The Frequency of Germline BRCA and Non-BRCA HR-Gene-Variants in a Cohort of Pancreatic Cancer Patients.

Germline DNA alterations affecting homologous recombination pathway genes have been associated with pancreatic cancer (PC) risk. BRCA2 is the most studied gene and affects the management of PC patients and their families. Even though recent reports have suggested a similar role of germline ATM pathogenic variants (PV) in familial PC, there is still a disagreement between experts on how it could affect patient management given the lack of proper PC risk estimates. We retrospectively analyzed the germline data of 257 PC patients among whom nearly 50% were sporadic cases. We showed similar frequencies of BRCA2 (4.9%) and ATM (4.4%) PV or likely pathogenic variants, which were not related to familial history. Based on our findings and that of the literature, we suggest including ATM gene among the panel of genes analyzed in PC patients pending the publication of prospective studies.

Spanish Consensus on the Management of Chronic Rhinosinusitis With Nasal Polyps (POLIposis NAsal/POLINA 2.0).

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a highly prevalent and burdensome disease for both individuals and health systems. Its management involves many specialties, including otorhinolaryngology, allergology, pulmonology, primary care, pharmacy, and pediatrics. A multidisciplinary approach and the participation of the patient in decision-making are essential, both for diagnosis and for therapy. The authors of the consensus aim to translate current knowledge into an easy-to-read practical guide and emphasize those aspects requiring further discussion or with unmet needs owing to the lack of appropriate scientific evidence. An iterative approach for the development of an evidence-based systematic review with recommendations was followed using a standard quality assessment approach (Scottish Intercollegiate Guidelines Network [SIGN] and National Institute for Health and Care Excellence [NICE]). The guideline was critically evaluated using the Appraisal of Guidelines for Research and Evaluation (AGREE II) and Recommendation Excellence (AGREE REX) instruments. Consequently, POLINA has been considered a high-quality guideline by an independent agency. The POLINA consensus provides new definitions of control, therapeutic management (including surgery and evaluation of severity), indications for use of biologics, and response. Finally, this guideline focuses on unmet research needs in CRSwNP.

Severity and duration of allergic conjunctivitis: are they associated with severity and duration of allergic rhinitis and asthma?

Summary: Objective. The association of allergic conjunctivitis (AC) with rhinitis and/or asthma is poorly understood. The objective of this study was to apply the Consensus Document for Allergic Conjunctivitis (DECA) criteria for the classification of AC to a population of patients with AC to assess the association between the severity and duration of AC and rhinitis and/or asthma. Methods. Patients with ocular symptoms of AC who participated in the 'Alergológica 2015' study were included. The demographics, classification according to the DECA criteria, etiology, and comorbidities were evaluated by age groups (less or equal than 14 and greater than 14 years). Results. A total of 2,914 patients (age range, 1-90 years) were included in the "Alergológica 2015" study. Of these, 965 patients (33.1%) were diagnosed with AC (77.5% > 14 years). AC was classified as severe, moderate, or mild in 1.8%, 46.4%, and 51.8%, respectively; and as intermittent or persistent in 51.6% and 48.4% of the patients. AC alone occurred in 4% of patients. AC was mainly associated with rhinitis (88.4%), asthma (38.2%), food allergy (8.3%) and atopic dermatitis (3.5%). In allergic respiratory disease rhinitis preceded AC and asthma developed later. The severity and duration of AC was significantly associated with severity and duration of rhinitis (p less than 0.001 for both age groups) and asthma (p less than 0.001 only in adults). Conclusions. The application of the new DECA classification for AC reveals a direct relationship between AC, rhinitis and asthma respect to severity and duration. These relationships suggest that AC should be considered an integral part of the "one airway, one disease" hypothesis.

High Frequency of Smell and Taste Dysfunction in Health Care Professionals With COVID-19 Working in Allergy Departments.

