Consensus on the management of united airways disease with type 2 inflammation: a multidisciplinary Delphi study.

BACKGROUND: Scientific evidence on patients with multimorbid type 2 asthma and chronic rhinosinusitis with nasal polyps (CRSwNP) from a united airways disease (UAD) perspective remains scarce, despite the frequent coexistence of these entities. We aimed to generate expert consensus-based recommendations for the management of UAD patients. METHODS: Using a two-round Delphi method, Spanish expert allergists, pulmonologists and otolaryngologists expressed their agreement on 32 statements (52 items) on a 9-point Likert scale, classified as appropriate (median 7-9), uncertain (4-6) or inappropriate (1-3). Consensus was considered when at least two-thirds of the panel scored within the range containing the median. RESULTS: A panel of 30 experts reached consensus on the appropriateness of 43 out of the 52 (82.7%) items. The usefulness of certain biomarkers (tissue and peripheral blood eosinophil count, serum total IgE, and fraction of exhaled nitric oxide [FeNO]) in the identification and follow-up of type 2 inflammation, and assessment of the response to biologics, were agreed. Some of these biomarkers were also associated with disease severity and/or recurrence after endoscopic sinus surgery (ESS). Consensus was achieved on treatment strategies related to the prescription of anti-IL-4/IL-13 or anti-IgE agents, concomitant treatment with systemic corticosteroids, and combining or switching to biologics with a different mechanism of action, considering a number of UAD clinical scenarios. CONCLUSION: We provide expert-based recommendations to assist in clinical decision-making for the management of patients with multimorbid type 2 asthma and CRSwNP. Specific clinical trials and real-world studies focusing on the single-entity UAD are required to address controversial items.

Therapeutic management of allergic rhinitis: a survey of otolaryngology and allergology specialists.

PURPOSE: To describe the current management of allergic rhinitis (AR) in Spain's specialized care according to the next-generation ARIA guidelines. METHODS: An ad hoc online survey was distributed to AR specialists to appraise their perceptions of pathology management, knowledge of next-generation ARIA guidelines (including four case clinics), and their views on the principal barriers and the actions to proper AR management. RESULTS: one hundred nine specialists (38.5% allergists and 61.5% otolaryngologists) completed the study survey. Most respondents (87.2%) had read all or part of the Next-Generation ARIA Guidelines, and 81.6% stated that they considered the patient's treatment choice preferences. However, only 20.2% of specialists answered according to the recommendations in at least three of the four case clinics. Most participants failed to fulfill the treatment duration according to the guidelines. They regarded the lack of multidisciplinary teams (21.7%) and the lack of patients' AR treatment adherence (30.6%) as the most critical healthcare system- and patient-related barriers to the correct management of AR, respectively. Promoting patients' education was considered the most crucial action to improve it. CONCLUSION: Despite specialists' awareness, there is a gap between the evidence-based guidelines' recommendations and their implementation in clinical practice.

Development of a Tool to Measure the Clinical Response to Biologic Therapy in Uncontrolled Severe Asthma: The FEV1, Exacerbations, Oral Corticosteroids, Symptoms Score.

BACKGROUND: There is a lack of tools to quantify the response to monoclonal antibodies (mAbs) holistically in severe uncontrolled asthma patients. OBJECTIVE: To develop a valid score to assist specialists in this clinical context. METHODS: The score was developed in four subsequent phases: (1) elaboration of the theoretical model of the construct intended to be measured (response to mAbs); (2) definition and selection of items and measurement instruments by Delphi survey; (3) weight assignment of the selected items by multicriteria decision analysis using the Potentially All Pairwise RanKings of All Possible Alternatives methodology using the 1000minds software; and (4) face validity assessment of the obtained score. RESULTS: Four core items, with different levels of response for each, were selected: severe exacerbations, oral corticosteroid use, symptoms (evaluated by Asthma Control Test), and bronchial obstruction (assessed by FEV1 percent predicted). Severe exacerbations and oral corticosteroid maintenance dose were weighted most heavily (38% each), followed by symptoms (13%) and FEV1 (11%). Higher scores in the weighted system indicate a better response and the range of responses runs from 0 (worsening) to 100 (best possible response). Face validity was high (intraclass correlation coefficient of 0.86). CONCLUSIONS: The FEV1, exacerbations, oral corticosteroids, symptoms score allows clinicians to quantify response in severe uncontrolled asthma patients who are being treated with mAbs.

