The Importance of Preventing and Managing Tear Dysfunction Syndrome in Allergic Conjunctivitis and How to Tackle This Problem.

Tear dysfunction syndrome, also known as dry eye disease (DED), is a multifactorial disease of the ocular surface characterized by the loss of tear film homeostasis. DED shows a significant clinical overlap with ocular allergy (OA), which alters tear film homeostasis, thus predisposing the patient to DED. Both conditions constitute the most common ocular surface disorders and have a potentially severe impact on patients' quality of life. Clinical practice guidelines recommend topical therapies as first-line treatment for OA. However, eye drop formulations may contain additional substances that can contribute to ocular surface damage and the development of DED. Therefore, physicians treating ocular allergy should be aware of problems affecting the tear film, the role of tear film disruption in OA, and topical treatment to prevent or minimize DED. The aim of this review is to present an updated overview of the topic.

A Prospective Study of Costs Associated With the Evaluation of Allergic Reactions to Radiological Contrast Media.

BACKGROUND AND OBJECTIVE: The prevalence of hypersensitivity reactions to radiological contrast media (RCM) is increasing owing to the improved performance of diagnostic and therapeutic tests that require RCMs. Objective: We carried out a year-long real-life observational study to prospectively evaluate patients referred to the allergy department from primary care, the emergency department, and other specialties with suspected moderate-to-severe RCM hypersensitivity reactions. METHODS: To study the costs of evaluating RCM hypersensitivity reactions, we systematically recorded direct and indirect costs. RESULTS: Sixty-nine patients with previous reactions to RCM were evaluated in the allergy department from June 1, 2017, to May 31, 2018.Total direct health care costs were €10 715.84, with a mean (SD) cost per patient of €155.30 (77.08). Specifically, direct non-health care costs reached €1605.42 (mean, €23.27 [41.14]), and indirect costs were €6490.85 (mean, €94.07 [110.61]). In summary, the total cost was €18 812.11, that is, a mean cost of €272.64 (164.77). CONCLUSION: Our study shows that the costs of an elective evaluation of hypersensitivity reactions to RCM are low, thus confirming that correct and safe management of affected patients are cost-effective. Therefore, our efforts should be directed toward ensuring the necessary logistics.

Response to Monoclonal Antibodies in Asthma: Definitions, Potential Reasons for Failure, and Therapeutic Options for Suboptimal Response.

Real-life data reveal that more than half of severe asthma patients treated with monoclonal antibodies (mAbs) do not achieve a complete response. Response to mAbs must be assessed holistically, considering all the clinically meaningful therapeutic goals, not only reduction of exacerbations and oral corticosteroids. There are 2 different ways of measuring the response to mAbs. One, qualitative, classifies patients according to the degree of disease control they have achieved, without explaining how much a given patient improves relative to the baseline (pre-mAb) clinical situation; the other, quantitative, scores the changes occurring after treatment. Both methods are complementary and essential to making clinical decisions on whether to continue treatment. The various potential causes of suboptimal response to mAbs include incorrect identification of the specific T2 pathways, comorbidities that reduce the room for improvement, insufficient dose, autoimmune phenomena, infections, change in the initial inflammatory endotype, and adverse events. Once a suboptimal response has been confirmed, a well-structured and multifaceted assessment of the potential causes of failure should be performed, with emphasis on the resulting inflammatory process of the airway after mAb therapy and the presence of chronic or recurrent infection. This investigation should guide the decision on the best therapeutic approach. The present review aims to help clinicians gain insights into how to measure response to mAbs and proceed in cases of suboptimal response.

Dupilumab: A Review of Present Indications and Off-Label Uses.

Recent advances in our understanding of T2 inflammation have revealed more diseases in which T2 inflammation is involved. Dupilumab is a recently developed monoclonal antibody that blocks signaling of IL-4 and IL-13, both of which are crucial cytokines in the T2 response. New possible indications are increasingly explored and include skin diseases, such as prurigo nodularis, nummular eczema, allergic contact dermatitis, chronic hand eczema, spontaneous chronic urticaria, bullous pemphigoid, alopecia areata, and Netherton syndrome, as well as respiratory diseases, such as allergic bronchopulmonary aspergillosis, chronic eosinophilic pneumonia, and allergic rhinitis. In addition, eosinophilic gastrointestinal disorders, particularly eosinophilic esophagitis, and food allergy, are also research fields of interest. Here, we review published data and clinical trials examining the use of dupilumab in these disorders.

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.

Clinical Recommendations for the Management of Biological Treatments in Severe Asthma Patients: A Consensus Statement.