INTRODUCTION AND OBJECTIVE: Since the early stages of the novel coronavirus 2019 (SARS-CoV-2) outbreak, smell and/or taste dysfunction (STD) has been reported in 5% to 88% of COVID-19 patients. Objective: We aimed to assess STD in health care professionals (HCPs), mainly allergists, affected by COVID-19. We carried out a survey to evaluate the association between STD and its severity and demographic characteristics, symptoms, comorbidities, and hospital admission. METHODS: We designed a 15-item questionnaire comprising various sections, as follows: demographics, diagnostic characteristics, STD patterns, medication use, and comorbidities. The questionnaire was developed using Google forms. It was distributed to members of the Spanish Society of Allergology and Clinical Immunology (SEAIC) and sent via social media to be completed by HCPs with COVID-19. RESULTS: The survey was completed by HCPs (n=234), of whom 76.5% were aged ≤55 years and 73.5% were female. STD was detected in 74.4% of respondents, of whom 95.6% reported moderate-severe impairment. Mean time until recovery of taste dysfunction was 21.6 (24.0) days in HCPs aged ≤55 years and 33.61±26.2 days in those aged >55 years (P=.019). Analysis stratified by severity of STD showed that more than a half of COVID-19 patients presented severe loss of smell. Older age (>55 years) was associated with fever, anorexia, lower frequency of headache, and longer persistence of taste dysfunction. CONCLUSION: STD is a common symptom in COVID-19, even as a unique or preceding symptom. HCPs who reported smell dysfunction were younger than those not affected with STD. Taste dysfunction may imply more systemic involvement in COVID-19-positive HCPs.

Adaptation to Spanish and Validation of the Rhinitis Control Assessment Test questionnaire.

BACKGROUND AND OBJECTIVE: The Rhinitis Control Assessment Test (RCAT) is a patient-based questionnaire that is widely used to evaluate control of rhinitis. Objective: To develop and validate a Spanish version of the RCAT (RCATe). METHODS: After translation and cultural adaptation of the original RCAT, this multicenter, observational, prospective study evaluated the properties/attributes of the RCATe by assessing its validity, reliability, responsiveness, effect size, minimal important difference and cut point. RESULTS: The recruited sample comprised 252 allergic rhinitis (AR) patients from 27 allergy and otolaryngology departments in hospitals throughout Spain. Significant and strong correlations were found between the RCATe and the total nasal symptom score and the visual analog scale (-0.79 and -0.77, respectively; P<.0001). The RCATe revealed significant differences between patients grouped in the different categories of severity or duration of AR (P<.001). The internal consistency (Cronbach α) was good (0.84), and the test-retest reliability was moderate (0.54 evaluated by the physician and 0.49 by the patient). The responsiveness to change was high and significant for RCATe (P<.0001) and correlated linearly with the improvement in AR. The overall effect size was 1.62. The cut-off point to identify patients with adequate control of AR was >20 (area under the receiver operating characteristic curve, 0.746; sensitivity, 58.3%; specificity, 90.9%). CONCLUSION: The psychometric evaluation and validation of the RCATe indicated good reliability, validity, and responsiveness, thus suggesting that it is effective for measuring control of AR symptoms by Spanish-speaking patients.

Clinical and anatomopathological features of eosinophilic oesophagitis in children and adults.

INTRODUCTION: Eosinophilic oesophagitis (EoE) is a chronic clinical-pathological disorder with an immunological basis characterised by symptoms of oesophageal dysfunction and, histologically, eosinophilic inflammation. OBJECTIVE: To evaluate the clinical characteristics and differences in children and adults diagnosed with EoE in a tertiary level hospital. METHOD: Descriptive, retrospective and cross-sectional study. We randomly selected 40 children and 40 adults diagnosed with EoE between 2009 and 2016. The patient characteristics were analysed by means of epidemiological, clinical, diagnostic and therapeutic variables. RESULTS: The average age at diagnosis was 10 years (children) and 34 years (adults), with a higher frequency in males. The majority were sensitised to aeroallergens (77.5% children vs. 82.5% adults) and foods (75% children vs. 82.5% adults). Statistically significant differences were detected in sensitisation to fruits (p=0.007) and grains (p<0.001). Differences were observed in impaction (22.5% children vs. 82.5% adults), dysphagia (42.5% children vs. 77.5% adults) and abdominal pain (25% children vs. 7.5% adults). Endoscopy showed that children had a higher frequency of exudates (92.5%) and adults, trachealisation (50% vs. 5%) and stenosis (17.5% vs. 2.5%). Statistically significant differences were found in treatment with topical corticosteroids (30% children vs. 77.5% adults), with a variable positive response. 77.5% of the patients received elimination diets. CONCLUSIONS: Statistically significant differences were observed between the paediatric and adult populations in the food sensitisation profiles, clinical manifestations, endoscopic findings and treatments received. This is a complex pathology that calls for a multidisciplinary team and would require new non-invasive techniques to facilitate its management.

