Response to Various Biologics in Patients with Both Asthma and Chronic Obstructive Pulmonary Disease.

INTRODUCTION: Patients can have features of both chronic obstructive pulmonary disease (COPD) and asthma. However, there is still no consensus how to precisely define this patient population. In addition, there are little data on the effectiveness of biologics in these patients. METHOD: Presence of COPD was defined by a smoking history of ≥10 pack years (PY), a postbronchodilator FEV1/FVC ratio < lower limit of normal (LLN) and FEV1 < 80% predicted, a carbon monoxide diffusion capacity (DLCO) < LLN, and dyspnoea on exertion as a leading symptom. Presence of asthma was defined by high type 2 biomarkers (blood eosinophils ≥300 cells/µL and/or FeNO ≥50 ppb), typical clinical features of asthma (including nocturnal respiratory symptoms), and a documented history of a clinical benefit from inhaled and/or oral glucocorticoid treatment. We analysed data from 20 patients fulfilling the criteria for both COPD and asthma who were newly treated with a biologic due to recurrent exacerbations despite high-dose inhaled triple therapy. RESULTS: Median values before treatment with a biologic were as follows: 40 PY, FEV1 42% predicted, DLCO 45% predicted, 475 eosinophils/µL blood, FeNO 48 ppb. Median duration of biologic treatment (mepolizumab, benralizumab, dupilumab, omalizumab, or tezepelumab) was 12 months. There were significant improvements in exacerbations (most prominent effect), asthma control, and lung function during biologic treatment. CONCLUSIONS: Various types of biologics approved for severe asthma treatment can be effective in patients with both COPD and asthma. We propose an easy-to-use definition of these patients for routine clinical practice.

Allergen immunotherapy (AIT) in asthma.

Bronchial asthma remains one of the most common chronic diseases with a high degree of morbidity and still a considerable mortality with an increasing prevalence in many countries. Although remarkable progress has been made in the past decades in the medical treatment for asthma, curative or disease modifying approaches are still limited to allergen immunotherapy (AIT). Despite a plethora of potential immunological actions observed during AIT, the precise mechamisms that might exert beneficial effects especially in asthma remain unclear. Clinical studies in the past have suggested clinical benefits in symptom control and medication use with a small reduction in allergen-specific and non-specific bronchial hyperresponsiveness but these results were mainly derived from small, frequently suboptimally designed studies which were poorly comparable. Only recently have larger, dose ranging studies with well standardized allergens with patient relevant endpoints such as corticosteroid requirements for asthma control or the onset of exacerbations following inhaled corticosteroid (ICS) withdrawal corroborated the potential clinical effects of AIT in asthma, suggesting that it might replace some of the controller effects of ICS. In addition, newer, up-do-date designed studies support previous data that in patient populations at risk to develop asthma AIT might have a role in secondary prevention. Further studies on the long term effects as well as comparative studies are needed to further corroborate the role of AIT in the prevention and the control of asthma are needed.

Dupilumab is effective in type 2-high asthma patients receiving high-dose inhaled corticosteroids at baseline.