BACKGROUND AND OBJECTIVE: The definition of severe uncontrolled asthma and the best phenotype-driven management are not fully established. Objective: We aimed to reach a consensus on the definition of severe uncontrolled asthma and give recommendations on optimal management with phenotype-targeted biological therapies. METHODS: A modified Delphi technique was used. A scientific committee provided statements addressing the definition of severe uncontrolled asthma and controversial issues about its treatment with biologics. The questionnaire was evaluated in 2 rounds by expert allergists. With the results, the scientific committee developed recommendations and a practical algorithm. RESULTS: A panel of 27 allergists reached agreement on 27 out of the 29 items provided (93.1%). A consensus definition of severe uncontrolled asthma was agreed. Prior to initiation of therapy, it is mandatory to establish the asthma phenotype and assess the presence of clinically important allergic sensitizations. Anti-IgE, anti-IL-5, anti-IL-5 receptor, and anti-IL-13/IL-4 receptor inhibitors are suitable options for patients with allergic asthma and a blood eosinophil level >300/µL (>150/µL in patients receiving oral corticosteroids). IL-5 and anti-IL-5 receptor inhibitors are recommended for patients with an eosinophilic phenotype and can also be used for patients with severe eosinophilic allergic asthma with no or a suboptimal response to omalizumab. Dupilumab is recommended for patients with moderate-severe asthma and a TH2-high phenotype. Only physicians with experience in the treatment of severe uncontrolled asthma should initiate biological treatment. CONCLUSION: We provide consensus clinical recommendations that may be useful in the management of patients with severe uncontrolled asthma.

Genetics and Epigenetics of Nasal Polyposis: A Systematic Review.

Chronic rhinosinusitis (CRS) is an inflammatory disease of the nose and paranasal sinuses that is often associated with nasal polyposis (CRSwNP) in the most severe cases. As in other complex diseases, genetic factors are thought to play an important role in the risk and development of the disease. Environment may also modulate the epigenetic signature in affected patients. In the present systematic review, we aimed to compile all published data on genetic and epigenetic variations in CRSwNP since 2000. We found 104 articles, 24 of which were related to epigenetic studies. We identified more than 150 genetic variants in 99 genes involved in the pathogenesis of nasal polyposis. These were clustered into 8 main networks, linking genes involved in inflammation and immune response (eg, MHC), cytokine genes (eg, TNF), leukotriene metabolism, and the extracellular matrix. A total of 89 miRNAs were also identified; these are associated mainly with biological functions such as the cell cycle, inflammation, and the immune response. We propose a potential relationship between genes and the miRNAs identified that may open new lines of investigation. An in-depth knowledge of gene variants and epigenetic traits could help us to design more tailored treatment for patients with CRSwNP.

ARADyAL: The Spanish Multidisciplinary Research Network for Allergic Diseases.

Thematic cooperative health research networks (RETICS) are organizational structures promoted by the Instituto de Salud Carlos III of the Spanish Ministry of Science with the objective of carrying out cooperative research projects addressing challenges of general interest for society as a whole in the field of health care. The RETICS of Asthma, Adverse Drug Reactions, and Allergy (ARADyAL) received funding in 2016 for a 5-year program (2017-2021). ARADyAL integrates basic and clinical research in the areas of allergy, immunology, genetics, nanomedicine, pharmacology, and chemistry, with special interest in research on new biomarkers and the design and evaluation of new interventions for allergic patients with severe phenotypes. The consortium comprises 28 groups across Spain, including 171 clinical and basic researchers, 17 clinical groups that cover more than 10 000 000 patients of all ages from urban and rural areas and 11 basic groups active mostly at universities and research institutes. ARADyAL has proposed a research program organized into 3 different areas focusing on precision medicine, as follows: Program 1, Mechanisms and prediction of adverse drug reactions and allergic diseases; Program 2, Toward a precise diagnosis of allergic diseases; and Program 3, Predicting interventions in allergic diseases. There is also 1 common program dedicated to training. The network has a Steering Committee and an External Advisory Scientific Committee, which advise the global network coordinator, who has recognized expertise in the field. ARADyAL is a unique meeting point for clinicians and basic scientists who are already working in allergy.

A Comprehensive Prospective Study of the Costs Associated With Evaluation of ß-Lactam Allergy.