Validation of the DECA criteria for allergic conjunctivitis severity and control.

BACKGROUND: Allergic conjunctivitis (AC) is usually associated to allergic rhinitis (AR), but the severity and control of ocular symptoms should be assessed independently to improve diagnosis and treatment. The criteria from the Spanish consensus document on allergic conjunctivitis (DECA) aimed to be used as a patient-reported instrument for AC management. Here we validate these criteria for classifying AC severity and defining its control following COSMIN guidelines recommendations. METHODS: Patients with moderate or severe AR [reflective total nasal symptom score (rTNSS) score ≥ 8] and concomitant AC were recruited from hospitals in Spain. Patients were classified according to the severity of ocular symptoms as mild, moderate, or severe, and classified with respect to control as controlled and non-controlled, using the DECA criteria. To validate these criteria, comparisons with the validated modified allergic rhinitis and its impact on asthma (mARIA), reflective total ocular symptom score (rTOSS), rhinitis control assessment test (RCAT), ESPRINT-15 questionnaires, a conjunctival hyperemia scale and a visual analogue scale (VAS) for ocular symptoms were performed. RESULTS: A total of 128 patients participated in the validation. Mean age was 34.4 ± 12.1 years; 72.7% were women. The DECA criteria showed a good discriminant validity, reflecting a high capacity to differentiate between mild, moderate, and severe patients, and controlled from uncontrolled patients. A strong association between AC and AR was reflected in the comparison between the DECA and the mARIA criteria (p < 0.0001). The DECA criteria for severity and control presented satisfactory properties for longitudinal validity and responsiveness. CONCLUSIONS: Validation of the DECA criteria for severity and control of AC suggested that it can be useful in the evaluation of eye symptoms and follow-up of therapies.

Effect of high pressure and pulsed electric field on denaturation and allergenicity of Pru p 3 protein from peach.

The effect of high pressure (HP) and pulsed electric field (PEF) treatments combined or not with heat on denaturation and allergenicity of Pru p 3, the major allergenic protein of peach, was studied. Denaturation of Pru p 3, determined by ELISA using rabbit IgG, occurred when the protein was treated at 500 and 600 MPa at 20 °C and at 400 MPa at 50 °C. PEF treatment at 25 kV/cm at 50 °C denatures Pru p 3. Allergenicity of Pru p 3 was estimated in vitro by a competitive fluorescent immunoassay using three pools of sera from peach allergic patients. Any treatment applied did not show to influence the binding of Pru p 3 to IgE. When HP and PEF treated samples were tested by the prick test, the skin response was dependent on the particular sensitization of each patient, obtaining an increased reaction in more than 50% of individuals.

A Hypoallergenic Polygalacturonase Isoform from Olive Pollen Is Implicated in Pollen-Pollen Cross-Reactivity.

BACKGROUND: Cross-reactivity reactions between allergenic polygalacturonases (PGs) from different biological sources, especially foods and pollens from the Oleaceae family, have been described using Salsola kali PG (Sal k 6). No PG from olive pollen has been characterized to date, hampering further knowledge about cross-reactions through PGs. OBJECTIVES: The aim of this work was to determine the potential allergenicity of the PG from olive pollen and clarify its role in cross-reactivity. METHODS: A cDNA-encoding olive pollen PG sequence was subcloned into the pET41b vector and used to transform BL21(DE3) Escherichia coli cells to produce a His-tag fusion recombinant protein. The allergenic properties of olive pollen PG were determined by immunoblotting and ELISA in comparison to Sal k 6. The cross-reactivity potential of the protein with other pollen sources was analyzed by inhibition immunoassays. RESULTS: The existence of other isoforms of Ole e 14 with different allergenicity was confirmed by proteomics and a meta-analysis of the recently reported olive genome. Sal k 6 showed a higher IgE recognition than Ole e 14 regardless of patient sensitization, suggesting the existence of more allergenic Ole e 14 isoforms in olive pollen. IgG and IgE inhibition assays supported the existence of cross-reactions between them and with other PGs from Oleaceae and Poaceae plant families. CONCLUSIONS: A new allergen from olive pollen, Ole e 14, has been identified, produced as a recombinant isoform, and structurally and immunologically characterized. Its role in cross-reactivity has been confirmed and, due to its smaller IgE binding capacity, it could have an important role for therapeutic purposes.

