Weight Loss and Vitamin D Improve Hyporesponsiveness to Corticosteroids in Obese Asthma.

BACKGROUND AND OBJECTIVES: Obesity negatively impacts on the response of asthma patients to inhaled corticosteroids. The mechanisms underlying this impact are unknown. Objective: To demonstrate that the poor response to inhaled corticosteroids in obese asthma patients is associated with impaired anti-inflammatory activity of corticosteroids and vitamin D deficiency, both of which are improved by weight loss. METHODS: The study population comprised 23 obese asthma patients (OA) (18 females; median (IQR) age 56 [51-59] years), 14 nonobese asthma patients (NOA) (11 females; 53 [43-60] years), 15 obese patients (OP) (13 females; 47 [45-60] years), and 19 healthy controls (HC) (14 females; 43 [34-56] years). Ten OA and 11 OP were evaluated at baseline (V1) and 6 months after bariatric surgery (V2). Corticosteroid response was measured using dexamethasone-induced inhibition of peripheral blood mononuclear cell (PBMC) proliferation. Lung function and serum levels of leptin, adiponectin, and vitamin D were measured at V1 and V2. RESULTS: We found a reduced response to dexamethasone in PBMCs of OP and OA with respect to NOA and HC; this inversely correlated with the adiponectin/leptin ratio and vitamin D levels. Bariatric surgery improved corticosteroid responses in OP and OA and normalized the adiponectin/leptin ratio and vitamin D levels. Exposure of PBMCs to vitamin D potentiated the antiproliferative effects of corticosteroids. Dexamethasone and vitamin D induced similar MKP1 expression in OP and OA. CONCLUSION: The efficacy of weight loss to improve symptoms and lung function in OA may be due, at least in part, to the recovered anti-inflammatory effects of corticosteroids. Vitamin D deficiency may contribute to corticosteroid hyporesponsiveness in OA.

Exacerbations Among Patients With Asthma Are Largely Dependent on the Presence of Multimorbidity.

BACKGROUND AND OBJECTIVE: Comorbidities can influence asthma control and promote asthma exacerbations (AEs). However, the impact of multimorbidity in AEs, assessed based on long-term follow-up of patients with asthma of different degrees of severity, has received little attention in real-life conditions. To describe the epidemiological and clinical characteristics and predictors of AEs in patients who had presented at least 1 AE in the previous year in the MEchanism of Genesis and Evolution of Asthma (MEGA) cohort. METHODS: The work-up included a detailed clinical examination, pulmonary function testing, fractional exhaled nitric oxide (FeNO), blood counts, induced sputum, skin prick-tests, asthma questionnaires, and assessment of multimorbidity. The number of moderate-severe AEs in the preceding year was registered for each patient. RESULTS: The study population comprised 486 patients with asthma (23.7% mild, 35% moderate, 41.3% severe). Disease remained uncontrolled in 41.9%, and 47.3% presented ≥1 moderate-severe AE, with a mean (SD) annual exacerbation rate of 0.47 (0.91) vs 2.11 (2.82) in mild and severe asthma, respectively. Comorbidity was detected in 56.4% (66.6% among those with severe asthma). Bronchiectasis, chronic rhinosinusitis with nasal polyps, atopy, psychiatric illnesses, hyperlipidemia, and hypertension were significantly associated with AEs. No associations were found for FeNO, blood eosinophils, or total serum IgE. Sputum eosinophilia and a high-T2 inflammatory pattern were significantly associated with AEs. Multivariable regression analysis showed a significant association with asthma severity, uncontrolled disease, and low prebronchodilator FEV1/FVC. CONCLUSION: Our study revealed a high frequency of AE in the MEGA cohort. This was strongly associated with multimorbidity, asthma severity, poor asthma control, airflow obstruction, higher sputum eosinophils, and a very high-T2 inflammatory pattern.

Improvement in Olfaction in Patients With CRSwNP and Severe Asthma Taking Anti-IgE and Anti-IL-5 Biologics: A Real-Life Study.