BACKGROUND: Dupilumab blocks the shared receptor component for interleukin (IL)-4/IL-13, key drivers of type 2 inflammation. In phase 2b (NCT01854047) and phase 3 LIBERTY ASTHMA QUEST (NCT02414854), add-on dupilumab 200/300 mg every 2 weeks (q2w) reduced severe exacerbations, improved prebronchodilator (pre-BD) forced expiratory volume in 1 second (FEV1 ) and quality of life measures, and it was generally well tolerated in patients with uncontrolled, persistent (phase 2b), or moderate-to-severe (phase 3) asthma. METHODS: In patients on high-dose inhaled corticosteroids (ICS) with type 2-high asthma (subgroups including baseline blood eosinophils ≥150/300 cells/µL and/or fractional exhaled nitric oxide [FeNO] ≥25 ppb), annualized severe exacerbation rates over the treatment period, changes from baseline in pre-BD FEV1 and asthma control (5-item asthma control questionnaire [ACQ-5]) were analyzed. RESULTS: In high-dose ICS type 2-high subgroups, dupilumab 200/300 mg q2w vs placebo in the phase 2b (24 weeks) and phase 3 (52 weeks) studies significantly reduced severe exacerbations by 55%-69%/57%-60% (all P<.05) and 53%-69%/48%-66% (all P < .001), respectively, except in patients with ≥ 300 eosinophils/µL in phase 2b study (24%/50% (P = .52/0.15). Across subgroups, pre-BD FEV1 improved by 0.18-0.22 L/0.19-0.24 L (all P < .05) and 0.23-0.36 L/0.15-0.25 L (all P < .01) and ACQ-5 scores were reduced by 0.46-0.55/0.47-0.85 (all P < .05) and 0.38-0.50/0.24-0.30 (all P < .05), respectively, except dupilumab 200 mg q2w in phase 2b in patients with FeNO ≥ 25 ppb (0.41; P = .09). Dupilumab was also effective in patients taking medium-dose ICS. CONCLUSION: Dupilumab significantly reduced severe exacerbations and improved lung function and asthma control in patients with type 2-high asthma on high-dose ICS at baseline.

Personalized medicine for allergy treatment: Allergen immunotherapy still a unique and unmatched model.

The introduction of personalized medicine (PM) has been a milestone in the history of medical therapy, because it has revolutionized the previous approach of treating the disease with that of treating the patient. It is known today that diseases can occur in different genetic variants, making specific treatments of proven efficacy necessary for a given endotype. Allergic diseases are particularly suitable for PM, because they meet the therapeutic success requirements, including a known molecular mechanism of the disease, a diagnostic tool for such disease, and a treatment blocking the mechanism. The stakes of PM in allergic patients are molecular diagnostics, to detect specific IgE to single-allergen molecules and to distinguish the causative molecules from those merely cross-reactive, pursuit of patient's treatable traits addressing genetic, phenotypic, and psychosocial features, and omics, such as proteomics, epi-genomics, metabolomics, and breathomics, to forecast patient's responsiveness to therapies, to detect biomarker and mediators, and to verify the disease control. This new approach has already improved the precision of allergy diagnosis and is likely to significantly increase, through the higher performance achieved with the personalized treatment, the effectiveness of allergen immunotherapy by enhancing its already known and unique characteristics of treatment that acts on the causes.

An unexpected role for uric acid as an inducer of T helper 2 cell immunity to inhaled antigens and inflammatory mediator of allergic asthma.

Although deposition of uric acid (UA) crystals is known as the cause of gout, it is unclear whether UA plays a role in other inflammatory diseases. We here have shown that UA is released in the airways of allergen-challenged asthmatic patients and mice, where it was necessary for mounting T helper 2 (Th2) cell immunity, airway eosinophilia, and bronchial hyperreactivity to inhaled harmless proteins and clinically relevant house dust mite allergen. Conversely, administration of UA crystals together with protein antigen was sufficient to promote Th2 cell immunity and features of asthma. The adjuvant effects of UA did not require the inflammasome (Nlrp3, Pycard) or the interleukin-1 (Myd88, IL-1r) axis. UA crystals promoted Th2 cell immunity by activating dendritic cells through spleen tyrosine kinase and PI3-kinase δ signaling. These findings provide further molecular insight into Th2 cell development and identify UA as an essential initiator and amplifier of allergic inflammation.

Perspectives in allergen immunotherapy: 2019 and beyond.

The seventh "Future of the Allergists and Specific Immunotherapy (FASIT)" workshop held in 2019 provided a platform for global experts from academia, allergy clinics, regulatory authorities and industry to review current developments in the field of allergen immunotherapy (AIT). Key domains of the meeting included the following: (a) Biomarkers for AIT and allergic asthma; (b) visions for the future of AIT; (c) progress and data for AIT in asthma and the updates of GINA and EAACI Asthma Guidelines (separated for house dust mite SCIT, SLIT tablets and SLIT drops; patient populations) including a review of clinically relevant endpoints in AIT studies in asthma; (d) regulatory prerequisites such as the "Therapy Allergen Ordinance" in Germany; (e) optimization of trial design in AIT clinical research; (f) challenges planning and conducting phase III (field) studies and the future role of Allergen Exposure Chambers (AEC) in AIT product development from the regulatory point of view. We report a summary of panel discussions of all six domains and highlight unmet needs and possible solutions for the future.