Position paper on nasal obstruction: evaluation and treatment.

Nasal obstruction (NO) is defined as the subjective perception of discomfort or difficulty in the passage of air through the nostrils. It is a common reason for consultation in primary and specialized care and may affect up to 30%-40% of the population. It affects quality of life (especially sleep) and lowers work efficiency. The aim of this document is to agree on how to treat NO, establish a methodology for evaluating and diagnosing it, and define an individualized approach to its treatment. NO can be unilateral or bilateral, intermittent or persistent and may be caused by local or systemic factors, which may be anatomical, inflammatory, neurological, hormonal, functional, environmental, or pharmacological in origin. Directed study of the medical history and physical examination are key for diagnosing the specific cause. NO may be evaluated using subjective assessment tools (visual analog scale, symptom score, standardized questionnaires) or by objective estimation (active anterior rhinomanometry, acoustic rhinometry, peak nasal inspiratory flow). Although there is little correlation between the results, they may be considered complementary and not exclusive. Assessing the impact on quality of life through questionnaires standardized according to the underlying disease is also advisable. NO is treated according to its cause. Treatment is fundamentally pharmacological (topical and/or systemic) when the etiology is inflammatory or functional. Surgery may be necessary when medical treatment fails to complement or improve medical treatment or when other therapeutic approaches are not possible. Combinations of surgical techniques and medical treatment may be necessary.

Estimate of the total costs of allergic rhinitis in specialized care based on real-world data: the FERIN Study.

BACKGROUND: Despite the socioeconomic importance of allergic rhinitis (AR), very few prospective studies have been performed under conditions of clinical practice and with a sufficiently long observation period outside the clinical trial scenario. We prospectively estimated the direct and indirect costs of AR in patients attending specialized clinics in Spain. METHODS: Patients were recruited at random from allergy outpatient clinics in 101 health centers throughout Spain over 12 months. We performed a multicenter, observational, prospective study under conditions of clinical practice. We analyzed direct costs from a funder perspective (healthcare costs) and from a societal perspective (healthcare and non-healthcare costs). Indirect costs (absenteeism and presenteeism [productivity lost in the workplace]) were also calculated. The cost of treating conjunctivitis was evaluated alongside that of AR. RESULTS: The total mean cost of AR per patient-year (n = 498) was €2326.70 (direct, €553.80; indirect, €1772.90). Direct costs were significantly higher in women (€600.34 vs €484.46, P = 0.02). Total costs for intermittent AR were significantly lower than for persistent AR (€1484.98 vs €2655.86, P < 0.001). Total indirect costs reached €1772.90 (presenteeism, €1682.71; absenteeism, €90.19). The direct costs of AR in patients with intermittent asthma (€507.35) were lower than in patients with mild-persistent asthma (€719.07) and moderate-persistent asthma (€798.71) (P = 0.006). CONCLUSIONS: The total cost of AR for society is considerable. Greater frequency of symptoms and more severe AR are associated with higher costs. Indirect costs are almost threefold direct costs, especially in presenteeism. A reduction in presenteeism would generate considerable savings for society.

Results of a 1-year quality-improvement process to reduce door-to-needle time in acute ischemic stroke with MRI screening.