BACKGROUND AND OBJECTIVES: Chronic rhinosinusitis with nasal polyps (CRSwNP), which is characterized by partial loss of smell (hyposmia) or total loss of smell (anosmia), is commonly associated with asthma and/or nonsteroidal anti-inflammatory drug-exacerbated respiratory disease (N-ERD). CRSwNP worsens disease severity and quality of life. The objective of this real-world study was to determine whether biological treatments prescribed for severe asthma can improve olfaction in patients with CRSwNP. A further objective was to compare the improvement in in olfaction in N-ERD and non-N-ERD subgroups. METHODS: We performed a multicenter, noninterventional, retrospective, observational study of 206 patients with severe asthma and CRSwNP undergoing biological treatment (omalizumab, mepolizumab, benralizumab, or reslizumab). RESULTS: Olfaction improved after treatment with all 4 monoclonal antibodies (omalizumab [35.8%], mepolizumab [35.4%], reslizumab [35.7%], and benralizumab [39.1%]), with no differences between the groups. Olfaction was more likely to improve in patients with atopy, more frequent use of short-course systemic corticosteroids, and larger polyp size. The proportion of patients whose olfaction improved was similar between the N-ERD (37%) and non-N-ERD (35.7%) groups. CONCLUSIONS: This is the first real-world study to compare improvement in olfaction among patients undergoing long-term treatment with omalizumab, mepolizumab, reslizumab, or benralizumab for severe asthma and associated CRSwNP. Approximately 4 out of 10 patients reported a subjective improvement in olfaction (with nonsignificant differences between biologic drugs). No differences were found for improved olfaction between the N-ERD and non-N-ERD groups.

Self-perception of olfactory dysfunction is associated with history of Traumatic Brain Injury: post-hoc analysis from the OLFACAT survey.

BACKGROUND: Traumatic brain injury (TBI) is one of the main causes of smell loss. However, epidemiological studies evaluating the incidence in general population are scarce. The aim of this analysis is to investigate the prevalence of TBI-induced olfactory dysfunction (OD) in a general-based population study. METHODOLOGY: A cross-sectional population-based survey was distributed to general population (260,000 households) through the newspaper. The survey included four microencapsulated odorants (smell test) to assess smell loss and two self-administered questionnaires (odour description and epidemiology/health status). Participants were divided into two groups, with or without a history of TBI. RESULTS: From 10,783 returned surveys, 9,348 were analysed. The survey profile was a 43-year old woman with medium-high educational level, living in a city. The overall prevalence of TBI was 5% (N=464, 44.5±14.1 years old, 57% females). Recorded causes of TBI were traffic, domestic, or work accidents. Subjects with TBI reported a poorer subjective smell self-perception compared to non-TBI participants, and a decreases ability to identify mercaptan (odour added to gas used in cities). Although, using the smell test, both groups showed similar smell capacities. CONCLUSIONS: Subjects with TBI history report a higher frequency of self-perceived OD, and a decrease ability to smell the odour added to domestic gas. Having said that, the prevalence of OD, according to the smell test, was similar in both groups.

Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea.

BACKGROUND: Continuous positive airway pressure (CPAP) in asthma patients with concomitant obstructive sleep apnea syndrome (OSAS) seems to have a favorable impact on asthma, but data are inconsistent due to methodological limitations of previous studies. METHODS: Prospective, multicenter study. We examined asthma outcomes after 6 months of CPAP in 99 adult asthma patients (mean age 57 years) with OSAS (respiratory disturbance index ≥20). Asthma control and quality of life were assessed with the Asthma Control Questionnaire (ACQ) and the Mini Asthma Quality of Life Questionnaire (MiniAQLQ), respectively. Data were analyzed by intention-to-treat basis. RESULTS: The mean ± SD score of the ACQ decreased from 1.39 ± 0.91 at baseline to 1.0 ± 0.78 at 6 months (P = 0.003), the percentage of patients with uncontrolled asthma from 41.4% to 17.2% (P = 0.006), and the percentage of patients with asthma attacks in the 6 months before and after treatment from 35.4% to 17.2% (P = 0.015). The score of the mAQLQ increased from 5.12 ± 1.38 to 5.63 ± 1.17 (P = 0.009). There were also significant improvements in symptoms of gastroesophageal reflux and rhinitis, bronchial reversibility, and exhaled nitric oxide values (all P < 0.05). No significant changes were observed in drug therapy for asthma or their comorbidities nor in the patients' weight. CONCLUSIONS: Asthma control (both actual and future risk), quality of life, and lung function improved after starting continuous positive airway pressure in asthmatics with moderate to severe obstructive sleep apnea syndrome.

