Nasal and blood transcriptomic pathways underpinning the clinical response to grass pollen immunotherapy.

BACKGROUND: Allergen immunotherapy (AIT) is a well-established disease-modifying therapy for allergic rhinitis, yet the fundamental mechanisms underlying its clinical effect remain inadequately understood. Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy was a randomized, double-blind, placebo-controlled trial of individuals allergic to timothy grass who received 2 years of placebo (n = 30), subcutaneous immunotherapy (SCIT) (n = 27), or sublingual immunotherapy (SLIT) (n = 27) and were then followed for 1 additional year. OBJECTIVE: We used yearly biospecimens from the Gauging Response in Allergic Rhinitis to Sublingual and Subcutaneous Immunotherapy study to identify molecular mechanisms of response. METHODS: We used longitudinal transcriptomic profiling of nasal brush and PBMC samples after allergen provocation to uncover airway and systemic expression pathways mediating responsiveness to AIT. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01335139, EudraCT Number: 2010-023536-16. RESULTS: SCIT and SLIT demonstrated similar changes in gene module expression over time. In nasal samples, alterations included downregulation of pathways of mucus hypersecretion, leukocyte migration/activation, and endoplasmic reticulum stress (log2 fold changes -0.133 to -0.640, false discovery rates [FDRs] <0.05). We observed upregulation of modules related to epithelial development, junction formation, and lipid metabolism (log2 fold changes 0.104 to 0.393, FDRs <0.05). In PBMCs, modules related to cellular stress response and type 2 cytokine signaling were reduced by immunotherapy (log2 fold changes -0.611 to -0.828, FDRs <0.05). Expression of these modules was also significantly associated with both Total Nasal Symptom Score and peak nasal inspiratory flow, indicating important links between treatment, module expression, and allergen response. CONCLUSIONS: Our results identify specific molecular responses of the nasal airway impacting barrier function, leukocyte migration activation, and mucus secretion that are affected by both SCIT and SLIT, offering potential targets to guide novel strategies for AIT.

AllergoOncology: Danger signals in allergology and oncology: A European Academy of Allergy and Clinical Immunology (EAACI) Position Paper.

The immune system interacts with many nominal 'danger' signals, endogenous danger-associated (DAMP), exogenous pathogen (PAMP) and allergen (AAMP)-associated molecular patterns. The immune context under which these are received can promote or prevent immune activating or inflammatory mechanisms and may orchestrate diverse immune responses in allergy and cancer. Each can act either by favouring a respective pathology or by supporting the immune response to confer protective effects, depending on acuity or chronicity. In this Position Paper under the collective term danger signals or DAMPs, PAMPs and AAMPs, we consider their diverse roles in allergy and cancer and the connection between these in AllergoOncology. We focus on their interactions with different immune cells of the innate and adaptive immune system and how these promote immune responses with juxtaposing clinical outcomes in allergy and cancer. While danger signals present potential targets to overcome inflammatory responses in allergy, these may be reconsidered in relation to a history of allergy, chronic inflammation and autoimmunity linked to the risk of developing cancer, and with regard to clinical responses to anti-cancer immune and targeted therapies. Cross-disciplinary insights in AllergoOncology derived from dissecting clinical phenotypes of common danger signal pathways may improve allergy and cancer clinical outcomes.

Allergen-specific IgG+ memory B cells are temporally linked to IgE memory responses.

BACKGROUND: IgE is the least abundant immunoglobulin and tightly regulated, and IgE-producing B cells are rare. The cellular origin and evolution of IgE responses are poorly understood. OBJECTIVE: The cellular and clonal origin of IgE memory responses following mucosal allergen exposure by sublingual immunotherapy (SLIT) were investigated. METHODS: In a randomized double-blind, placebo-controlled, time course SLIT study, PBMCs and nasal biopsy samples were collected from 40 adults with seasonal allergic rhinitis at baseline and at 4, 8, 16, 28, and 52 weeks. RNA was extracted from PBMCs, sorted B cells, and nasal biopsy samples for heavy chain variable gene repertoire sequencing. Moreover, mAbs were derived from single B-cell transcriptomes. RESULTS: Combining heavy chain variable gene repertoire sequencing and single-cell transcriptomics yielded direct evidence of a parallel boost of 2 clonally and functionally related B-cell subsets of short-lived IgE+ plasmablasts and IgG+ memory B cells. Mucosal grass pollen allergen exposure by SLIT resulted in highly diverse IgE and IgGE repertoires. These were extensively mutated and appeared relatively stable as per heavy chain isotype, somatic hypermutations, and clonal composition. Single IgGE+ memory B-cell and IgE+ preplasmablast transcriptomes encoded antibodies that were specific for major grass pollen allergens and able to elicit basophil activation at very low allergen concentrations. CONCLUSION: For the first time, we have shown that on mucosal allergen exposure, human IgE memory resides in allergen-specific IgG+ memory B cells. These cells rapidly switch isotype, expand into short-lived IgE+ plasmablasts, and serve as a potential target for therapeutic intervention.

