Rhinitis associated with asthma is distinct from rhinitis alone: The ARIA-MeDALL hypothesis.

Asthma, rhinitis, and atopic dermatitis (AD) are interrelated clinical phenotypes that partly overlap in the human interactome. The concept of "one-airway-one-disease," coined over 20 years ago, is a simplistic approach of the links between upper- and lower-airway allergic diseases. With new data, it is time to reassess the concept. This article reviews (i) the clinical observations that led to Allergic Rhinitis and its Impact on Asthma (ARIA), (ii) new insights into polysensitization and multimorbidity, (iii) advances in mHealth for novel phenotype definitions, (iv) confirmation in canonical epidemiologic studies, (v) genomic findings, (vi) treatment approaches, and (vii) novel concepts on the onset of rhinitis and multimorbidity. One recent concept, bringing together upper- and lower-airway allergic diseases with skin, gut, and neuropsychiatric multimorbidities, is the "Epithelial Barrier Hypothesis." This review determined that the "one-airway-one-disease" concept does not always hold true and that several phenotypes of disease can be defined. These phenotypes include an extreme "allergic" (asthma) phenotype combining asthma, rhinitis, and conjunctivitis. Rhinitis alone and rhinitis and asthma multimorbidity represent two distinct diseases with the following differences: (i) genomic and transcriptomic background (Toll-Like Receptors and IL-17 for rhinitis alone as a local disease; IL-33 and IL-5 for allergic and non-allergic multimorbidity as a systemic disease), (ii) allergen sensitization patterns (mono- or pauci-sensitization versus polysensitization), (iii) severity of symptoms, and (iv) treatment response. In conclusion, rhinitis alone (local disease) and rhinitis with asthma multimorbidity (systemic disease) should be considered as two distinct diseases, possibly modulated by the microbiome, and may be a model for understanding the epidemics of chronic and autoimmune diseases.

Gut microbial-derived short-chain fatty acids and bone: a potential role in fracture healing.

Bone healing complications such as delayed healing or non-union affect 5-10 % of patients with a long-bone fracture and lead to reduced quality of life and increased health-care costs. The gut microbiota and the metabolites they produce, mainly short-chain fatty acids (SCFAs), have been shown to impact nearly all organs of the human body including bone. SCFAs show broad activity in positively influencing bone healing outcomes either by acting directly on cell types involved in fracture healing, such as osteoblasts, osteoclasts, chondrocytes and fibroblasts, or indirectly, by shaping an appropriate anti-inflammatory and immune regulatory response. Due to the ability of SCFAs to influence osteoblast and osteoclast differentiation, SCFAs may also affect the integration of orthopaedic implants in bone. In addition, SCFA-derivatives have already been used in a variety of tissue engineering constructs to reduce inflammation and induce bone tissue production. The present review summarises the current knowledge on the role of the gut microbiota, in particular through the action of SCFAs, in the individual stages of bone healing and provides insights into how SCFAs may be utilised in a manner beneficial for fracture healing and surgical reconstruction.

Highlights and recent developments in allergic diseases in EAACI journals (2019).

The European Academy of Allergy and Clinical Immunology (EAACI) owns three journals: Allergy, Pediatric Allergy and Immunology and Clinical and Translational Allergy. One of the major goals of EAACI is to support health promotion in which prevention of allergy and asthma plays a critical role and to disseminate the knowledge of allergy to all stakeholders including the EAACI junior members. There was substantial progress in 2019 in the identification of basic mechanisms of allergic and respiratory disease and the translation of these mechanisms into clinics. Better understanding of molecular and cellular mechanisms, efforts for the development of biomarkers for disease prediction, novel prevention and intervention studies, elucidation of mechanisms of multimorbidities, entrance of new drugs in the clinics as well as recently completed phase three clinical studies and publication of a large number of allergen immunotherapy studies and meta-analyses have been the highlights of the last year.

Correction to: Highlights and recent developments in skin allergy and related diseases in EAACI journals (2018).