Addressing unmet needs in understanding asthma mechanisms: From the European Asthma Research and Innovation Partnership (EARIP) Work Package (WP)2 collaborators.

Asthma is a heterogeneous, complex disease with clinical phenotypes that incorporate persistent symptoms and acute exacerbations. It affects many millions of Europeans throughout their education and working lives and puts a heavy cost on European productivity. There is a wide spectrum of disease severity and control. Therapeutic advances have been slow despite greater understanding of basic mechanisms and the lack of satisfactory preventative and disease modifying management for asthma constitutes a significant unmet clinical need. Preventing, treating and ultimately curing asthma requires co-ordinated research and innovation across Europe. The European Asthma Research and Innovation Partnership (EARIP) is an FP7-funded programme which has taken a co-ordinated and integrated approach to analysing the future of asthma research and development. This report aims to identify the mechanistic areas in which investment is required to bring about significant improvements in asthma outcomes.

[IgE and Anti-IgE in Asthma: A Chequered History]. / IgE und Anti-IgE bei Asthma: eine wechselvolle Geschichte.

A long and winding road led to the discovery of immunoglobulin E (IgE) in 1966 and 1967. We are currently on a long and winding road to understand the immunologic basis of the clinical effects of the anti-IgE antibody omalizumab in asthma. It is possible that patients with asthma (as patients with chronic spontaneous urticaria) benefit in different immunologic ways from omalizumab treatment. This article reviews the history of IgE discovery and current concepts of anti-IgE therapy in asthma.

Diagnostic challenges of adult asthma.

PURPOSE OF REVIEW: Bronchial asthma is a common disorder that affects about 300 million people worldwide. Its signs and symptoms however, can be present in other pulmonary and/or airway diseases and therefore a careful workup of patients with respiratory symptoms that might be due to asthma is required to a) keep a broad differential diagnosis, especially in cases that do not respond well to standard antiasthmatic therapy and b) attempt to subphenotype patients within the syndrome of asthma to diagnose e.g. precipitating factors, inflammatory subtypes and comorbidities. RECENT FINDINGS: The syndrome of asthma contains a number of different phenotypes that offer the possibility of personalized medicine based on the respective asthma phenotype. There are attempts to combine asthma and COPD in newly postulated overlap syndromes which this review discourages to do but instead, based on new and old information concerning asthma phenotyping, suggests to rule in comorbidities and rule out a number of other diseases that can mimick asthma clinically. SUMMARY: Bronchial asthma, although one of the most common respiratory diseases, can be mimicked by a number of other pulmonary and airway diseases, and especially patients with so called severe or treatment refractory asthma should receive a detailed diagnostic workup with a rather broad differential diagnosis.

A randomized, double-blinded, double-dummy efficacy and safety study of budesonide-formoterol Spiromax® compared to budesonide-formoterol Turbuhaler® in adults and adolescents with persistent asthma.