BACKGROUND AND OBJECTIVE: Being labeled as allergic to penicillin (unverified ß-lactam allergy) can result in patients receiving broader-spectrum antibiotics than necessary that may be more toxic, less effective, and/or more expensive than alternative options. Objective: We aimed to evaluate the real costs of evaluating ß-lactam allergy. METHODS: We performed a prospective real-life observational study designed to evaluate all adult patients who consulted for suspected ß-lactam allergy over a 1-year period. Direct and indirect costs were systematically recorded. Direct health costs were calculated based on the number of visits and all additional and diagnostic tests performed, direct nonhealth costs based on the number of visits and the distance from their homes to the Allergy Department, and indirect costs based on absenteeism. RESULTS: A total of 296 patients with suspected allergy to ß-lactams were evaluated in our outpatient clinic from June 1, 2017 to May 31, 2018. Total direct health care costs were €28 176.70, with a mean (SD) cost of €95.19 (37.20). Direct nonhealth costs reached €6551.73, that is, €22.13 (40.44) per patient. Indirect health costs reached €20 769.20, with a mean of €70.17 (127.40). In summary, the total cost was €55 497.63, that is, a cost per patient of €187.49 (148.14). CONCLUSIONS: When all possible costs are taken into account, the evaluation of ß-lactam allergy is not expensive and can reduce future expense arising from unnecessary use of more expensive and less effective antibiotics.

Comparison of brain microstructure after prenatal spina bifida repair by either laparotomy-assisted fetoscopic or open approach.

OBJECTIVE: To compare prenatal and postnatal brain microstructure between infants that underwent fetoscopic myelomeningocele (MMC) repair and those that had open-hysterotomy repair. METHODS: This was a longitudinal retrospective cohort study of 57 fetuses that met the Management of Myelomeningocele Study (MOMS) trial criteria and underwent prenatal MMC repair, by a fetoscopic (n = 27) or open-hysterotomy (n = 30) approach, at 21.4-25.9 weeks' gestation. Fetoscopic repair was performed under CO2 insufflation, according to our protocol. Diffusion-weighted magnetic resonance imaging (MRI) was performed before surgery in 30 cases (14 fetoscopic and 16 open), at 6 weeks postsurgery in 48 cases (24 fetoscopic and 24 open) and within the first year after birth in 23 infants (five fetoscopic and 18 open). Apparent diffusion coefficient (ADC) values from the basal ganglia, frontal, occipital and parietal lobes, mesencephalon and genu as well as splenium of the corpus callosum were calculated. ADC values at each of the three timepoints (presurgery, 6 weeks postsurgery and postnatally) and the percentage change in the ADC values between the timepoints were compared between the fetoscopic-repair and open-repair groups. ADC values at 6 weeks after surgery in the two prenatally repaired groups were compared with those in a control group of eight healthy fetuses that underwent MRI at a similar gestational age (GA). Comparison of ADC values was performed using the Student's t-test for independent samples (or Mann-Whitney U-test if non-normally distributed) and multivariate general linear model analysis, adjusting for GA or age at MRI and mean ventricular width. RESULTS: There were no differences in GA at surgery or GA/postnatal age at MRI between the groups. No significant differences were observed in ADC values in any of the brain areas assessed between the open-repair and fetoscopic-repair groups at 6 weeks after surgery and in the first year after birth. No differences were detected in the ADC values of the studied areas between the control and prenatally repaired groups, except for significantly increased ADC values in the genu of the corpus callosum in the open-hysterotomy and fetoscopic-repair groups. Additionally, there were no differences between the two prenatally repaired groups in the percentage change in ADC values at any of the time intervals analyzed. CONCLUSIONS: Fetoscopic MMC repair has no detectable effect on brain microstructure when compared to babies repaired using an open-hysterotomy technique. CO2 insufflation of the uterine cavity during fetoscopy does not seem to have any isolated deleterious effects on fetal brain microstructure. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Promoter Genotyping and mRNA Expression - Based Analysis of the PTGDR Gene in Allergy.

BACKGROUND AND OBJECTIVE: Prostaglandin D2 receptors are acquiring a relevant role as potential therapeutic targets in allergy. PTGDR has been described as a candidate gene in allergic disease, although functional studies on this gene are lacking. Objective: The objective of this case-control study was to investigate the potential role of PTGDR in allergy. METHODS: The study population comprised 195 allergic patients and 112 healthy controls. The PTGDR promoter polymorphisms -1289G>A, -1122T>C, -881C>T, -834C>T, -613C>T, -549T>C, -441C>T, -197T>C, and -95G>T were amplified by polymerase chain reaction (PCR) and sequenced. PTGDR expression levels were analyzed using quantitative PCR and normalized to GAPDH and TBP mRNA levels. All procedures were performed following the Minimum Information for Publication of Quantitative Real-Time PCR Experiment guidelines. RESULTS: PTGDR expression levels were significantly higher in allergic patients than in controls (P<.001). Receiver operating characteristic analysis for expression of PTGDR showed a sensitivity of 81.4% compared with 67% for IgE levels. In addition, differences in the genotypic distribution of the polymorphisms -1289G>A and -1122T>C were found in allergic patients (P=.009). CONCLUSIONS: The results indicate that PTGDR overexpression is associated with allergy. The polymorphisms -1289G>A and -1122T>C partly explain the variation in expression we observed. PTGDR expression could have a potential role as a biomarker and pharmacogenetic factor in allergy.