OBJECTIVE: To determine the effects of a 1-year quality-improvement (QI) process to reduce door-to-needle (DTN) time in a secondary general hospital in which multimodal MRI screening is used before tissue plasminogen activator (tPA) administration in patients with acute ischemic stroke (AIS). METHODS: The QI process was initiated in January 2015. Patients who received intravenous (iv) tPA<4.5h after AIS onset between 26 February 2015 to 25 February 2016 (during implementation of the QI process; the "2015 cohort") were identified (n=130), and their demographic and clinical characteristics and timing metrics compared with those of patients treated by iv tPA in 2014 (the "2014 cohort", n=135). RESULTS: Of the 130 patients in the 2015 cohort, 120 (92.3%) of them were screened by MRI. The median DTN time was significantly reduced by 30% (from 84min in 2014 to 59min; P<0.003), while the proportion of treated patients with a DTN time≤60min increased from 21% to 52% (P<0.0001). Demographic and baseline characteristics did not significantly differ between cohorts, and the improvement in DTN time was associated with better outcomes after discharge (patients with a 0-2 score on the modified rankin scale: 59% in the 2015 cohort vs 42.4% in the 2014 cohort; P<0.01). During the 1-year QI process, the median DTN time decreased by 15% (from 65min in the first trimester to 55min in the last trimester; P≤0.04) with a non-significant 1.5-fold increase in the proportion of treated patients with a DTN time≤60min (from 41% to 62%; P=0.09). CONCLUSION: It is feasible to deliver tPA to patients with AIS within 60min in a general hospital, using MRI as the routine screening modality, making this QI process to reduce DTN time widely applicable to other secondary general hospitals.

Constitutional mismatch repair deficiency syndrome: clinical description in a French cohort.

BACKGROUND: Constitutional mismatch repair deficiency (CMMRD) syndrome is a childhood cancer predisposition syndrome involving biallelic germline mutations of MMR genes, poorly recognised by clinicians so far. METHODS: Retrospective review of all 31 patients with CMMRD diagnosed in French genetics laboratories in order to describe the characteristics, treatment and outcome of the malignancies and biological diagnostic data. RESULTS: 67 tumours were diagnosed in 31 patients, 25 (37%) Lynch syndrome-associated malignancies, 22 (33%) brain tumours, 17 (25%) haematological malignancies and 3 (5%) sarcomas. The median age of onset of the first tumour was 6.9 years (1.2-33.5). Overall, 22 patients died, 9 (41%) due to the primary tumour. Median survival after the diagnosis of the primary tumour was 27 months (0.26-213.2). Failure rate seemed to be higher than expected especially for T-cell non-Hodgkin's lymphoma (progression/relapse in 6/12 patients). A familial history of Lynch syndrome was identified in 6/23 families, and consanguinity in 9/23 families. PMS2 mutations (n=18) were more frequent than other mutations (MSH6 (n=6), MLH1 (n=4) and MSH2 (n=3)). CONCLUSIONS: In conclusion, this unselected series of patients confirms the extreme severity of this syndrome with a high mortality rate mostly related to multiple childhood cancers, and highlights the need for its early detection in order to adapt treatment and surveillance.

Mould and grass pollen allergy as risk factors for childhood asthma in Zaragoza, Spain.

OBJECTIVE: Examine the prevalence of asthma and associated predictive factors in a group of 468 students. PATIENTS AND METHODS: A descriptive, cross-sectional observational study in a randomly selected population of 468 children aged 10-12, in the city of Zaragoza. We used the ISAAC questionnaire on asthma completed by children under supervision of the investigators. We assessed the genetic risk (family history of asthma) and environmental risks. The risk for atopy was assessed by the presence of positive skin prick tests. RESULTS: 25.3% of the children had symptoms consistent with asthma in the city of Zaragoza. Among them 33.1% reported a history of asthma in close relatives (OR=1.78, p<0.001). The history of hospitalisations for lower respiratory tract illness was strongly associated with the presence of asthma (OR=6.72, p<0.0001). Positive skin tests to Alternaria (OR=2.00, p<0.0001) and grass pollen (OR=1.76, p<0.001) were predictors of asthma. 63.6% of asthmatic children had presented clinical rhinitis in the previous 12 months, compared with 32% of non-asthmatics, and this difference was statistically significant (OR=3.89, p<0.0001). 47% of asthmatics presented with or previously had eczema, whereas only 26.9% of non-asthmatics presented with or previously had these types of lesions (p<0.0001). CONCLUSION: The following are predictors of asthma: History of hospital admissions for lower respiratory tract illness, presence of rhinitis and/or eczema, positive prick test for certain aeroallergens, especially Alternaria and grass pollen, and family history of asthma.

