneva, and Valencia) assessing the challenge-proven rate of coexistent peanut, tree nut, and/or sesame seed allergy. METHODS: Children aged 0 to 16 years with at least 1 confirmed nut or sesame seed allergy underwent sequential diagnostic food challenges to all other nuts and sesame seed. RESULTS: Overall, the rate of coexistent peanut, tree nut, and sesame seed allergy was 60.7% (n = 74/122; 95% CI, 51.4% to 69.4%). Peanut allergy was more common in London, cashew and pistachio nut allergies were more common in Geneva, and walnut and pecan allergies were more common in Valencia. Strong correlations were found between cashew-pistachio, walnut-pecan, and walnut-pecan-hazelnut-macadamia clusters. Age (>36 months) and center (Valencia > Geneva > London) were associated with an increased odds of multiple nut allergies. By pursuing the diagnostic protocol to demonstrate tolerance to other nuts, participants were able to introduce a median of 9 nuts. CONCLUSION: We found a higher rate of coexistent nut and sesame seed allergies than previously reported. Performing sequential food challenges was labor intensive and could result in severe allergic reactions; however, it reduced dietary restrictions. Age was a significant predictor of multiple nut allergies, and thus the secondary spread of nut allergies occurred in older children.

"Whole" vs. "fragmented" approach to EAACI pollen season definitions: A multicenter study in six Southern European cities.

BACKGROUND: The adequate definition of pollen seasons is essential to facilitate a correct diagnosis, treatment choice, and outcome assessment in patients with seasonal allergic rhinitis. A position paper by the European Academy of Allergy and Clinical Immunology (EAACI) proposed season definitions for Northern and Middle Europe. OBJECTIVE: To test the pollen season definitions proposed by EAACI in six Mediterranean cities for seven pollen taxa. METHODS: As part of the @IT.2020 multi-center study, pollen counts for Poaceae, Oleaceae, Fagales, Cupressaceae, Urticaceae (Parietaria spp.), and Compositae (Ambrosia spp., Artemisia spp.) were collected from January 1 to December 31, 2018. Based on these data, pollen seasons were identified according to EAACI criteria. A unified monitoring period for patients in AIT trials was created and assessed for feasibility. RESULTS: The analysis revealed a great heterogeneity between the different locations in terms of pattern and length of the examined pollen seasons. Further, we found a fragmentation of pollen seasons in several segments (max. 8) separated by periods of low pollen counts (intercurrent periods). Potential monitoring periods included often many recording days with low pollen exposure (max. 341 days). CONCLUSION: The Mediterranean climate leads to challenging pollen exposure times. Monitoring periods for AIT trials based on existing definitions may include many intermittent days with low pollen concentrations. Therefore, it is necessary to find an adapted pollen season definition as individual solution for each pollen and geographical area.

Double-blind, randomized, placebo-controlled trial of allergen-specific immunotherapy with the major allergen Alt a 1.

BACKGROUND: There have been few studies conducted on the efficacy and safety of specific immunotherapy with allergen extracts of fungi compared with other allergen extracts, and there are no data on the major allergen Alt a 1 of the fungus Alternaria alternata. OBJECTIVES: We sought to evaluate the efficacy and safety of subcutaneous immunotherapy with 2 different doses of Alt a 1 in patients with rhinoconjunctivitis caused by sensitization to A alternata. METHOD: We performed a multicenter, randomized, double-blind, placebo-controlled trial with Alt a 1 administered subcutaneously in patients with allergic rhinoconjunctivitis with or without controlled asthma aged 12 to 65 years. Three groups were included: the placebo group and active groups receiving 0.2 or 0.37 µg of Alt a 1 per dose. The main end point was the combined symptom and medication score. Secondary end points were cutaneous reactivity and serum IgE and IgG4 levels to Alt a 1. Recorded adverse reactions were graded according to World Allergy Organization criteria. RESULTS: There were significant reductions in the combined symptom and medication score for the 0.37-µg dose of Alt a 1 compared with placebo at 12 months of treatment. Reduced cutaneous reactivity and IgE levels, together with increased IgG4 levels, were demonstrated for the 2 active groups versus the placebo group. A similar safety profile was found for both active groups compared with the placebo group. No serious adverse drug reactions were reported. CONCLUSION: Immunotherapy with Alt a 1 was efficacious and safe, reducing the symptoms and medication consumption associated with rhinoconjunctivitis after only 1 year of treatment. The clinical benefits were associated with reduced skin reactivity and specific IgE levels and increased IgG4 levels.