Effects of Rupatadine on Platelet- Activating Factor-Induced Human Mast Cell Degranulation Compared With Desloratadine and Levocetirizine (The MASPAF Study).

BACKGROUND AND OBJECTIVE: Platelet-activating factor (PAF) is a lipid mediator involved in the pathophysiology of several allergic diseases, for example, in the amplification of mast cell (MC) activation in anaphylaxis. Rupatadine is an antihistamine with a demonstrated anti-PAF effect, although its capacity to inhibit PAF-induced MC degranulation has not been fully evaluated. Objectives: To compare the ability of rupatadine to inhibit PAF-induced MC degranulation with that of desloratadine and levocetirizine and to confirm the dual anti-H1 and anti-PAF activity of rupatadine. METHODS: The human MC line LAD2 and primary MCs (human lung tissue MCs [hLMCs]) were used. MC mediator release was evaluated using the b-hexosaminidase and histamine release assay. The effects of rupatadine (H1 antagonist + PAF receptor antagonist), desloratadine, and levocetirizine (H1 antagonists) on LAD2 and hLMCs were compared. The PAF receptor antagonists WEB2086, BN52021, and CV6209 were also tested. PAF receptor protein expression was evaluated in both LAD2 and hLMCs. RESULTS: CV6209 and rupatadine inhibited PAF-induced MC degranulation in both LAD2 and hLMCs. In LAD2, rupatadine (5 and 10 µM) and levocetirizine (5 µM), but not desloratadine, inhibited PAF-induced b-hexosaminidase release. Rupatadine (1-10 µM), levocetirizine (1-10 µM), and desloratadine (10 µM) inhibited PAF-induced histamine release. Rupatadine at 10 µM had an inhibitory effect on hLMC degranulation, but levocetirizine and desloratadine did not. CONCLUSIONS: This study shows that rupatadine and, to a lesser extent, levocetirizine, but not desloratadine, inhibit PAF-induced degranulation in both LAD2 and hLMCs. These findings support the dual antihistamine and anti-PAF effect of rupatadine in allergic disorders.

Nonsteroidal anti-inflammatory drugs enhance IgE-mediated activation of human basophils in patients with food anaphylaxis dependent on and independent of nonsteroidal anti-inflammatory drugs.

BACKGROUND: Nonsteroidal anti-inflammatory drugs (NSAIDs) act as cofactors worsening the allergic reactions induced by food allergens. AIM: The aim of this study was to evaluate the effect of both lysine acetylsalicylate (L-ASA) (non-selective cyclooxygenase (COX) inhibitor) and valdecoxib (selective COX-2 inhibitor) in basophils activated by peach lipid transfer protein (Pru p 3) in patients with food-dependent NSAID-induced anaphylaxis (FDNIA). METHODS: Twenty Pru p 3-allergic patients with FDNIA group, eleven peach anaphylaxis not exacerbated by NSAIDs (no-NSAID group) and 5 healthy volunteers were recruited. Basophil activation (BA) was measured as expression of CD63 (Flow(2) CAST(™) ; Bühlmann(®) ), after stimulation with Pru p 3, both alone and in combination with L-ASA (1.13, 3.38 and 6.78 mm) or valdecoxib (0.87, 7.8 and 31.25 µm). RESULTS: Basophils from no-NSAID group were significantly more reactive and sensitive to Pru p 3 than those from the FDNIA group. In both groups, an increase in BA was observed when basophils were exposed to Pru p 3 and L-ASA. In the FDNIA group, valdecoxib partially terminates the BA induced by Pru p 3, whereas in the no-NSAID group, a dual effect was observed depending on the concentration tested. CONCLUSIONS: This study indicates that subjects with food-induced anaphylaxis differ from FDNIA subjects in the higher reactivity and sensitivity of their basophils to allergen challenge. We have shown a direct effect of NSAIDs on basophils using a human model of FDNIA. Our results also suggest that selective COX2 inhibitors might be a safe alternative. BA test may be a useful tool in the study of the pathogenic mechanism of the cofactor phenomenon.