Relationship between respiratory and food allergy and evaluation of preventive measures.

Food allergy and respiratory allergy are two frequently associated diseases and with an increasing prevalence. Several reports show the presence of respiratory symptoms in patients with food allergy, while certain foods may be related to the development or exacerbation of allergic rhinitis and asthma. The present update focuses on this relationship, revealing a pathogenic and clinical association between food and respiratory allergy. This association is even more intense when the food hypersensitivity is persistent or starts in the early years of life. Food allergy usually precedes respiratory allergy and may be a risk factor for allergic rhinitis and asthma, becoming a relevant clinical marker for severe atopic asthma. Furthermore, the presence of co-existing asthma may enhance life-threatening symptoms occurring during a food allergic reaction. Recommendations for dietary restrictions during pregnancy and breastfeeding to prevent the development of respiratory allergy are controversial and not supported by consistent scientific data. Current recommendations from medical societies propose exclusive breastfeeding during the first four months of life, with the introduction of solid food in the fourth to the seventh month period of life. A delayed introduction of solid food after this period may increase the risk of developing subsequent allergic conditions. Further studies are encouraged to avoid unjustified recommendations involving useless dietary restrictions.

Guidelines for surveillance of individuals with constitutional mismatch repair-deficiency proposed by the European Consortium "Care for CMMR-D" (C4CMMR-D).

Lynch syndrome (LS) is an autosomal dominant disorder caused by a defect in one of the DNA mismatch repair genes: MLH1, MSH2, MSH6 and PMS2. In the last 15 years, an increasing number of patients have been described with biallelic mismatch repair gene mutations causing a syndrome referred to as 'constitutional mismatch repair-deficiency' (CMMR-D). The spectrum of cancers observed in this syndrome differs from that found in LS, as about half develop brain tumours, around half develop digestive tract cancers and a third develop haematological malignancies. Brain tumours and haematological malignancies are mainly diagnosed in the first decade of life, and colorectal cancer (CRC) and small bowel cancer in the second and third decades of life. Surveillance for CRC in patients with LS is very effective. Therefore, an important question is whether surveillance for the most common CMMR-D-associated cancers will also be effective. Recently, a new European consortium was established with the aim of improving care for patients with CMMR-D. At a workshop of this group held in Paris in June 2013, one of the issues addressed was the development of surveillance guidelines. In 1968, criteria were proposed by WHO that should be met prior to the implementation of screening programmes. These criteria were used to assess surveillance in CMMR-D. The evaluation showed that surveillance for CRC is the only part of the programme that largely complies with the WHO criteria. The values of all other suggested screening protocols are unknown. In particular, it is questionable whether surveillance for haematological malignancies improves the already favourable outcome for patients with these tumours. Based on the available knowledge and the discussions at the workshop, the European consortium proposed a surveillance protocol. Prospective collection of all results of the surveillance is needed to evaluate the effectiveness of the programme.

Clinical Management and Use of Health Care Resources in the Treatment of Nasal Polyposis in Spanish Allergy Centers: The POLAR Study.

BACKGROUND: Nasal polyposis (NP) is a chronic inflammatory disease that constitutes a major health problem with significant comorbidities and a considerable associated socioeconomic burden. OBJECTIVE: To describe the clinical features and management of patients with NP attending Spanish allergy centers, the use of health care resources, and the degree of compliance with the diagnostic and therapeutic recommendations of the European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS). METHODS: We performed a multicenter, observational, and cross-sectional epidemiologic study of 671 patients consulting for NP in 67 Spanish allergy departments. We used sociodemographic and clinical questionnaires to evaluate clinical characteristics, use of health care resources, diagnostic methods, and treatment administered. RESULTS: NP was closely associated with asthma (66%), allergic rhinitis (45.9%), and hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) (26%). Atopy was present in the 50% of cases, with Dermatophagoides pteronyssinus as the most frequent sensitizing allergen. Eleven percent of NP patients visited the emergency department during the previous year, and more than 58% used primary care, allergy, or otorhinolaryngology services. The most frequently used diagnostic tests were skin prick tests (93.6%) and anterior rhinoscopy (79.4%). Intranasal corticosteroids were the drug class most frequently prescribed by allergists (74.6%). Specific immunotherapy was prescribed in 21% of patients. CONCLUSIONS: NP is a chronic inflammatory disease that generates considerable use of health care resources. The close association with atopy, asthma, and NSAID hypersensitivity highlights the usefulness of an allergy workup in all patients with NP. Analysis of the clinical management of NP by allergists in Spain revealed a high degree of compliance with EPOS diagnostic and therapeutic recommendations.