BACKGROUND: Budesonide and formoterol (BF) Spiromax® is a dry powder inhaler designed to deliver BF with maximum ease of use for patients with asthma or chronic obstructive pulmonary disease. METHODS: A phase 3b, 12-week, multicenter, double-blind, double-dummy, randomized, controlled trial in patients (≥12 years) with persistent asthma. PRIMARY OBJECTIVE: to demonstrate non-inferiority of twice-daily BF Spiromax 160/4.5 mcg to BF Turbuhaler® 200/6 mcg in change from baseline in weekly average of daily trough morning peak expiratory flow (PEF). Secondary endpoints included: Patient Satisfaction and Preference Questionnaire scores, change from baseline in evening PEF, trough forced expiratory volume in one second, percentage of symptom-free and rescue-free 24-hour periods, and safety. RESULTS: The analysis was based on the per-protocol population (BF Spiromax, n = 290; BF Turbuhaler, n = 284). The least squares mean change from baseline to week 12 in morning PEF was: BF Spiromax, 18.8 L/min and BF Turbuhaler, 21.8 L/min. Non-inferiority of BF Spiromax vs BF Turbuhaler was demonstrated (the lower limit of the 95% two-sided confidence interval was -9.02 L/min, which is greater than -15 L/min [the criteria specified for non-inferiority]). The mean difference in the total performance domains scores for BF Spiromax vs BF Turbuhaler were 0.248 at baseline and 0.353 at week 12 (both, p <0.001), indicating statistical superiority for BF Spiromax. No statistical or numerical differences were recorded in the total convenience domain score between the two devices. Scores for 'device preference' and 'willingness to continue' supported BF Spiromax at baseline and at week 12 (p = 0.0005 vs BF Turbuhaler). No significant between-group differences were observed in the other secondary efficacy endpoints. Both treatments were well tolerated, with no significant differences in adverse events or asthma exacerbations. CONCLUSIONS: This study demonstrates the non-inferiority of BF Spiromax vs BF Turbuhaler in patients (≥12 years) with asthma. More patients preferred the Spiromax device over Turbuhaler for its performance, and were willing to continue therapy with BF Spiromax beyond the 12-week study period. TRIAL REGISTRATION: NCT01803555; February 28, 2013.

Efficacy of a House Dust Mite Sublingual Allergen Immunotherapy Tablet in Adults With Allergic Asthma: A Randomized Clinical Trial.

IMPORTANCE: The house dust mite (HDM) sublingual allergen immunotherapy (SLIT) tablet is a potential novel treatment option for HDM allergy-related asthma. OBJECTIVES: To evaluate the efficacy and adverse events of the HDM SLIT tablet vs placebo for asthma exacerbations during an inhaled corticosteroid (ICS) reduction period. DESIGN, SETTINGS, AND PARTICIPANTS: Double-blind, randomized, placebo-controlled trial conducted between August 2011 and April 2013 in 109 European trial sites. The trial included 834 adults with HDM allergy-related asthma not well controlled by ICS or combination products, and with HDM allergy-related rhinitis. Key exclusion criteria were FEV1 less than 70% of predicted value or hospitalization due to asthma within 3 months before randomization. Efficacy was assessed during the last 6 months of the trial when ICS was reduced by 50% for 3 months and then completely withdrawn for 3 months. INTERVENTIONS: 1:1:1 randomization to once-daily treatment with placebo (n = 277) or HDM SLIT tablet (dosage groups: 6 SQ-HDM [n = 275] or 12 SQ-HDM [n = 282]) in addition to ICS and the short-acting ß2-agonist salbutamol. MAIN OUTCOMES AND MEASURES: Primary outcome was time to first moderate or severe asthma exacerbation during the ICS reduction period. Secondary outcomes were deterioration in asthma symptoms, change in allergen-specific immunoglobulin G4 (IgG4), change in asthma control or asthma quality-of-life questionnaires, and adverse events. RESULTS: Among 834 randomized patients (mean age, 33 years [range, 17-83]; women, 48%), 693 completed the study. The 6 SQ-HDM and 12 SQ-HDM doses both significantly reduced the risk of a moderate or severe asthma exacerbation compared with placebo (hazard ratio [HR]: 0.72 [95% CI, 0.52-0.99] for the 6 SQ-HDM group, P = .045, and 0.69 [95% CI, 0.50-0.96] for the 12 SQ-HDM group, P = .03). The absolute risk differences based on the observed data (full analysis set) in the active groups vs the placebo group were 0.09 (95% CI, 0.01-0.15) for the 6 SQ-HDM group and 0.10 (95% CI, 0.02-0.16) for the 12 SQ-HDM group. There was no significant difference between the 2 active groups. Compared with placebo, there was a reduced risk of an exacerbation with deterioration in asthma symptoms (HR, 0.72 [95% CI, 0.49-1.02] for the 6 SQ-HDM group, P = .11, and 0.64 [95% CI, 0.42-0.96] for the 12 SQ-HDM group, P = .03) and a significant increase in allergen-specific IgG4. However, there was no significant difference for change in asthma control questionnaire or asthma quality-of-life questionnaire for either dose. There were no reports of severe systemic allergic reactions. The most frequent adverse events were mild to moderate oral pruritus (13% for the 6 SQ-HDM group, 20% for the 12 SQ-HDM group, and 3% for the placebo group), mouth edema, and throat irritation. CONCLUSIONS AND RELEVANCE: Among adults with HDM allergy-related asthma not well controlled by ICS, the addition of HDM SLIT to maintenance medications improved time to first moderate or severe asthma exacerbation during ICS reduction, with an estimated absolute reduction at 6 months of 9 to 10 percentage points; the reduction was primarily due to an effect on moderate exacerbations. Treatment-related adverse events were common at both active doses. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrialsregister.eu Identifier: 2010-018621-19.