A relevant IgE-reactive 28kDa protein identified from Salsola kali pollen extract by proteomics is a natural degradation product of an integral 47kDa polygalaturonase.

A highly prevalent IgE-binding protein band of 28kDa is observed when Salsola kali pollen extract is incubated with individual sera from Amaranthaceae pollen sensitized patients. By an immunoproteomic analysis of S. kali pollen extract, we identified this protein band as an allergenic polygalacturonase enzyme. The allergen, named Sal k 6, exhibits a pI of 7.14 and a molecular mass of 39,554.2Da. It presents similarities to Platanaceae, Poaceae, and Cupressaceae allergenic polygalacturonases. cDNA-encoding sequence was subcloned into the pET41b vector and produced in bacteria as a His-tag fusion recombinant protein. The far-UV CD spectrum determined that rSal k 6 was folded. Immunostaining of the S. kali pollen protein extract with a rSal k 6-specific pAb and LC-MS/MS proteomic analyses confirmed the co-existence of the 28kDa band together with an allergenic band of about 47kDa in the pollen extract. Therefore, the 28kDa was assigned as a natural degradation product of the 47kDa integral polygalacturonase. The IgE-binding inhibition to S. kali pollen extract using rSal k 6 as inhibitor showed that signals directed to both protein bands of 28 and 47kDa were completely abrogated. The average prevalence of rSal k 6 among the three populations analyzed was 30%, with values correlating well with the levels of grains/m3 of Amaranthaceae pollen. Sal k 6 shares IgE epitopes with Oleaceae members (Fraxinus excelsior, Olea europaea and Syringa vulgaris), with IgE-inhibition values ranging from 20% to 60%, respectively. No IgE-inhibition was observed with plant-derived food extracts.

Filaggrin gene mutations and new SNPs in asthmatic patients: a cross-sectional study in a Spanish population.

BACKGROUND: Several null-mutations in the FLG gene that produce a decrease or absence of filaggrin in the skin and predispose to atopic dermatitis and ichthyosis vulgaris have been described. The relationship with asthma is less clear and may be due to the influence of atopy in patients with associated asthma. METHODS: Four hundred individuals were included, 300 patients diagnosed with asthma divided into two groups according to their phenotype (allergic and non-allergic asthma) and 100 strictly characterized controls. The coding region and flanking regions of the FLG gene were amplified by PCR. We proceeded to the characterization of potential gene variants in that region by RFLP and sequencing and analysed their association with lung function parameters, asthma control and severity, and quality of life. RESULTS: We identified two null-mutations (R501X and 2282del4), seven SNPs previously described in databases and three SNPs that had not been previously described. One of the SNP identified in this study (1741A > T) was more frequently detected in patients with non-allergic asthma, worse FVC, FEV1 and PEF values and a higher treatment step. In addition, lowered spirometric values were observed in the non-allergic group carrying any of the nonsynonymous SNPs. CONCLUSIONS: In the association study of genetic variants of the FLG gene in our population the 1741A > T polymorphism seems to be associated with non-allergic asthma.

A recombinant Sal k 1 isoform as an alternative to the polymorphic allergen from Salsola kali pollen for allergy diagnosis.

BACKGROUND: The incidence of Amaranthaceae pollen allergy has increased due to the desertification occurring in many countries. In some regions of Spain, Salsola kali is the main cause of pollinosis, at almost the same level as olive and grass pollen. Sal k 1 - the sensitization marker of S. kali pollinosis - is used in clinical diagnosis, but is purified at a low yield from pollen. We aimed to produce a recombinant (r)Sal k 1 able to span the structural and immunological properties of the natural isoforms from pollen, and validate its potential use for diagnosis. METHODS: Specific cDNA was amplified by PCR, cloned into the pET41b vector and used to transform BL21 (DE3) Escherichia coli cells. Immunoblotting, ELISA, basophil activation and skin-prick tests were used to validate the recombinant protein against Sal k 1 isolated from pollen. Sera and blood cells from S. kali pollen-sensitized patients and specific monoclonal and polyclonal antisera were used. RESULTS: rSal k 1 was produced in bacteria with a yield of 7.5 mg/l of cell culture. The protein was purified to homogeneity and structural and immunologically validated against the natural form. rSal k 1 exhibited a higher IgE cross-reactivity with plant-derived food extracts such as peanut, almond or tomato than with pollen sources such as Platanus acerifolia and Oleaceae members. CONCLUSIONS: rSal k 1 expressed in bacteria retains intact structural and immunological properties in comparison to the pollen-derived allergen. It spans the immunological properties of most of the isoforms found in pollen, and it might substitute natural Sal k 1 in clinical diagnosis.