Pediatric asthma: An unmet need for more effective, focused treatments.

BACKGROUND: Despite remarkable advances in our understanding of asthma, there are still several unmet needs associated with the management of pediatric asthma. METHODS: A two-day, face-to-face meeting was held in London, United Kingdom, on October 28 and 29, 2017, involving a group of international expert clinicians and scientists in asthma management to discuss the challenges and unmet needs that remain to be addressed in pediatric asthma. RESULTS: These unmet needs include a lack of clinical efficacy and safety evidence, and limited availability of non-steroid-based alternative therapies in patients <6 years of age. An increased focus on children is needed in the context of clinical practice guidelines for asthma; current pediatric practice relies mostly on extrapolations from adult recommendations. Furthermore, no uniform definition of pediatric asthma exists, which hampers timely and robust diagnosis of the condition in affected patients. CONCLUSIONS: There is a need for a uniform definition of pediatric asthma, clearly distinguishable from adult asthma. Furthermore, guidelines which provide specific treatment recommendations for the management of pediatric asthma are also needed. Clinical trials and real-world evidence studies assessing anti-immunoglobulin E (IgE) therapies and other monoclonal antibodies in children <6 years of age with asthma may provide further information regarding the most appropriate treatment options in these vulnerable patients. Early intervention with anti-IgE and non-steroid-based alternative therapies may delay disease progression, leading to improved clinical outcomes.

Current state and future of pediatric allergology in Europe: A road map.

The history of pediatric allergology (PA) in Europe is relatively youthful, dating back to 1984, when a small group of pediatricians founded the European Working Group on Pediatric Allergy and Immunology-later giving rise to ESPACI (European Society on Pediatric Allergology and Clinical Immunology). In 1990, the first dedicated journal, Pediatric Allergy and Immunology (PAI), was founded. There are striking differences across Europe, and even within European countries, in relation to the training pathways for doctors seeing children with allergic disease(s). In 2016, the EAACIClemens von Pirquet Foundation (CvP) organized and sponsored a workshop with the European Academy of Allergy and Clinical Immunology (EAACI) Pediatric Section. This collaboration focussed on the future of PA and specifically on education, research, and networking/ advocacy. The delegates representing many countries across Europe have endorsed the concept that optimal care of children with allergic diseases is delivered by pediatricians who have received dedicated training in allergy, or allergists who have received dedicated training in pediatrics. In order to meet the needs of children and families with allergic disease(s), the pediatric allergist is highly encouraged to develop several networks. Our challenge is to reinforce a clear strategic approach to scientific excellence to across our member base and to ensure and enhance the relevance of European pediatric research in allergy. With research opportunities in basic, translational, clinical, and epidemiologic trials, more trainees and trained specialists are needed and it is an exciting time to be a pediatric allergologist.

Abstract analysis method facilitates filtering low-methodological quality and high-bias risk systematic reviews on psoriasis interventions.