[This corrects the article DOI: 10.1186/s13601-019-0299-y.].

Trigeminal endonasal perception - an outcome predictor for septoplasty.

BACKGROUND: No adequate test exists to predict outcome after septoplasty. Despite adequate surgery, patients still might experience nasal breathing impairment. The aim of this study was to determine if pre-operative trigeminal sensitivity can predict satisfaction after septoplasty. METHODS: Single centre prospective cohort study in tertiary referral centre with follow-up time of 6 weeks postoperatively. Patients scheduled for septoplasty or septorhinoplasty with turbinoplasty were consecutively selected the day before surgery. Standard preoperative examinations (acoustic rhinometry and Sniffin’ Sticks 12 test), the evaluation of nasal obstruction on a visual analogue scale (VAS) and the trigeminal lateralisation task were performed before and 6 weeks after surgery. Biopsies were taken during surgery and TRPV1 mRNA expression was measured by PCR. RESULTS: Thirty patients were included with a median age of 29 years and equal gender distribution. Trigeminal perception and sensation of nasal obstruction showed a significant correlation: preoperative lateralisation test scores, representing endonasal trigeminal sensitivity, correlated significantly with the mean VAS change scores, which demonstrate subjective improvement. A lateralisation test score of 31.5 and more had a sensitivity of 88% to predict an improvement of more than 3 VAS points. Additionally, high TRPV1 mRNA expression was linked with good postoperative VAS scores. CONCLUSION: The preoperative evaluation of the trigeminal sensitivity could improve patients’ selection for septoplasty with a higher rate of satisfaction. Endonasal trigeminal sensitivity is directly linked with subjective outcome. Therefore, patients with low trigeminal sensitivity should undergo septoplasty only after thorough counselling.

Highlights and recent developments in skin allergy and related diseases in EAACI journals (2018).

The European Academy of Allergy and Clinical Immunology (EAACI) supports three journals: Allergy, Paediatric Allergy and Immunology as well as Clinical and Translational Allergy. The major goals of EAACI include (i) supporting health promotion in which the prevention of allergy and asthma plays a critical role and (ii) disseminating the knowledge of allergy to all stakeholders including the EAACI junior members. Substantial progress was made in 2018 in the identification of basic mechanisms of atopic dermatitis and urticaria and the translation of these mechanisms into clinics. Many large epidemiologic studies and meta-analyses have been the highlights of the last year.

Highlights and recent developments in airway diseases in EAACI journals (2017).

The European Academy of Allergy and Clinical Immunology (EAACI) owns three journals: Allergy, Pediatric Allergy and Immunology and Clinical and Translational Allergy. One of the major goals of EAACI is to support health promotion in which prevention of allergy and asthma plays a critical role and to disseminate the knowledge of allergy to all stakeholders including the EAACI junior members. There was substantial progress in 2017 in the identification of basic mechanisms of allergic and respiratory disease and the translation of these mechanisms into clinics. Better understanding of molecular and cellular mechanisms, efforts for the development of biomarkers for disease prediction, novel prevention and intervention studies, elucidation of mechanisms of multimorbidies, entrance of new drugs in the clinics as well as recently completed phase three clinical studies and publication of a large number of allergen immunotherapy studies and metaanalyses have been the highlights of the last year.

Exopolysaccharide from Bifidobacterium longum subsp. longum 35624™ modulates murine allergic airway responses.