Mechanisms of Anaphylaxis Beyond IgE.

Anaphylaxis is an acute, life-threatening, multisystem syndrome resulting from the sudden release of mediators derived from mast cells and basophils. Food allergens are the main triggers of anaphylaxis, accounting for 33%-56% of all cases and up to 81% of cases of anaphylaxis in children. Human anaphylaxis is generally thought to be mediated by IgE, with mast cells and basophils as key players, although alternative mechanisms have been proposed. Neutrophils and macrophages have also been implicated in anaphylactic reactions, as have IgG-dependent, complement, and contact system activation. Not all allergic reactions are anaphylactic, and the presence of the so-called accompanying factors (cofactors or augmenting factors) may explain why some conditions lead to anaphylaxis, while in other cases the allergen elicits a milder reaction or is even tolerated. In the presence of these factors, allergic reactions may be induced at lower doses of allergen or become more severe. Cofactors are reported to be relevant in up to 30% of anaphylactic episodes. Nonsteroidal anti-inflammatory drugs and exercise are the best-documented cofactors, although estrogens, angiotensin-converting enzyme inhibitors, ß-blockers, lipid-lowering drugs, and alcohol have also been involved. The mechanisms underlying anaphylaxis are complex and involve several interrelated pathways. Some of these pathways may be key to the development of anaphylaxis, while others may only modulate the severity of the reaction. An understanding of predisposing and augmenting factors could lead to the development of new prophylactic and therapeutic approaches.

Altered expression and signalling of EP2 receptor in nasal polyps of AERD patients: role in inflammation and remodelling.

BACKGROUND: Down-regulation of the E-prostanoid (EP)2 receptor has been reported in aspirin exacerbated respiratory disease (AERD). We aimed to evaluate the expression and activation of EP receptors in AERD and their role in prostaglandin (PG) E2 signalling. METHODS: Samples were obtained from nasal mucosa of control subjects (NM-C, n=7) and from nasal polyps of AERD patients (NP-AERD, n=7). Expression of EP1-4 was assessed at baseline. Fibroblasts were stimulated with receptor agonists to measure cAMP levels, cell proliferation and granulocyte-macrophage colony-stimulating factor (GM-CSF) release. RESULTS: NM-C and NP-AERD samples and fibroblasts expressed EP2, EP3 and EP4 at baseline. Lower expression of EP2 and higher expression of EP4 was observed in NP-AERD compared with NM-C. Stimulation with PGE2 and butaprost caused a higher increase in cAMP in NM-C than in NP-AERD. On the contrary, CAY10598 produced a higher production of cAMP in NP-AERD compared with NM-C. The anti-proliferative effect of PGE2 and butaprost was lower in NP-AERD than in NM-C fibroblasts. Similarly, the capacity of PGE2 and butaprost to inhibit GM-CSF release was lower in NP-AERD than in NM-C. CONCLUSIONS: The altered expression of EP2 in AERD may contribute to reduce the capacity of PGE2 to mediate anti-proliferative and anti-inflammatory effects.

Activation of the Prostaglandin E2 receptor EP2 prevents house dust mite-induced airway hyperresponsiveness and inflammation by restraining mast cells' activity.

