Background
Periostin has been suggested as a novel, phenotype‐specific biomarker for asthma driven by type 2 inflammation. However, large studies examining relationships between circulating periostin ...and patient characteristics are lacking and the suitability of periostin as a biomarker in asthma remains unclear.
Aim
To examine circulating periostin in healthy controls and subjects with asthma from the general population with different severity and treatment profiles, both with and without chronic rhinosinusitis (CRS), in relation to other biomarkers and clinical characteristics.
Methods
Serum periostin was examined by ELISA in 1100 subjects aged 17‐76 from the Swedish Global Allergy and Asthma European Network (GA(2)LEN) study, which included 463 asthmatics with/without chronic rhinosinusitis (CRS), 98 individuals with CRS only, and 206 healthy controls. Clinical tests included measurement of lung function, Fraction of exhaled NO (FeNO), IgE, urinary eosinophil‐derived neurotoxin (U‐EDN), and serum eosinophil cationic protein (S‐ECP), as well as completion of questionnaires regarding respiratory symptoms, medication, and quality of life.
Results
Although median periostin values showed no differences when comparing disease groups with healthy controls, multiple regression analyses revealed that periostin was positively associated with higher FeNO, U‐EDN, and total IgE. In patients with asthma, an inverse relationship with lung function was also observed. Current smoking was associated with decreased periostin levels, whereas increased age and lower body mass index (BMI) related to higher periostin levels in subjects both with and without asthma.
Conclusion
We confirm associations between periostin and markers of type 2 inflammation, as well as lung function, and identify novel constitutional factors of importance to the use of periostin as a phenotype‐specific biomarker in asthma.
Summary
Background
Exacerbations represent a major source of morbidity and mortality in asthma and are a prominent feature of poorly controlled, difficult‐to‐treat disease.
Objective
The goal of our ...study was to provide a detailed characterization of the frequent exacerbator phenotype and to identify risk factors associated with frequent and seasonal exacerbations.
Methods
Ninety‐three severe asthmatics (SA) and 76 mild‐to‐moderate patients (MA) were screened and prospectively followed up for 1 year (NCT00555607). Medical history, baseline clinical data and biomarkers were used to assess risk factors for frequent exacerbations.
Results
During the study, 104 exacerbations were recorded in the SA group and 18 in the MA. Frequent exacerbators were characterized by use of higher doses of inhaled (1700 vs. 800 μg) and oral (6.7 vs. 1.7 mg) glucocorticosteroids, worse asthma control (ACQ score 2.3 vs. 1.4), lower quality of life (SGRQ score 48.5 vs. 33.3), higher sputum eosinophils (25.7% vs. 8.2%) and a more rapid decline in FEV1/FVC ratio (−0.07 vs. −0.01 ΔFEV1/FVC, frequent vs. non‐frequent, respectively, P < 0.05). Exhaled NO > 45 p.p.b. and a history of smoking were associated with an increased risk of frequent exacerbations (odds ratios: 4.32 and 2.90 respectively).
Conclusion and Clinical Relevance
We were able to distinguish and characterize a subphenotype of asthma subjects – frequent exacerbators – who are significantly more prone to exacerbations. Patients with FeNO > 45 p.p.b. and a history of smoking are at increased risk of frequent exacerbations and require careful monitoring in clinical practice.
Summary
Background
Systemic mastocytosis (SM) is a clonal mast cells disorder characterized by the proliferation, accumulation and activation of mast cells in extracutaneous tissues. The clinical ...picture is heterogeneous and may range from asymptomatic to potentially fatal anaphylactic reactions due to excessive mast cell mediator release.
Objective
The aim of this study was to investigate the prevalence and trigger factors of anaphylactic reactions among adult SM patients. We also explored the clinical spectrum of mast cell mediator‐related symptoms in patients with SM.
Methods
This descriptive study was performed among 84 consecutive adult (≥ 18 years) patients those were diagnosed with SM according to WHO criteria. Sixty‐six of the patients also underwent a comprehensive allergy work‐up.
Results
Sixty of 84 patients with SM (71%) had bone marrow mast cell aggregates and fulfilled the major criteria for SM and 76 patients (91%) had indolent disease. Simultaneous occurrence of cutaneous mastocytosis was observed in 59 patients (70%). Thirty‐six patients (43%) had had at least one episode of an anaphylactic reaction. The clinical courses of the reactions were usually severe and patients often presented with syncope attacks (72%). Most patients reacted after hymenoptera venom stings (19/36; 53%). In 39% (14/36), a clear aetiology could not be determined. While males and females were equally frequent among the patients with SM, anaphylaxis patients showed a male predominance (61%). Anaphylactic reactions occurred more frequently in patients without cutaneous engagement. The rate of allergy sensitization was significantly higher in SM patients with anaphylaxis as compared with non‐anaphylaxis SM patients, 70% vs. 23%, respectively (P = 0.0002).