Interactions between the host and the microbiota are thought to significantly influence immunological tolerance mechanisms at mucosal sites. We recently described that the loss of an exopolysaccharide (EPS) from Bifidobacterium longum 35624™ eliminated its protective effects in colitis and respiratory allergy murine models. Our goal was to investigate the immune response to purified EPS from B. longum 35624, determine if it has protective effects within the lung and identify the protective mechanisms. Isolated EPS from B. longum 35624 cultures was used for in vitro, ex vivo and in vivo studies. Human monocyte-derived dendritic cells (MDDCs) were used to investigate in vitro immunological responses to EPS. Cytokine secretion, expression of surface markers and signalling pathways were examined. The ovalbumin (OVA) respiratory allergy murine model was used to evaluate the in vivo immunomodulatory potential of EPS. In addition, interleukin (IL)-10 knockout (KO) mice and anti-Toll-like receptor (TLR)-2 blocking antibody were used to examine the underlying protective mechanisms of intranasal EPS administration. Stimulation of human MDDCs with EPS resulted in IL-10 secretion, but not proinflammatory cytokines. IL-10 secretion was TLR-2-dependent. Eosinophil recruitment to the lungs was significantly decreased by EPS intranasal exposure, which was associated with decreased expression of the Th2-associated markers C-C motif chemokine 11 (CCL11), C-C chemokine receptor type 3 (CCR3), IL-4 and IL-13. TLR-2-mediated IL-10 secretion was shown to be required for the reduction in eosinophils and Th2 cytokines. EPS-treatment reduced eosinophil recruitment within the lung in a respiratory inflammation mouse model, which is both TLR-2 and IL-10 mediated. EPS can be considered as a novel molecule potentially reducing the severity of chronic eosinophil-related airway disorders.

EAACI Guidelines on Allergen Immunotherapy: Allergic rhinoconjunctivitis.

Allergic rhinoconjunctivitis (AR) is an allergic disorder of the nose and eyes affecting about a fifth of the general population. Symptoms of AR can be controlled with allergen avoidance measures and pharmacotherapy. However, many patients continue to have ongoing symptoms and an impaired quality of life; pharmacotherapy may also induce some side-effects. Allergen immunotherapy (AIT) represents the only currently available treatment that targets the underlying pathophysiology, and it may have a disease-modifying effect. Either the subcutaneous (SCIT) or sublingual (SLIT) routes may be used. This Guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on AIT for AR and is part of the EAACI presidential project "EAACI Guidelines on Allergen Immunotherapy." It aims to provide evidence-based clinical recommendations and has been informed by a formal systematic review and meta-analysis. Its generation has followed the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included involvement of the full range of stakeholders. In general, broad evidence for the clinical efficacy of AIT for AR exists but a product-specific evaluation of evidence is recommended. In general, SCIT and SLIT are recommended for both seasonal and perennial AR for its short-term benefit. The strongest evidence for long-term benefit is documented for grass AIT (especially for the grass tablets) where long-term benefit is seen. To achieve long-term efficacy, it is recommended that a minimum of 3 years of therapy is used. Many gaps in the evidence base exist, particularly around long-term benefit and use in children.

EAACI Guidelines on allergen immunotherapy: IgE-mediated food allergy.

Food allergy can result in considerable morbidity, impairment of quality of life, and healthcare expenditure. There is therefore interest in novel strategies for its treatment, particularly food allergen immunotherapy (FA-AIT) through the oral (OIT), sublingual (SLIT), or epicutaneous (EPIT) routes. This Guideline, prepared by the European Academy of Allergy and Clinical Immunology (EAACI) Task Force on Allergen Immunotherapy for IgE-mediated Food Allergy, aims to provide evidence-based recommendations for active treatment of IgE-mediated food allergy with FA-AIT. Immunotherapy relies on the delivery of gradually increasing doses of specific allergen to increase the threshold of reaction while on therapy (also known as desensitization) and ultimately to achieve post-discontinuation effectiveness (also known as tolerance or sustained unresponsiveness). Oral FA-AIT has most frequently been assessed: here, the allergen is either immediately swallowed (OIT) or held under the tongue for a period of time (SLIT). Overall, trials have found substantial benefit for patients undergoing either OIT or SLIT with respect to efficacy during treatment, particularly for cow's milk, hen's egg, and peanut allergies. A benefit post-discontinuation is also suggested, but not confirmed. Adverse events during FA-AIT have been frequently reported, but few subjects discontinue FA-AIT as a result of these. Taking into account the current evidence, FA-AIT should only be performed in research centers or in clinical centers with an extensive experience in FA-AIT. Patients and their families should be provided with information about the use of FA-AIT for IgE-mediated food allergy to allow them to make an informed decision about the therapy.