BACKGROUND: Article summaries' information and structure may influence researchers/clinicians' decisions to conduct deeper full-text analyses. Specifically, abstracts of systematic reviews (SRs) and meta-analyses (MA) should provide structured summaries for quick assessment. This study explored a method for determining the methodological quality and bias risk of full-text reviews using abstract information alone. METHODS: Systematic literature searches for SRs and/or MA about psoriasis were undertaken on MEDLINE, EMBASE, and Cochrane database. For each review, quality, abstract-reporting completeness, full-text methodological quality, and bias risk were evaluated using Preferred Reporting Items for Systematic Reviews and Meta-analyses for abstracts (PRISMA-A), Assessing the Methodological Quality of Systematic Reviews (AMSTAR), and ROBIS tools, respectively. Article-, author-, and journal-derived metadata were systematically extracted from eligible studies using a piloted template, and explanatory variables concerning abstract-reporting quality were assessed using univariate and multivariate-regression models. Two classification models concerning SRs' methodological quality and bias risk were developed based on per-item and total PRISMA-A scores and decision-tree algorithms. This work was supported, in part, by project ICI1400136 (JR). No funding was received from any pharmaceutical company. RESULTS: This study analysed 139 SRs on psoriasis interventions. On average, they featured 56.7% of PRISMA-A items. The mean total PRISMA-A score was significantly higher for high-methodological-quality SRs than for moderate- and low-methodological-quality reviews. SRs with low-bias risk showed higher total PRISMA-A values than reviews with high-bias risk. In the final model, only 'authors per review > 6' (OR: 1.098; 95%CI: 1.012-1.194), 'academic source of funding' (OR: 3.630; 95%CI: 1.788-7.542), and 'PRISMA-endorsed journal' (OR: 4.370; 95%CI: 1.785-10.98) predicted PRISMA-A variability. Reviews with a total PRISMA-A score < 6, lacking identification as SR or MA in the title, and lacking explanation concerning bias risk assessment methods were classified as low-methodological quality. Abstracts with a total PRISMA-A score ≥ 9, including main outcomes results and explanation bias risk assessment method were classified as having low-bias risk. CONCLUSIONS: The methodological quality and bias risk of SRs may be determined by abstract's quality and completeness analyses. Our proposal aimed to facilitate synthesis of evidence evaluation by clinical professionals lacking methodological skills. External validation is necessary.

dIvergEnt: How IgE Axis Contributes to the Continuum of Allergic Asthma and Anti-IgE Therapies.

Asthma is an airway disease characterised by chronic inflammation with intermittent or permanent symptoms including wheezing, shortness of breath, chest tightness, and cough, which vary in terms of their occurrence, frequency, and intensity. The most common associated feature in the airways of patients with asthma is airway inflammation. In recent decades, efforts have been made to characterise the heterogeneous clinical nature of asthma. The interest in improving the definitions of asthma phenotypes and endotypes is growing, although these classifications do not always correlate with prognosis nor are always appropriate therapeutic approaches. Attempts have been made to identify the most relevant molecular and cellular biomarkers underlying the immunopathophysiological mechanisms of the disease. For almost 50 years, immunoglobulin E (IgE) has been identified as a central factor in allergic asthma, due to its allergen-specific nature. Many of the mechanisms of the inflammatory cascade underlying allergic asthma have already been elucidated, and IgE has been shown to play a fundamental role in the triggering, development, and chronicity of the inflammatory responses within the disease. Blocking IgE with monoclonal antibodies such as omalizumab have demonstrated their efficacy, effectiveness, and safety in treating allergic asthma. A better understanding of the multiple contributions of IgE to the inflammatory continuum of asthma could contribute to the development of novel therapeutic strategies for the disease.

A phase II trial of trabectedin in triple-negative and HER2-overexpressing metastatic breast cancer.