Imbalance of dendritic cell co-stimulation in COPD.

BACKGROUND: Dendritic cells (DCs) control immunity and play a role in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the expression of function-associated surface molecules on circulating DCs in COPD is unknown. METHODS: Four-colour flow cytometry was used to compare blood DC surface molecules of 54 patients with COPD (median age: 59 years; median FEV1: 38% predicted, median CAT score: 24) with two age-matched control groups with normal lung function: 21 current smokers and 21 never-smokers. RESULTS: Concentrations of plasmacytoid DCs (pDCs) and myeloid DCs (mDCs) and the mDC/pDC ratio did not differ between the groups. The increased expression of BDCA-1, BDCA-3, CD86 and CCR5 on mDCs in patients with COPD did not significantly differ from smokers with normal lung function. In contrast, COPD was specifically characterised by a decreased expression of the anti-inflammatory co-stimulatory molecule PD-L1 on pDCs and an increased expression of the pro-inflammatory co-stimulatory molecule OX40 ligand (OX40L) on mDCs. These changes were not confined to patients with elevated systemic inflammation markers (leukocytes, c-reactive protein, interleukin-6, fibrinogen). The ratio of OX40L to PD-L1 expression (OX40L/PD-L1 ratio), a quantitative measure of imbalanced DC co-stimulation, correlated with the severity of pulmonary emphysema in patients with COPD. CONCLUSION: An imbalance of DC co-stimulation might contribute to the pathogenesis of COPD.

Effectiveness of MP29-02 for the treatment of allergic rhinitis in real-life: results from a noninterventional study.

The efficacy of MP29-02 (a novel intranasal formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) has been well established in controlled clinical trials. This study was designed to assess the use of MP29-02 and its effectiveness in routine clinical practice. This was a German multicenter, prospective, noninterventional study, including 1781 allergic rhinitis (AR) patients. Eligible patients (i.e., acute AR symptoms and visual analog scale [VAS] score >50 mm) were included, assigned MP29-02 at baseline, and reassessed after ∼14 days. Patients assessed symptom control using a VAS from 0 (not at all bothersome) to 100 mm (very bothersome) in the morning before MP29-02 use, on days 0, 1, 3, and 7 and after ∼ 14 days. Patients' perceived levels of disease control were assessed on day 3. The Youden index determined patient-reported VAS score cutoffs on day 3 for "well controlled" and "partly controlled." MP29-02 reduced the VAS score from 75.4 mm (SD = 17.2) at baseline to 21.3 mm (SD = 18.3) by the last visit, a shift of 54.1 mm (SD = 24.6). One in every two patients felt their symptoms were well controlled at day 3. This perception of well-controlled symptoms at day 3 corresponded to an optimal VAS cutoff of 36 mm. On average, patients treated with MP29-02 crossed this well-controlled VAS cutoff by last visit. Similar results were found in adolescents, adults, and older adults, in those with perennial AR (PAR), seasonal AR (SAR), or PAR + SAR and in those with more and less severe disease. MP29-02 provides effective and rapid symptom control across all age groups in a real-life setting with responder rates higher than those observed in controlled clinical trials, supporting MP29-02's position as the drug of choice for the treatment for AR.