Fiction, Falsehoods, and Few Facts: Cross-Sectional Study on the Content-Related Quality of Atopic Eczema-Related Videos on YouTube.

BACKGROUND: In recent years, YouTube has become a recognized source of medical information for health care consumers. Although YouTube has advantages in this context, there are potential dangers as videos may contain nonscientific, misleading, or even harmful information. OBJECTIVE: As little is known about YouTube as a source of information on atopic dermatitis (AD), we investigated the content-related quality of AD videos and their perception among YouTube users. METHODS: The quality of the 100 most viewed AD videos was assessed by using the Global Quality Scale (GQS) and the DISCERN instrument. Videos were classified as "useful," "misleading," and "potentially harmful," and the correlations of viewers' ratings (likes) with the GQS and DISCERN scores were assessed. RESULTS: Among the 100 videos, 68.0% (68/100) and 62.0% (62/100) were of poor and very poor scientific quality, respectively. Additionally, 32.0% (32/100) of the videos were classified as useful, 48.0% (48/100) were classified as misleading, and 34.0% (34/100) were classified as potentially harmful. Viewers' ratings did not correlate with the GQS and DISCERN scores. Overall, 50.0% (50/100) of the videos were posted by private individuals and promoters of complementary/alternative treatments, 42.0% (42/100) by therapeutical advertisers, and only 8.0% (8/100) by nonprofit organizations/universities. CONCLUSIONS: Our study demonstrated that two-thirds of the videos analyzed were below acceptable medical quality standards and that many videos were disseminating misleading or even dangerous content. Subjective and anecdotal content was overrepresented, and viewers did not appear to be able to distinguish between high- and low-quality videos. Health promotion strategies by professional medical organizations are needed to improve their presence and visibility on YouTube.

Nasal allergen-neutralizing IgG4 antibodies block IgE-mediated responses: Novel biomarker of subcutaneous grass pollen immunotherapy.

BACKGROUND: Grass pollen subcutaneous immunotherapy (SCIT) is associated with induction of serum IgG4-associated inhibitory antibodies that prevent IgE-facilitated allergen binding to B cells. OBJECTIVE: We sought to determine whether SCIT induces nasal allergen-specific IgG4 antibodies with inhibitory activity that correlates closely with clinical response. METHODS: In a cross-sectional controlled study, nasal fluid and sera were collected during the grass pollen season from 10 SCIT-treated patients, 13 untreated allergic patients (with seasonal allergic rhinitis [SAR]), and 12 nonatopic control subjects. Nasal and serum IgE and IgG4 levels to Phleum pratense components were measured by using the Immuno Solid Allergen Chip microarray. Inhibitory activity was measured by IgE-facilitated allergen binding assay. IL-10+ regulatory B cells were quantified in peripheral blood by using flow cytometry. RESULTS: Nasal and serum Phl p 1- and Phl p 5-specific IgE levels were increased in patients with SAR compared to nonatopic control subjects (all, P < .001) and SCIT-treated patients (nasal, P < .001; serum Phl p 5, P = .073). Nasal IgG4 levels were increased in the SCIT group compared to those in the SAR group (P < .001) during the pollen season compared to out of season. IgG-associated inhibitory activity in nasal fluid and serum was significantly increased in the SCIT group compared to that in the SAR (both, P < .01). The magnitude of the inhibitory activity was 93% (P < .001) in nasal fluid compared to 66% (P < .001) in serum and was reversed after depletion of IgG. Both nasal fluid (r = -0.69, P = .0005) and serum (r = -0.552, P = .0095) blocking activity correlated with global symptom improvement. IL-10+ regulatory B cells were increased in season compared to out of season in the SCIT group (P < .01). CONCLUSION: For the first time, we show that nasal IgG4-associated inhibitory activity correlates closely with the clinical response to allergen immunotherapy in patients with allergic rhinitis with or without asthma.

Predictors of the overlap syndrome and its association with comorbidities in patients with chronic obstructive pulmonary disease.