Does fetoscopic or open repair for spina bifida affect fetal and postnatal growth?

OBJECTIVE: The effect of fetoscopic myelomeningocele (MMC) repair on fetal growth is unknown. Fetal surgery itself and/or exposure to a carbon dioxide (CO2 ) environment during spina bifida repair may affect placental function and impair fetal growth. Our aim was to assess and compare growth in fetuses, neonates and infants who underwent prenatal fetoscopic or open MMC repair. METHODS: Fetal biometrics were obtained serially using ultrasound after fetoscopic (n = 32) or open hysterotomy (n = 34) MMC repair in utero at a single institution between November 2011 and July 2017. Measurements obtained during growth scans on initial evaluation prior to surgery, and those taken at 6 weeks post-surgery, were transformed into percentiles and compared between groups. Additional neonatal and infant anthropometric measurements, including weight, length/height and head circumference, were also transformed into percentiles and compared between the groups. The proportions of cases in each group with estimated fetal weight (EFW) or postnatal weight < 10th and < 3rd percentiles were calculated and compared. A linear mixed model was used to analyze the serial fetal growth measurements of each parameter, and random intercepts and slopes were used to compare study variables between the study groups. The duration of surgery (skin-to-skin time at fetoscopic and open MMC repair) and duration of CO2 exposure (fetoscopic repair) were evaluated for any effect on the fetal, neonatal or infant biometric percentiles. RESULTS: Fetuses which underwent fetoscopic repair had a larger abdominal circumference percentile at referral (57 ± 21 vs 46 ± 23; P = 0.04). There were no other differences between the two groups in fetal biometric percentiles at the time of referral, 6 weeks post-surgery or at birth. There were no differences between groups in EFW percentile or in proportions of cases with birth weight < 10th and < 3rd percentiles. Linear mixed-model analysis did not show any significant differences in any fetal growth parameter between the groups over time. There were no significant correlations between duration of surgery or duration of CO2 exposure and any of the biometric percentiles evaluated. Postnatal growth showed no significant differences between the groups in weight, height or head circumference percentiles, at 6-18, 18-30 or > 30 months of age. CONCLUSIONS: Babies exposed to fetoscopic or open MMC repair in-utero did not show significant differences in fetal or postnatal growth parameters. These results support the safety of the use of CO2 gas for fetoscopic surgery. Copyright © 2019 ISUOG. Published by John Wiley & Sons Ltd.

Adjuvants in Allergen-Specific Immunotherapy: Modulating and Enhancing the Immune Response.

Allergen-specific immunotherapy (AIT) is the only treatment that can affect the natural course of allergic diseases such as allergic asthma, allergic rhinitis, and IgE-mediated food allergy. Adjuvants are used to induce a quicker, more potent, and longer-lasting immune response. Only 4 compounds are used as adjuvants in currently marketed AIT products: aluminum hydroxide, calcium phosphate, microcrystalline tyrosine (MCT), and monophosphoryl lipid A (MPL). The first 3 adjuvants are delivery systems with a depot effect, although they may also have immunomodulatory properties. These first-generation adjuvants are still widely used, especially aluminum hydroxide. However, aluminum is subject to limitations. MCT is the depot formulation of L-tyrosine; it enhances IgG production without inducing a significant increase in IgE, is biodegradable, and has good local and systemic tolerability. In turn, MPL is an immunostimulatory agent that is the only second-generation adjuvant currently used for AIT. In addition, multiple adjuvants are currently being studied, including immunostimulatory sequences (ISSs), nanoparticles (liposomes, virus-like particles, and biodegradable polymers), and phosphatidylserine derivatives. In a murine model of allergic bronchial inflammation by sensitization to olive pollen, the specific IgE level was significantly higher in sensitized mice treated with olive pollen and aluminum hydroxide. However, specific IgE levels were significantly reduced and bronchial hyperreactivity significantly improved in sensitized mice treated with olive pollen and bacterial derivatives (MPL or ISSs).