Aeroallergen sensitization influences quality of life and comorbidities in patients with nasal polyposis.

BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease of unknown etiology that impairs quality of life (QoL). The role of atopy in NP is not established. The aim of this study was to describe the clinical characteristics and QoL in a broad sample of patients with NP and to evaluate the influence of allergy on this disease. METHODS: A multicenter, observational, cross-sectional study was conducted in 67 allergy units in Spain. NP and nonsteroidal anti-inflammatory drug (NSAID) hypersensitivity were diagnosed following EP(3)OS guidelines. Rhinitis and asthma were classified following Allergic Rhinitis and Its Impact on Asthma and the Global Initiative for Asthma guidelines, respectively. Skin tests with a battery of aeroallergens were performed on all patients. A visual analog scale (VAS) and Short-Form 12 (SF-12) and 31-item Rhinosinusitis Outcome Measure (RSOM 31) questionnaires were completed by all the patients. RESULTS: Of the 671 patients included, 611 were evaluable. Mean age was 46 years and 50% of patients were men. Also, 50% were atopic. Asthma was present in 66% of patients and NSAID hypersensitivity was present in 26%. The most frequent symptoms were nasal congestion and rhinorrhea. Mean value of VAS was 58.6. Global health and bodily pain were the items most frequently identified in the SF-12 questionnaire and nasal and ocular symptoms in the RSOM-31 questionnaire. There was a good correlation between VAS score and QoL (p < 0.0001). Rhinitis was more severe in nonallergic patients. Asthma was more frequent in atopic patients, whereas ASA triad was more frequent in nonatopic patients. Atopic patients showed higher VAS scores and worse QoL. CONCLUSION: Atopic NP patients showed worse QoL, higher incidence of asthma and a less severe form of rhinitis than non-atopic patients.

Allergic rhinitis and its impact on work productivity in primary care practice and a comparison with other common diseases: the Cross-sectional study to evAluate work Productivity in allergic Rhinitis compared with other common dIseases (CAPRI) study.

BACKGROUND: Allergic rhinitis (AR) is a highly prevalent allergic disease and also counts among the 10 most frequent reasons for medical consultation. Its impact on quality of life (QoL) and work productivity has been established but comparisons with other diseases are rare in the literature. The aim of this study was to evaluate the impact of AR in health-related QoL (HRQoL) and work productivity in primary care patients, compared with other prevalent diseases such as hypertension, diabetes mellitus (DM) type II, and symptomatic depression. METHODS: Six hundred sixteen patients were included in a multicenter cross-sectional observational study. A generic HRQoL questionnaire, 36-item Short Form, and a specific questionnaire, "Work Productivity and Activity Impairment" were handed out to measure QoL and work productivity impact of the diseases. To assess clinical severity with a comparable scale between diseases Clinical Global Impression (CGI) had been used. RESULTS: Symptomatic depression was found to produce the greatest impairment on work productivity with a decrease of 59.5%, with significant differences compared with AR, hypertension, and DM type II (p < 0.05). Symptomatic depression was found to produce the highest negative impact on daily activities with a statistically significant reduction of 59.4% (p < 0.05) compared with AR (26.6% decrease), hypertension (8.8% decrease), and DM (16.7% decrease) patients. Differences between AR and DM or hypertension were also significant (p < 0.05). Restriction on daily activities for AR was 27.8%, which is significantly higher (p < 0.05) than hypertension (19.8% decrease) but not DM (25.7% decrease). Depression had the highest impairment on daily activities (59.4%), compared with the remaining three groups (p < 0.05). CONCLUSION: AR impairs work productivity in a greater magnitude than hypertension and DM type II.