BACKGROUND: The occurrence of both chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) in an individual patient has been described as 'overlap syndrome', which has been associated with poor prognosis. Little is known about the possible predictors of the overlap syndrome and its association with comorbidities contributing to impaired outcome. OBJECTIVES: This study aimed to evaluate the prevalence and possible predictors of the overlap syndrome and its association with comorbidities in a cohort of COPD patients. METHODS: Individuals with COPD (GOLD stages I-IV, risk groups A-D) were recruited from outpatient clinics. Information on age, gender, body mass index (BMI), smoking status, Epworth sleepiness scale (ESS), COPD assessment test, comorbidities, medications and exacerbations in the past year was collected and a spirometry was performed. Participants underwent a nocturnal polygraphy using the ApneaLink™ device at home. An apnea-hypopnea index (AHI) >10 per hour was considered to indicate OSA. RESULTS: We enrolled 177 COPD patients (112 men) with a mean age of 64 years (range 42-90), of whom 35 (20%) had an ESS score above 10. During nocturnal polygraphy, 33 patients (19%) had evidence of OSA. In multivariate analysis, BMI and pack years were positively associated with AHI, independent of other significant AHI determinants from univariate analysis. Arterial hypertension and diabetes were more common in patients with the overlap syndrome. CONCLUSIONS: Almost 20% of COPD patients also have OSA. BMI and smoking history seem to be predictors of the overlap syndrome, and these patients may be more often affected by hypertension and diabetes.

Daily physical activity, functional capacity and quality of life in patients with COPD.

INTRODUCTION: In the therapy of chronic obstructive pulmonary disease (COPD), it is a major goal to improve health-related quality of life (HRQOL). Patients with COPD often suffer from exertional dyspnea and adopt a sedentary lifestyle, which could be associated with poorer HRQOL. The aim of this study was to investigate the independent association of objectively measured daily physical activity and functional capacity with HRQOL in patients with COPD. METHODS: In this cross-sectional study conducted at the University Hospital Basel, Switzerland, 87 stable patients (58.6% male, mean age: 67.3 ± 9.6 yrs) with COPD in GOLD grades I (n = 23), II (n = 46), III (n = 12) and IV (n = 6) were investigated. To assess HRQOL, the COPD assessment test (CAT) was completed. Patients performed spirometry and 6-min walk test. Physical activity was measured by the SenseWear Mini Armband on 7 consecutive days. By performing a multiple linear regression analysis, independent predictors of CAT score were identified. RESULTS: Age (ß = -0.39, p = 0.001), average daily steps (ß = -0.31, p = 0.033) and 6-min walk distance (ß = -0.32, p = 0.019) were found to be independent predictors of CAT score, whereas physical activity duration above 3 METs (p = 0.498) and forced expiratory volume in 1 s in% of predicted (p = 0.364) showed no significant association. CONCLUSIONS: This study showed that average daily steps and functional capacity are independent determinants of HRQOL in patients with COPD. This emphasizes the importance to remain active and mobile, which is associated with better HRQOL.

Systemic Allergic Reaction to the GLP-1 Receptor Agonist Exenatide.

Objective: To report a case of systemic hypersensitivity to the glucagon-like peptide-1 (GLP-1) receptor agonist exenatide used in diabetes care to provide significant information within the context of postmarketing safety surveillance of this new drug class. Case Summary: We report on a 52-year-old male with insufficiently controlled diabetes. GLP-1 agonist treatment was indicated and the patient was started on 5 to 10 µg exenatide (Byetta) twice daily, which had to be stopped after 1 month due to intolerable nausea. One year later, an attempt with 0.6 to 1.8 mg liraglutide (Victoza) once daily was well tolerated but lacked efficacy after a few months. Finally, the patient was started on 2 mg exenatide (Bydureon) once weekly. Concomitant treatment included metformine 1000 mg twice daily and candesartan/hydrochlorothiazide (Blopress Plus) 16/12.5 mg once daily. A few hours after the second injection, local urticaria and disseminated pruritus evolved and after the third injection pruritus, urticaria, and shortness of breath developed, which resolved to antihistamines and corticosteroids. Intradermal tests were positive for Byetta (1:1000) and Bydureon (1:100) (both exenatide), while Victoza (liraglutide) was negative (1:10). Specific immunoglobulin E (IgE) to the drugs was not available for testing. Discussion: An objective causality assessment revealed that the adverse effect to exenatide (Bydureon) was probable (Naranjo probability scale: score of 8). Consistency was established through positive skin tests and the biological explanation that the administration of GLP-1 receptor agonists has been associated with antibody formation. Conclusion: Considering emerging use of GLP-1 receptor agonists, systemic hypersensitivity should be recognized as a risk in clinical practice.