Trabectedin is an alkylating agent that binds to the minor groove of DNA. Early studies with trabectedin suggested efficacy in triple-negative and HER2-overexpressing metastatic breast cancer (MBC). The efficacy and safety of trabectedin in pretreated patients with these tumors were evaluated in this parallel-cohort phase II trial. Patients received a 3-h infusion of trabectedin 1.3 mg/m(2) intravenously every 3 weeks until progression or unmanageable/unacceptable toxicity. The primary objective was to evaluate the efficacy using the objective response rate (ORR) as per Response Evaluation Criteria In Solid Tumors (RECIST). Secondary objectives comprised time-to-event endpoints and safety assessed with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v.3.0. Patients with heavily pretreated triple-negative (n = 50) or HER2-overexpressing (n = 37) MBC were enrolled. No confirmed responses were found in triple-negative MBC patients, with median progression-free survival (PFS) of 2.2 months (95 % CI 1.3-2.7 months). Confirmed partial responses occurred in 4 of 34 evaluable HER2-overexpressing MBC patients (ORR = 12 %; 95 % CI 3-27 %) and lasted a median of 12.5 months (95 % CI, 6.2-14.7 months); median PFS was 3.8 months (95 % CI, 1.8-5.5 months). Most trabectedin-related adverse events were mild or moderate, and the most frequent were fatigue, nausea, vomiting, constipation, and anorexia. Severe neutropenia and transaminase increases were non-cumulative and transient and were mostly managed by infusion delays or dose reductions. Single-agent trabectedin is well tolerated in aggressive MBC and has moderate activity in HER2-overexpressing tumors. Further studies are warranted to evaluate trabectedin combined with HER2-targeted treatments in this subtype.

Efficacy of MP-AzeFlu in children with seasonal allergic rhinitis: Importance of paediatric symptom assessment.

BACKGROUND: This study aimed to assess the efficacy of MP-AzeFlu (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in a single spray) in children with seasonal allergic rhinitis (SAR) and explore the importance of child symptom severity assessment in paediatric allergic rhinitis (AR) trials. METHODS: A total of 348 children (4-11 years) with moderate/severe SAR were randomized into a double-blind, placebo-controlled, 14-day, parallel-group trial. Efficacy was assessed by changes from baseline in reflective total nasal symptom score (rTNSS), reflective total ocular symptom score (rTOSS) and individual symptom scores over 14 days (children 6-11 years; n = 304), recorded by either children or caregivers. To determine whether a by-proxy effect existed, efficacy outcomes were assessed according to degree of child/caregiver rating. Moreover, total Paediatric Rhinitis Quality of Life Questionnaire (PRQLQ) score was compared between the groups. RESULTS: A statistically superior, clinically relevant efficacy signal of MP-AzeFlu versus placebo was apparent for PRQLQ overall score (diff: -0.29, 95% CI -0.55, -0.03; p = 0.027), but not for rTNSS (diff: -0.80; 95% CI: -1.75; 0.15; p = 0.099). However, as the extent of children's self-rating increased, so too did the treatment difference between MP-AzeFlu and placebo; MP-AzeFlu provided significantly better relief than placebo for rTNSS (p = 0.002), rTOSS (p = 0.009) and each individual nasal and ocular symptom assessed (except rhinorrhoea; p = 0.064) when children mostly rated their own symptoms. CONCLUSIONS: MP-AzeFlu is an effective treatment for AR in childhood. Caregivers are less able than children to accurately assess response to treatment with available tools. A simple paediatric-specific tool to assess efficacy in AR trials in children is needed.

Otophyma: a rare variant of phymatous rosacea.

BACKGROUND: Phymatous rosacea is characterized by thickened skin and irregular surface contours as the result of variable combinations of fibrosis, sebaceous hyperplasia and lymphoedema. Otic phyma is rarely seen and has been rarely reported in the English literature. METHODS: We present another case of this uncommon condition, frequently misdiagnosed, maybe due to its underrecognition. RESULTS: Phymatous rosacea most commonly occurs on the nose, but may also develop on any sebaceous facial region, including the ears. Although it is a benign condition, there are significant morbidities associated with rosacea, and can even result in conductive deafness because of the obstruction of the external auditory canal. CONCLUSIONS: The knowledge of this entity may be important for clinicians, especially dermatologists, ENT specialists and plastic surgeons, for an appropriate treatment and follow-up.