The natural profilin from Russian thistle (Salsola kali) contains a low IgE-binding ability isoform--molecular and immunological characterization.

Chenopodiaceae pollens such as those from Salsola kali and Chenopodium album are important causes of allergy in Mediterranean areas because of the progress of desertification in European countries. Among the various allergenic protein families, profilins constitute a group of pan-allergens that are involved in polysensitization and pollen-food allergy syndrome. Two-dimensional electrophoresis analysis of S. kali profilin highlighted a polymorphic pattern, with several isoforms that have different molecular features (isoelectric point and molecular mass) and immunological features. Two isoforms have been cloned and sequenced. Sal k 4.02 and Sal k 4.03 displayed non-conservative amino acid changes in critical positions of the IgE epitopes. Both isoforms were produced in Escherichia coli and structurally and spectroscopically characterized. Changes in the electrophoretic mobility and in their IgG and IgE immunological behavior were observed in comparison with Che a 2, their counterpart from C. album. The IgE-binding ability of Sal k 4.03 is similar to that of Che a 2, whereas Sal k 4.02 showed a 35% reduction in IgE binding in 86% of patients, suggesting a hypoallergenic character. Three-dimensional modeling allowed us to propose which amino acid residues are involved in those immunological changes based on epitope mapping studies previously performed in other profilins. These profilin isoforms constitute suitable candidates for specific immunotherapy with recombinant allergens.

The impact of allergic rhinitis on symptoms, and quality of life using the new criterion of ARIA severity classification.

INTRODUCTION: Allergic rhinitis (AR) is a common disease with major socieconomic burden and a significant impact on quality of life. OBJECTIVE: The objective of the study was to assess the impact of AR severity, using the modified ARIA (m-ARIA) severity criterion in order to discriminate among moderate and severe AR, in symptoms and quality of life assessed with the questionnaire ESPRINT-15. METHODS: The specific quality of life questionnaire (ESPRINT-15) was applied in over thousand untreated RA patients. Severity was evaluated by the m-ARIA classification, which categorizes AR as mild, moderate, and severe. Nasal symptoms were evaluated by using categorized (none, low, middle, and high) Total Four Symptom Score (T4SS). RESULTS: Using the m-ARIA severity classification, significant differences in quality of life, both global score and specific domains, and categorized T4SS were found among the AR severity groups. CONCLUSION: Modified ARIA severity classification in mild, moderate, and severe allergic rhinitis clearly discriminates the impact of AR in all domains of quality of life and categorized symptom`s score.

Assessing degree of flowering implicates multiple Chenopodiaceae/Amaranthaceae species in allergy.

BACKGROUND: IgE-mediated sensitization to the Chenopodiaceae/Amaranthaceae families is a cause of allergic symptoms in arid areas. Salsola kali and Chenopodium album are considered the main species responsible; however, there is a discrepancy between the pollination period of these two plants and clinical symptoms. The objectives of this study were to identify new Chenopodiaceae/Amaranthaceae members with sensitization capacity and to correlate symptoms, pollen counts and degree of flowering of different species. METHODS: A total of 37 individuals monosensitized to S. kali and C. album were included in the study. All patients recorded daily symptom scores between May and October 2007. Extracts from Chenopodium (album, vulvaria and murale), Salsola (kali, vermiculata, and oppositifolia), Bassia scoparia, Atriplex (patula and halimus) and Amaranthus (deflexus and muricatus) were manufactured and used in skin prick tests (SPTs). Protein content and IgE binding were assessed for each extract. Pollen counts and degree of flowering (based on the Orshan specific semiquantitative method) were assessed weekly. RESULTS: Symptom scores demonstrated a positive correlation with pollen counts even outside the pollination period of S. kali. Positive SPTs were obtained with all 11 species tested, which showed common proteins with IgE-binding capacity. Different species flowered at different times during the pollen season. CONCLUSION: Different taxonomically related species of Chenopodiaceae/Amaranthaceae can induce allergic sensitization and should be considered for use in diagnosis and treatment. Degree of flowering is a complementary method for assessing pollination that could be used for botanical families with indistinguishable pollen grains.

Ambroxol-induced systemic contact dermatitis confirmed by positive patch test

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