EAACI guidelines on allergen immunotherapy: Hymenoptera venom allergy.

Hymenoptera venom allergy is a potentially life-threatening allergic reaction following a honeybee, vespid, or ant sting. Systemic-allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate to severe with a risk of life-threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H1 -antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence-based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta-analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom-allergic children and adults to prevent further moderate-to-severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline autoinjector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence-based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence.

Respiratory syncytial virus infection influences tight junction integrity.

Respiratory syncytial virus (RSV) is an important risk factor of asthma development and is responsible for severe respiratory tract infections. However, the influence of RSV infection on barrier function of bronchial epithelial cells in vitro and in vivo is still unclear. The aim of this study was to analyse the role of RSV in tight junction (TJ) regulation and to compare epithelial integrity between asthmatic and healthy individuals upon RSV infection. Healthy and asthmatic human bronchial epithelial cells (HBECs) were differentiated at air-liquid interface (ALI) and infected with RSV and ultraviolet (UV)-irradiated RSV. TJ expression and their integrity were analysed by quantitative polymerase chain reaction (qPCR), transepithelial resistance (TER) and paracellular flux. To determine the effect in vivo, BALB/c mice were infected intranasally with RSV or UV-irradiated RSV A2. Bronchoalveolar lavage and TJ integrity were analysed on days 1, 2, 4 and 6 post-infection by qPCR, bioplex and confocal microscopy. RSV increased barrier integrity in ALI cultures of HBEC from healthy subjects, but no effect was found in HBECs from asthmatics. This was not associated with an increase in TJ mRNA expression. In vivo, RSV induced lung inflammation in mice and down-regulated claudin-1 and occludin mRNA expression in whole lungs. Surprisingly, RSV infection was not observed in bronchial epithelial cells, but was found in the lung parenchyma. Decreased expression of occludin upon RSV infection was visible in mouse bronchial epithelial cells in confocal microscopy. However, there was no regulation of claudin-1 and claudin-7 at protein level.

Histamine receptor 2 modifies iNKT cell activity within the inflamed lung.

BACKGROUND: Histamine is a key immunoregulatory mediator and can dampen proinflammatory responses via activation of histamine receptor 2 (H2 R). The aim of this study was to determine the role of H2 R in modulating lung inflammatory responses. METHODS: H2 R was blocked using famotidine or activated using dimaprit in both the ovalbumin (OVA) and house dust mite extract (HDM) murine models of respiratory inflammation. H2 R-deficient animals and CD1d/H2 R-deficient animals were utilized to examine the CD1d presentation of lipid antigens (αGalCer or OCH) to invariant natural killer T (iNKT) cells. RESULTS: Famotidine treatment resulted in more severe airway disease in the OVA model, while dimaprit treatment significantly reduced disease severity. Both OVA and HDM-induced airway diseases were more severe in H2 R-deficient animals. Flow cytometric analysis of lung tissue from H2 R-deficient animals revealed increased numbers of CD1d+ dendritic cells and increased numbers of iNKT cells. In vitro, αGalCer-stimulated iNKT cells from H2 R-deficient mice secreted higher levels of IL-4, IL-5, and GM-CSF. In vivo, αGalCer or OCH administration to the lung resulted in enhanced mucus secretion, inflammatory cell recruitment, and cytokine production in H2 R-deficient or famotidine-treated animals, while dimaprit dampened the lung iNKT cell response to αGalCer. Removal of iNKT cells in H2 R-deficient (CD1d-/- H2 R-/- ) animals normalized the lung response to HDM. CONCLUSION: The deliberate activation of H2 R, or its downstream signaling molecules, may represent a novel therapeutic target for chronic lung inflammatory diseases, especially when CD1d-mediated presentation of lipid antigens to iNKT cells is contributing to the pathology.