Conclusions and Clinical Relevance
Anaphylaxis is more prevalent in patients with SM, predominantly in patients with atopic SM. Hymenoptera venom‐induced and idiopathic anaphylaxis were the most frequent elicitors. Our findings implicate that all mastocytosis patients with anaphylaxis should undergo detailed allergological assessment before considering treatment and preventive measures.
Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most common causes of adverse drug reactions. Majority of them are of the hypersensitivity type. The two frequent ...clinical presentations of aspirin hypersensitivity are: aspirin-induced bronchial asthma/rhinosinusitis (AIA/R) and aspirin-induced urticaria/angioedema (AIU). The decisive diagnosis is based on provocation tests with aspirin, as the in vitro test does not hold diagnostic value as yet. Detailed protocols of oral, bronchial and nasal aspirin provocation tests are presented. Indications, contraindications for the tests, the rules of drug withdrawal and equipment are reviewed. Patient supervision and interpretations of the tests are proposed.
Summary
Background
The mechanisms by which mast cells in patients with unexplained anaphylaxis (UEA) are triggered remain elusive. Onset of episodes is unpredictable and often recurrent. The ...substantial overlap between the clinical manifestations of UEA and clonal mast cell disorders (CMD) suggests an association between these rare disorders. The two forms of CMD characterized to date are systemic mastocytosis (SM) and monoclonal mast cell activation syndrome (MMAS).
Objective
To examine the hypothesis that the pathogenesis of UEA reflects the presence of aberrant subpopulations of mast cells.
Methods
Thirty (14 men, 16 women) patients (≥ 18 years) suffering from UEA and with no signs of cutaneous mastocytosis were recruited. Patients underwent an initial complete allergy work‐up to confirm the diagnosis of UEA. Level of baseline serum tryptase (sBT) and total IgE were determined. In addition, a bone marrow examination was performed on all 30 patients to investigate possible underlying CMD.
Results
Fourteen (47%) of our cases (nine men, five women) were diagnosed with CMD: 10 with SM and four with MMAS. Four of the 10 patients with SM had mast cell aggregates in their bone marrow. All patients with SM exhibited a sBT level > 11.4 ng/mL, whereas this level was elevated in only two of those with MMAS and four with UAE but not diagnosed with CMD. Total IgE levels were lower in the group of patients with CMD (P < 0.03).
Conclusion and Clinical Relevance
The pathogenic mechanism underlying UEA could be explained by the presence of immunophenotypically aberrant mast cells with clonal markers in 47% of our subjects, indicating that clonal mast cell disorders are present in a substantial subset of these patients. Thus, the presence of CMD should be considered in patients with UEA if they have an elevated level of sBT (≥ 11.4 ng/mL) and cardiovascular symptoms such as syncope.
Mastocytosis is a complex disorder characterized by the accumulation of abnormal mast cells (MC) in the skin, bone marrow and/or other visceral organs. The clinical manifestations result from ...MC‐derived mediators and, less frequently, from destructive infiltration of MCs. Patients suffer from a variety of symptoms including pruritus, flushing and life‐threatening anaphylaxis. Whilst mastocytosis is likely to be suspected in a patient with typical skin lesions i.e. urticaria pigmentosa (UP), the absence of cutaneous signs does not rule out the diagnosis of this disease. Mastocytosis should be suspected in cases of recurrent, unexplained or severe insect‐induced anaphylaxis or symptoms of MC degranulation without true allergy. In rare cases, unexplained osteoporosis or unexplained haematological abnormalities can be underlying feature of mastocytosis, particularly when these conditions are associated with elevated baseline serum tryptase levels. The diagnosis is based on the World Health Organization criteria, in which the tryptase level, histopathological and immunophenotypic evaluation of MCs and molecular analysis are crucial. A somatic KIT mutation, the most common of which is D816V, is usually detectable in MCs and their progenitors. Once a diagnosis of systemic mastocytosis (SM) is made, it is mandatory to assess the burden of the disease, its activity, subtype and prognosis, and the appropriate therapy. Mastocytosis comprises seven different categories that range from indolent forms, such as cutaneous and indolent SM, to progressive forms, such as aggressive SM and MC leukaemia. Although prognosis is good in patients with indolent forms of the disease, patients with advanced categories have a poor prognosis.
Background
Mast cells are important in the pathophysiology of airway inflammation and evidence suggests their sub‐localisation within the airway is altered in asthma. Little is known about the effect ...of corticosteroids on mast cell localisation within the bronchi.
Methods
We therefore performed an immunohistochemical analysis of mast cell numbers within the smooth muscle, epithelium and submucosa of healthy subjects (n = 10) and well‐characterised asthmatic patients, using either β2‐agonists alone (n = 10) or β2‐agonists and inhaled corticosteroids (n = 10).