BACKGROUND: Prostaglandin E2 (PGE2 ) has been proposed to exert antiasthmatic effects in patients, to prevent antigen-induced airway pathology in murine models, and to inhibit mast cells (MC) activity in vitro. OBJECTIVE: To assess in a murine model whether the protective effect of PGE2 may be a consequence of its ability to activate the E-prostanoid (EP)2 receptor on airway MC. METHODS: Either BALB/c or C57BL/6 mice were exposed intranasally (i.n.) to house dust mite (HDM) aeroallergens. Both strains were given PGE2 locally (0.3 mg/kg), but only BALB/c mice were administered butaprost (EP2 agonist: 0.3 mg/kg), or AH6809 (EP2 antagonist; 2.5 mg/kg) combined with the MC stabilizer sodium cromoglycate (SCG: 25 mg/kg). Airway hyperresponsiveness (AHR) and inflammation, along with lung MC activity, were evaluated. In addition, butaprost's effect was assessed in MC-mediated passive cutaneous anaphylaxis (PCA) in mice challenged with 2,4-dinitrophenol (DNP). RESULTS: Selective EP2 agonism attenuated aeroallergen-caused AHR and inflammation in HDM-exposed BALB/c mice, and this correlated with a reduced lung MC activity. Accordingly, the blockade of endogenous PGE2 by means of AH6809 worsened airway responsiveness in sensitive BALB/c mice, and such worsening was reversed by SCG. The relevance of MC to PGE2 -EP2 driven protection was further highlighted in MC-dependent PCA, where butaprost fully prevented MC-induced ear swelling. Unlike in BALB/c mice, PGE2 did not protect the airways of HDM-sensitized C57BL/6 animals, a strain in which we showed MC to be irrelevant to aeroallergen-driven AHR and inflammation. CONCLUSIONS & CLINICAL RELEVANCE: The beneficial effect of both exogenous and endogenous PGE2 in aeroallergen-sensitized mice may be attributable to the activation of the EP2 receptor, which in turn acts as a restrainer of airway MC activity. This opens a path towards the identification of therapeutic targets against asthma along the 'EP2 -MC-airway' axis.

Profile of patients treated with omalizumab in routine clinical practice in Spain.

BACKGROUND: Omalizumab is indicated in patients with severe allergic asthma not controlled by high-dose inhaled glucocorticoids and long-acting beta-agonists. Few data are available on the profile of patients treated with this drug in routine clinical practice in Spain. OBJECTIVE: To describe the profile of patients with severe allergic asthma treated with omalizumab and the course of the disease after a period of treatment. METHODS: Retrospective, multicentre study, recording the data on patients of either sex and ≥12 years with uncontrolled severe allergic asthma, previously treated with omalizumab. Data were evaluated in relation to pulmonary function, symptoms, quality of life, and concomitant anti-asthma treatment before the prescription of omalizumab and at the time of the study visit. RESULTS: 214 patients were evaluable (mean age=48.2±17.7 years; mean age at the time of diagnosis=26.6±16.5 years). 90.7% had experienced exacerbations the year before receiving omalizumab, and the mean total IgE level was 273±205.4IU/ml. The mean monthly dose was 380.5±185.4mg. Compared with the baseline situation, differences were observed after treatment with omalizumab in mean FEV1 (62.7±15.9% vs. 70.8±18.7%), in the proportion of patients requiring oral corticosteroids (47.7% vs. 14.0%), and in the ACQ and AQLQ scores. 32.7% of the patients received doses not recommended by the Summary of Product Characteristics (SPC). CONCLUSIONS: Profile of asthmatic patients treated with omalizumab predominantly corresponds to uncontrolled severe asthma cases, in accordance with SPC's indications. The results of the study suggest a favourable clinical course similar to that observed in other studies.

Acoustic rhinometry and aspirin nasal challenge in the diagnosis of aspirin-intolerant asthma: clinical finding and safety aspects.

BACKGROUND: The safety and utility of nasal provocation tests with lysine-aspirin (L-ASA) in the diagnosis of aspirin-intolerant asthma (AIA) have previously been described in a short series of patients. OBJECTIVES: To describe the clinical features and safety of an L-ASA challenge test in patients with AIA. METHODS: We evaluated 72 patients (79% women), with a mean ± SD age of 47.9 ± 14.5 years. All patients were submitted to an L-ASA nasal provocation test (29 mg in each nostril) under acoustic rhinometry (AcR) control. Symptom score (0-3), visual analogical scale and nitric oxide determinations were performed at baseline and at 15, 30, 60 and 90 min. A decrease in nasal volume of at least 25% was considered a positive test. Nasal nitric oxide (nNO) and forced expiratory volume in 1 s were measured. RESULTS: Nasal congestion and rhinorrhea represented 51 and 32%, respectively, of total symptoms. According to AcR data, the L-ASA challenge test was positive in 20% of patients at 15 min, an additional 36% were positive at 30 min, 18% at 60 min, and the remaining 26% at 90 min. nNO nasal values decreased but did not reach statistical significance. No pulmonary or systemic reactions were observed. CONCLUSIONS: Symptoms of nasal congestion associated with the reduction in nasal volume measured by AcR are the most useful parameters for establishing the diagnosis of AIA using the L-ASA nasal challenge. The method is very well tolerated and can be safely used even in patients with severe asthma.