EUFOREA Rhinology Research Forum 2016: report of the brainstorming sessions on needs and priorities in rhinitis and rhinosinusitis.

The first European Rhinology Research Forum organized by the European Forum for Research and Education in Allergy and Airway Diseases (EUFOREA) was held in the Royal Academy of Medicine in Brussels on 17th and 18th November 2016, in collaboration with the European Rhinologic Society (ERS) and the Global Allergy and Asthma European Network (GA2LEN). One hundred and thirty participants (medical doctors from different specialties, researchers, as well as patients and industry representatives) from 27 countries took part in the multiple perspective discussions including brainstorming sessions on care pathways and research needs in rhinitis and rhinosinusitis. The debates started with an overview of the current state of the art, including weaknesses and strengths of the current practices, followed by the identification of essential research needs, thoroughly integrated in the context of Precision Medicine (PM), with personalized care, prediction of success of treatment, participation of the patient and prevention of disease as key principles for improving current clinical practices. This report provides a concise summary of the outcomes of the brainstorming sessions of the European Rhinology Research Forum 2016.

Allergen immunotherapy for allergic asthma: A systematic review and meta-analysis.

BACKGROUND: To inform the development of the European Academy of Allergy and Clinical Immunology's (EAACI) Guidelines on Allergen Immunotherapy (AIT) for allergic asthma, we assessed the evidence on the effectiveness, cost-effectiveness and safety of AIT. METHODS: We performed a systematic review, which involved searching nine databases. Studies were screened against predefined eligibility criteria and critically appraised using established instruments. Data were synthesized using random-effects meta-analyses. RESULTS: 98 studies satisfied the inclusion criteria. Short-term symptom scores were reduced with a standardized mean difference (SMD) of -1.11 (95% CI -1.66, -0.56). This was robust to a prespecified sensitivity analyses, but there was evidence suggestive of publication bias. Short-term medication scores were reduced SMD -1.21 (95% CI -1.87, -0.54), again with evidence of potential publication bias. There was no reduction in short-term combined medication and symptom scores SMD 0.17 (95% CI -0.23, 0.58), but one study showed a beneficial long-term effect. For secondary outcomes, subcutaneous immunotherapy (SCIT) improved quality of life and decreased allergen-specific airway hyperreactivity (AHR), but this was not the case for sublingual immunotherapy (SLIT). There were no consistent effects on asthma control, exacerbations, lung function, and nonspecific AHR. AIT resulted in a modest increased risk of adverse events (AEs). Although relatively uncommon, systemic AEs were more frequent with SCIT; however no fatalities were reported. The limited evidence on cost-effectiveness was mainly available for sublingual immunotherapy (SLIT) and this suggested that SLIT is likely to be cost-effective. CONCLUSIONS: AIT can achieve substantial reductions in short-term symptom and medication scores in allergic asthma. It was however associated with a modest increased risk of systemic and local AEs. More data are needed in relation to secondary outcomes, longer-term effectiveness and cost-effectiveness.

Altered fatty acid metabolism and reduced stearoyl-coenzyme a desaturase activity in asthma.

BACKGROUND: Fatty acids and lipid mediator signaling play an important role in the pathogenesis of asthma, yet this area remains largely underexplored. The aims of this study were (i) to examine fatty acid levels and their metabolism in obese and nonobese asthma patients and (ii) to determine the functional effects of altered fatty acid metabolism in experimental models. METHODS: Medium- and long-chain fatty acid levels were quantified in serum from 161 human volunteers by LC/MS. Changes in stearoyl-coenzyme A desaturase (SCD) expression and activity were evaluated in the ovalbumin (OVA) and house dust mite (HDM) murine models. Primary human bronchial epithelial cells from asthma patients and controls were evaluated for SCD expression and activity. RESULTS: The serum desaturation index (an indirect measure of SCD) was significantly reduced in nonobese asthma patients and in the OVA murine model. SCD1 gene expression was significantly reduced within the lungs following OVA or HDM challenge. Inhibition of SCD in mice promoted airway hyper-responsiveness. SCD1 expression was suppressed in bronchial epithelial cells from asthma patients. IL-4 and IL-13 reduced epithelial cell SCD1 expression. Inhibition of SCD reduced surfactant protein C expression and suppressed rhinovirus-induced IP-10 secretion, which was associated with increased viral titers. CONCLUSIONS: This is the first study to demonstrate decreased fatty acid desaturase activity in humans with asthma. Experimental models in mice and human epithelial cells suggest that inhibition of desaturase activity leads to airway hyper-responsiveness and reduced antiviral defense. SCD may represent a new target for therapeutic intervention in asthma patients.