Protocol for a randomised, double-blind, placebo-controlled study of grass allergen immunotherapy tablet for seasonal allergic rhinitis: time course of nasal, cutaneous and immunological outcomes.

BACKGROUND: Seasonal Allergic Rhinitis is characterised by inflammation of the nasal mucosa upon exposure to common aeroallergens, affecting up to 20-25 % of the population. For those patients whose symptoms are not controlled by standard medical treatment, allergen specific immunotherapy is a therapeutic alternative. Although several studies have shown changes in immunologic responses as well as long term tolerance following treatment with a sublingual allergy immunotherapy tablet, a detailed time course of the early mechanistic changes of local and systemic T and B cell responses and the effects on B cell repertoire in the nasal mucosa have not been fully examined. METHODS/DESIGN: This is a randomized, double-blind, single-centre, placebo controlled, two arm time course study based in the United Kingdom comparing sublingual allergy immunotherapy tablet (GRAZAX(®), ALK-Abello Horsholm, Denmark) plus standard treatment with placebo plus standard treatment. Up to 50 moderate to severe grass pollen allergic participants will be enrolled to ensure randomisation of at least 44. Further, we shall enrol 20 non-atopic volunteers. Screening will be completed before eligible atopic participants are randomised to one of the two treatment arms in a 1 to 1 ratio. The primary endpoint will be the total nasal symptom score assessed over 60 min following grass pollen nasal allergen challenge after 12 months of treatment. Clinical assessments and/or mechanistic analyses on blood, nasal fluid, brushing and biopsies will be performed at baseline at 1, 2, 3, 4 (coinciding with the peak pollen season), 6 and 12 months of treatment. After 12 months of treatment, unblinding will take place. Those atopic participants receiving active treatment will continue therapy for another 12 months followed by a post treatment phase of 12 months. Assessments and collection of biologic samples from these participants will take place again at 24 and at 36 months from the start of treatment. The 20 healthy, non-atopic controls will undergo screening and one visit only coinciding with the 12 month visit for the atopic participants. DISCUSSION: The trial will end in April 2017. The trial is registered with ClinicalTrials.gov and the trial identifying number is NCT02005627. TRIAL REGISTRATION: Primary Registry: ClinicalTrials.gov, Trial Identifying number: NCT02005627, Secondary identifying numbers: EudraCT number: 2013-003732-72 REC: 13/EM/0351, Imperial College London (Sponsor): 13IC0847, Protocol Version 6.0, Date: 16.05.2014.

[Alveolar hemorrhage und cocaine: cause or coincidence?]. / Alveoläre Hämorrhagie und Kokain: Ursache oder Zufall?

We report the case of a previously healthy young man who presented to the hospital with hemoptysis and dyspnea. Hemoptysis is a frequently encountered symptom in daily routine and investigations can easily be deferred to a longer time frame. Our case illustrates the importance of a prompt investigation and treatment of underlying causes. Furthermore one should not hesitate to include rare, yet life threatening conditions in differential diagnosis.

Differences in classification of COPD patients into risk groups A-D: a cross-sectional study.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease proposed in 2011 a new system to classify chronic obstructive pulmonary disease (COPD) patients into risk groups A-D, which considers symptoms and future exacerbation risk to grade disease severity. The aim of this study was to investigate the agreement between COPD risk group classifications using COPD assessment test (CAT) or modified Medical Research Council (mMRC) and severity grades or past-year exacerbations. Furthermore, physical activity across risk groups was examined. METHODS: 87 patients with stable COPD were classified into risk groups A-D. CAT and mMRC were completed. Severity grades I-IV were determined using spirometry and the number of past-year exacerbations was recorded. To test the interrater agreement, Cohen's Kappa was calculated. Daily physical activity was measured by the SenseWear Mini armband. RESULTS: Using CAT, 65.5% of patients were in high-symptom groups (B and D). With mMRC, only 37.9% were in B and D. Using severity grades, 20.7% of patients were in high-exacerbation risk groups (C and D). With past-year exacerbations, 9.2% were in C and D. Interrater agreement between CAT and mMRC (κ = 0.21) and between severity grades and past-year exacerbations (κ = 0.31) was fair. Daily steps were reduced in risk groups B and C + D compared to A (p < 0.01), using either classification. CONCLUSIONS: When classifying COPD patients into risk groups A-D, the use of CAT or mMRC and severity grades or past-year exacerbations does not provide equal results. Daily steps decreased with increasing COPD risk groups.