Impact of smoking on dendritic cell phenotypes in the airway lumen of patients with COPD.

BACKGROUND: Myeloid dendritic cells (DCs) are increased in the airway wall of patients with chronic obstructive pulmonary disease (COPD), and postulated to play a crucial role in COPD. However, DC phenotypes in COPD are poorly understood. METHODS: Function-associated surface molecules on bronchoalveolar lavage fluid (BALF) DCs were analyzed using flow cytometry in current smokers with COPD, in former smokers with COPD and in never-smoking controls. RESULTS: Myeloid DCs of current smokers with COPD displayed a significantly increased expression of receptors for antigen recognition such as BDCA-1 or Langerin, as compared with never-smoking controls. In contrast, former smokers with COPD displayed a significantly decreased expression of these receptors, as compared with never-smoking controls. A significantly reduced expression of the maturation marker CD83 on myeloid DCs was found in current smokers with COPD, but not in former smokers with COPD. The chemokine receptor CCR5 on myeloid DCs, which is also important for the uptake and procession of microbial antigens, was strongly reduced in all patients with COPD, independently of the smoking status. CONCLUSION: COPD is characterized by a strongly reduced CCR5 expression on myeloid DCs in the airway lumen, which might hamper DC interactions with microbial antigens. Further studies are needed to better understand the role of CCR5 in the pathophysiology and microbiology of COPD.

Eosinophilic esophagitis: asthma of the esophagus?

The question whether eosinophilic esophagitis (EoE) might be an 'asthma of the esophagus' is reasonable. There are a number of similarities between the two diseases: EoE and asthma, as well as other atopic diseases, are frequently associated and have a number of similarities in their pathogenesis. Thus, investigating differences and similarities between the diseases might be a worthwhile endeavor. Both EoE and asthma are chronic immune-mediated conditions characterized by inflammatory changes in the mucosa and submucosa with a characteristic and diagnostic infiltration of eosinophils. They result in organ dysfunction with considerable morbidity and (in the case of asthma) even mortality. Asthma and EoE affect all ages, but frequently start in childhood or adolescence. While asthma has seen a large increase in its prevalence in the past 50 years, EoE was first described in the 1970s. Since then the frequency of the diagnosis of EoE has increased significantly. The prevalence for both diseases seems to be highest in the Western world. In contrast to asthma, where females are more often affected, EoE is more frequent in males. Asthma in children, however, is also more common in boys, but this changes after puberty. EoE is frequently associated with asthma, and up to 80% of patients with EoE are atopic, similar to childhood asthma. Adult-onset asthma is not necessarily associated with atopy (termed intrinsic asthma) and similar observations have been made for EoE. Endoscopically, asthmatic airway mucosa as well as esophageal mucosa in EoE can appear normal, and biopsies are required for diagnosis. Long-standing disease in asthma has been associated with 'remodeling' compared to predominantly reversible inflammatory changes early in the course of the disease. Similar observations have been made in EoE. Toxic proteins derived from eosinophils such as major basic protein, eosinophil-derived neurotoxin and eosinophil cationic protein can be found in the mucosa of both diseases, which are also characterized by a thickening of the lamina propria or basement membrane, respectively. Despite these histologic and immunochemistry findings, asthma as well as EoE remain clinical diagnoses, and diagnosing either condition can be challenging. Therapeutically, both diseases respond well to corticosteroids. Ironically, corticosteroids for inhalation are deliberately swallowed in EoE to reach the esophageal mucosa. Allergen/food avoidance can improve symptoms in asthma and EoE. Taken together, allergic asthma and EoE have a number of common features which make a common pathogenesis manifested in different organs for reasons not yet fully understood likely. Combining allergological research with gastroenterologic and pneumologic expertise with a focus on similarities between these diseases might be a way forward.