National clinical practice guidelines for allergen immunotherapy: An international assessment applying AGREE-II.

BACKGROUND: Since 1988, numerous allergen immunotherapy guidelines (AIT-GLs) have been developed by national and international organizations to guide physicians in AIT. Even so, AIT is still severely underused. OBJECTIVE: To evaluate AIT-GLs with AGREE-II, developed in 2010 by McMaster University methodologists to comprehensively evaluate GL quality. METHODS: Allergist, from different continents, knowledgeable in AIT and AGREE-II trained were selected into the project team. The project received methodologists' guidance. AIT-GLs in any language were sought from 1980 to 2016; AIT-GLs were AGREE II-evaluated by at least 2 team members, independently; discrepancies were resolved in a second round, by team discussion or methodologists' consulting. RESULTS: We found 31 AIT-GLs (15 post-2010), ranging from local consensus reports to international position papers (EAACI, AAAAI-ACAAI, WAO). Pre-2010 GLs scored 1.6-4.6 (23%-67%) and post-2010 GLs scored 2.1-6 (30%-86%), on a 7-point Likert scale. The highest scores went to: German-Austrian-Swiss (6.0), Mexican (5.1), and the AAAAI/ACAAI AIT-GL (4.7). These were also the only 3 GLs that received "yes" of both evaluators to the item: "I would recommend this GL for use." The domains of "Stakeholder involvement" and "Rigor of Development" only scored 3/7, and "Applicability" scored the lowest. Strikingly, newer GLs only scored clearly better in "Editorial independence" and "Global evaluation." CONCLUSIONS: In AIT-GLs, there is still a lot of room for improvement, especially in domains crucial for the dissemination. For some GLs, the "Scientific rigor" domain flawed. When resources are limited, transculturizing a high-quality GL might be preferable over developing a GL from zero. Our study and AGREE-II could help to select the best candidate. CLINICAL IMPLICATIONS: We here evaluate allergen immunotherapy guideline (AIT-GL) quality. Only high-quality AIT-GLs should be consulted for AIT management decisions. In low-resource settings, transculturization of these is preferred over developing low-quality guidelines.

Consensus document on dog and cat allergy.

The prevalence of sensitization to dogs and cats varies by country, exposure time and predisposition to atopy. It is estimated that 26% of European adults coming to the clinic for suspected allergy to inhalant allergens are sensitized to cats and 27% to dogs. This document is intended to be a useful tool for clinicians involved in the management of people with dog or cat allergy. It was prepared from a consensus process based on the RAND/UCLA method. Following a literature review, it proposes various recommendations concerning the diagnosis and treatment of these patients, grounded in evidence and clinical experience. The diagnosis of dog and cat allergy is based on a medical history and physical examination that are consistent with each other and is confirmed with positive results on specific IgE skin tests. Sometimes, especially in polysensitized patients, molecular diagnosis is strongly recommended. Although the most advisable measure would be to avoid the animal, this is often impossible and associated with a major emotional impact. Furthermore, indirect exposure to allergens occurs in environments in which animals are not present. Immunotherapy is emerging as a potential solution to this problem, although further supporting studies are needed.

Dupilumab: A New Paradigm for the Treatment of Allergic Diseases.

Moderate and severe forms of allergic diseases such as atopic dermatitis and asthma are a challenge for clinicians. In these conditions, which severely affect the quality of life of the patient and frequently have associated allergic comorbidities, the therapeutic options are often very limited. Treatment with systemic corticosteroids and immunosuppressants has adverse effects in the long term, and a significant proportion of patients remain refractory to therapy. In this context, the emerging biological drugs constitute a truly innovative therapeutic approach. A leading example is dupilumab, a monoclonal antibody targeting the α chain of the interleukin (IL)-4 receptor. Dupilumab inhibits the biological effects of the cytokines IL-4 and IL-13, which are key drivers in the TH2 response. The efficacy and safety profile of dupilumab in the treatment of allergic diseases has been tested for more than 10 years in a variety of large clinical trials in atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, and eosinophilic esophagitis. In 2017, the United States Food and Drug Administration and the European Medicines Agency approved the use of dupilumab for the treatment of adult patients with moderateto-severe atopic dermatitis whose disease is not adequately controlled with prescribed topical treatment. The results of phase III clinical studies of dupilumab in patients with persistent, uncontrolled asthma have been highly promising. The safety and tolerability profile of dupilumab has proven to be very favorable in long-term clinical trials. In this review, we focus on the mechanism of action of dupilumab, its development, and its impact on daily clinical practice in allergic diseases.