Nasal Hyperreactivity: Nonspecific Nasal Provocation Tests. Review by the Rhinoconjunctivitis Committee of the Spanish Society of Allergy and Clinical Immunology.

Nasal hyperreactivity is the abnormal reaction of nasal tissue to a stimulus that is innocuous to most people. This response is caused by dysregulation of the autonomic nervous system at various levels of the nasal autonomic reflex arc. Various stimuli (methacholine, histamine, adenosine 5'-monophosphate, cold air, mannitol, rapsaicin, phentolamine, and distilled water) have been used in an attempt to find the test that most reliably differentiates between healthy individuals and patients and also between different types of rhinitis. Despite the small number of publications available, in the present review, we provide an update on current nonspecific nasal provocation techniques. The studies published to date are not comparable: the stimuli applied act through different mechanisms and are used to assess different pathways, and the methodologies differ in terms of selection of participants, concentrations used, and assessment of response (criteria for positivity). Given the limited use of nonspecific nasal provocation tests in routine clinical practice, we believe that more studies are warranted to address the research issues we present at the end of the present review, for example, the need to standardize the methodology for each test or even the clinical benefits of knowing whether or not a patient has nasal hyperreactivity.

Consensus document on allergic conjunctivitis (DECA).

Allergic conjunctivitis (AC) is an inflammatory disease of the conjunctiva caused mainly by an IgE-mediated mechanism. It is the most common type of ocular allergy. Despite being the most benign form of conjunctivitis, AC has a considerable effect on patient quality of life, reduces work productivity, and increases health care costs. No consensus has been reached on its classification, diagnosis, or treatment. Consequently, the literature provides little information on its natural history, epidemiological data are scarce, and it is often difficult to ascertain its true morbidity. The main objective of the Consensus Document on Allergic Conjunctivitis (Documento dE Consenso sobre Conjuntivitis Alérgica [DECA]), which was drafted by an expert panel from the Spanish Society of Allergology and Spanish Society of Ophthalmology, was to reach agreement on basic criteria that could prove useful for both specialists and primary care physicians and facilitate the diagnosis, classification, and treatment of AC. This document is the first of its kind to describe and analyze aspects of AC that could make it possible to control symptoms.

Sal k 5, a member of the widespread Ole e 1-like protein family, is a new allergen of Russian thistle (Salsola kali) pollen.

BACKGROUND: Salsola kali is an Amaranthaceae weed with important repercussions for pollinosis in temperate areas. Ole e 1-like members are relevant allergens in pollen from different species. We aimed to characterize and produce as recombinant allergen S. kali Ole e 1-like protein. METHODS: The natural allergen was purified at homogeneity after three chromatographic steps. Specific cDNA was sequenced and expressed in Pichia pastoris yeast. Structural relationships of natural and recombinant forms were carried out by 2D electrophoresis and spectroscopic analyses. Its immunological relevance was analyzed by ELISA and immunoblotting using an IgG antiserum and monoclonal antibodies specific to Ole e 1, as well as sera from 57 allergic patients recruited from two Spanish regions where this pollinosis is frequent. RESULTS: The purified allergen, Sal k 5, is an acidic glycoprotein of 151 amino acid residues and 17,628 Da of molecular mass. Its amino acid sequence exhibits 68 and 32% identity with the allergens of Che a 1 and Ole e 1, respectively. The recombinant protein was correctly processed and its structural and immunologic equivalence to the natural form was proven. A sensitization frequency between 30 and 40% was observed in pollinic patients from the center and east coast of Spain. CONCLUSIONS: Sal k 5 is a member of the Ole e 1-like protein family which can be considered an important allergen from S. kali. Its inclusion in diagnosis protocols would allow the accurate defining of patients allergic to this pollen.