Assessment of nasal obstruction: correlation between subjective and objective techniques.

BACKGROUND: Nasal sensation of airflow describes the perception of the passage of air through the nose. Nasal obstruction can be assessed using subjective techniques (symptom scores and visual analogue scales [VAS]) and objective techniques (anterior rhinomanometry [RMN], acoustic rhinometry [AR], and peak nasal inspiratory flow [PNIF]). Few studies have evaluated the correlation between these techniques. OBJECTIVE: The primary objective of our study was to determine the degree of correlation between subjective and objective techniques to assess nasal obstruction. MATERIALS AND METHODS: Nasal obstruction was assessed using a symptom score, VAS, RMN, AR (minimal cross-sectional area [MCSA] and volume), and PNIF in 184 volunteer physicians. Spearman's rho was recorded. Correlations were considered weak if r ≤ 0.4, moderate if 0.4 < r < 0.8, and strong if r > 0.8. RESULTS: Mean (SD) age was 37.1 (6.9) years (range, 25-56 years); 61% were women. We found a strong correlation (r > 0.8; p = 0.001) between the different parameters of RMN and a moderate correlation between symptom score and VAS (r = 0.686; p = 0.001) and between MCSA and RMN (resistance) (r = 0.496; p = 0.001) and PNIF (r = 0.459; p = 0.001). The correlations were weak or non-significant for the remaining comparisons. CONCLUSION: Nasal obstruction can be assessed using subjective and objective approaches. The correlations between objective techniques were moderate to strong. In addition, between subjective techniques we reported a moderate correlation. Finally, the correlations between the subjective and objective techniques were weak and absent. These findings suggest that each of the techniques assesses different aspects of nasal obstruction, thus making them complementary.

Lipid transfer protein syndrome: clinical pattern, cofactor effect and profile of molecular sensitization to plant-foods and pollens.

BACKGROUND: Multiple plant-food sensitizations with a complex pattern of clinical manifestations are a common feature of lipid transfer protein (LTP)-allergic patients. Component-resolved diagnosis permits the diagnosis of the allergen sensitization profile. OBJECTIVE: We sought to clinically characterize and describe the plant-food and pollen molecular sensitization profile in patients with LTP syndrome. METHODS: Forty-five subjects were recruited, after being diagnosed with multiple plant-food allergies sensitized to LTP, but not to any other plant-food allergen, according to the molecular allergen panel tested (Pru p 3 (LTP), Pru p 1 (Bet v 1-like), Pru p 4 (profilin) and those included in a commercial microarray of 103 allergenic components). IgE-mediated food-allergy symptoms and pollinosis were collected. Patients were skin prick tested with a plant-food and pollens panel, and specific IgE to Tri a 14 was evaluated. RESULTS: A heterogeneous group of plant-foods was involved in local and systemic symptoms: oral allergy syndrome (75.6%), urticaria (66.7%), gastrointestinal disorders (55.6%) and anaphylaxis (75.6%), 32.4% of which were cofactor dependent (Non-Steroidal Anti-inflammatory Drugs, exercise). All tested subjects were positive to peach and Pru p 3, Tri a 14 and to some of the LTPs included in the microarray. Pollinosis was diagnosed in 75.6% of subjects, with a broad spectrum of pollen and pollen-allergen sensitization. Plane tree and mugwort were the statistically significant pollens associated with Pru p 3. CONCLUSIONS AND CLINICAL RELEVANCE: Several plant-foods, taxonomically unrelated, independent of peach involvement, are implicated in LTP syndrome. Local symptoms should be evaluated as a risk marker for anaphylaxis because they are frequently associated with cofactor-dependent anaphylaxis. The association of these symptoms with pollinosis, especially plane tree pollinosis, could be part of this syndrome in our area.