Positioning the principles of precision medicine in care pathways for allergic rhinitis and chronic rhinosinusitis - A EUFOREA-ARIA-EPOS-AIRWAYS ICP statement.

Precision medicine (PM) is increasingly recognized as the way forward for optimizing patient care. Introduced in the field of oncology, it is now considered of major interest in other medical domains like allergy and chronic airway diseases, which face an urgent need to improve the level of disease control, enhance patient satisfaction and increase effectiveness of preventive interventions. The combination of personalized care, prediction of treatment success, prevention of disease and patient participation in the elaboration of the treatment plan is expected to substantially improve the therapeutic approach for individuals suffering from chronic disabling conditions. Given the emerging data on the impact of patient stratification on treatment outcomes, European and American regulatory bodies support the principles of PM and its potential advantage over current treatment strategies. The aim of the current document was to propose a consensus on the position and gradual implementation of the principles of PM within existing adult treatment algorithms for allergic rhinitis (AR) and chronic rhinosinusitis (CRS). At the time of diagnosis, prediction of success of the initiated treatment and patient participation in the decision of the treatment plan can be implemented. The second-level approach ideally involves strategies to prevent progression of disease, in addition to prediction of success of therapy, and patient participation in the long-term therapeutic strategy. Endotype-driven treatment is part of a personalized approach and should be positioned at the tertiary level of care, given the efforts needed for its implementation and the high cost of molecular diagnosis and biological treatment.

Erratum to: Scaling up strategies of the chronic respiratory disease programme of the European Innovation Partnership on Active and Healthy Ageing (Action Plan B3: Area 5).

[This corrects the article DOI: 10.1186/s13601-016-0116-9.].

Allergen immunotherapy for insect venom allergy: a systematic review and meta-analysis.

BACKGROUND: The European Academy of Allergy and Clinical Immunology (EAACI) is in the process of developing the EAACI Guidelines on Allergen Immunotherapy (AIT) for the management of insect venom allergy. To inform this process, we sought to assess the effectiveness, cost-effectiveness and safety of AIT in the management of insect venom allergy. METHODS: We undertook a systematic review, which involved searching 15 international biomedical databases for published and unpublished evidence. Studies were independently screened and critically appraised using established instruments. Data were descriptively summarized and, where possible, meta-analysed. RESULTS: Our searches identified a total of 16 950 potentially eligible studies; of which, 17 satisfied our inclusion criteria. The available evidence was limited both in volume and in quality, but suggested that venom immunotherapy (VIT) could substantially reduce the risk of subsequent severe systemic sting reactions (OR = 0.08, 95% CI 0.03-0.26); meta-analysis showed that it also improved disease-specific quality of life (risk difference = 1.41, 95% CI 1.04-1.79). Adverse effects were experienced in both the build-up and maintenance phases, but most were mild with no fatalities being reported. The very limited evidence found on modelling cost-effectiveness suggested that VIT was likely to be cost-effective in those at high risk of repeated systemic sting reactions and/or impaired quality of life. CONCLUSIONS: The limited available evidence suggested that VIT is effective in reducing severe subsequent systemic sting reactions and in improving disease-specific quality of life. VIT proved to be safe and no fatalities were recorded in the studies included in this review. The cost-effectiveness of VIT needs to be established.