Results
Patients using inhaled corticosteroids displayed significantly lower numbers of mast cells within their epithelium and smooth muscle compared to those not treated with inhaled corticosteroids. Submucosal mast cells were not affected by corticosteroid treatment. Numbers of smooth muscle mast cells correlated with bronchial responsiveness and epithelial mast cells with exhaled NO.
Conclusion
We demonstrate that glucocorticosteroids differentially affect mast cell numbers within specific airway sub‐locations highlighting the importance of mast cell and smooth muscle/epithelial interactions in asthma pathogenesis.
A diagnosis of aspirin-intolerant asthma requires aspirin provocation in specialist clinics. Urinary leukotriene E(4) (LTE(4)) is increased in aspirin-intolerant asthma. A study was undertaken to ...investigate new biomarkers of aspirin intolerance by comparing basal levels of cysteinyl-leukotrienes (CysLTs) and leukotriene B(4) (LTB(4)) in saliva, sputum and ex vivo stimulated blood in subjects with aspirin-intolerant and aspirin-tolerant asthma. The effects of aspirin- and allergen-induced bronchoconstriction on leukotriene levels in saliva and ex vivo stimulated blood were also compared with the effects of the provocations on urinary mediators.
Induced sputum, saliva, urine and blood were obtained at baseline from 21 subjects with asthma. At a separate visit, 11 subjects showed a positive response to lysine-aspirin inhalation and 10 were aspirin tolerant. Saliva, blood and urine were also collected on the provocation day. Analyses of CysLTs and LTB(4) and the prostaglandin D(2) metabolite 9alpha,11beta-prostaglandin F(2) were performed and the fraction of exhaled nitric oxide was measured.
Subjects with aspirin-intolerant asthma had higher exhaled nitric oxide levels and higher baseline levels of CysLTs in saliva, sputum, blood ex vivo and urine than subjects with aspirin-tolerant asthma. There were no differences in LTB(4) levels between the groups. Levels of urinary LTE(4) and 9alpha,11beta-prostaglandin F(2) increased after aspirin provocation whereas leukotriene levels in saliva and ex vivo stimulated blood did not increase.
These findings support a global and specific increase in CysLT production in aspirin-intolerant asthma. Measurement of CysLTs in saliva has the potential to be a new and convenient non-invasive biomarker of aspirin-intolerant asthma.
Release of bronchoactive mediators from mast cells during exercise hyperpnea is a key factor in the pathophysiology of exercise-induced bronchoconstriction (EIB). Our aim was to investigate the ...effect of a standard, single dose of an inhaled β2-adrenoceptor agonist on mast cell activation in response to dry air hyperpnea in athletes with EIB. Twenty-seven athletes with EIB completed a randomized, double-blind, placebo-controlled, crossover study. Terbutaline (0.5 mg) or placebo was inhaled 15 min prior to 8 min of eucapnic voluntary hyperpnea (EVH) with dry air. Pre- and postbronchial challenge, urine samples were analyzed by enzyme immunoassay for 11β-prostaglandin F2α (11β-PGF2α). The maximum fall in forced expiratory volume in 1 s of 14 (12-20)% (median and interquartile range) following placebo was attenuated to 7 (5-9)% with the administration of terbutaline (P < 0.001). EVH caused a significant increase in 11β-PGF2α from 41 (27-57) ng/mmol creatinine at baseline to 58 (43-72) ng/mmol creatinine at its peak post-EVH following placebo (P = 0.002). The rise in 11β-PGF2α was inhibited with administration of terbutaline: 39 (28-44) ng/mmol creatinine at baseline vs. 40 (33-58) ng/mmol creatinine at its peak post-EVH (P = 0.118). These data provide novel in vivo evidence of mast cell stabilization following inhalation of a standard dose of terbutaline prior to bronchial provocation with EVH in athletes with EIB.
Summary
Background
Prostaglandin (PG) D2 is a pro‐inflammatory and bronchoconstrictive mediator released from mast cells, and is currently evaluated as a new target for treatment of asthma and ...rhinitis. It is not known which cyclooxygenase (COX) isoenzyme catalyses its biosynthesis in subjects with asthma.
Objectives
Primarily, to assess whether treatment with the COX‐2 selective inhibitor celecoxib inhibited biosynthesis of PGD2, monitored as urinary excretion of its major tetranor metabolite (PGDM). Secondarily, to determine the effects of the treatment on biosynthesis of PGE2, thromboxane A2 and PGI2, also measured as major urinary metabolites.
Methods
Eighteen subjects with asthma participated in a cross‐over study where celecoxib 200 mg or placebo were given b.i.d. on 3 consecutive days following 2 untreated baseline days. Six healthy controls received active treatment with the same protocol. Urinary excretion of the eicosanoid metabolites was determined by liquid chromatography/tandem mass spectrometry (LC/MS/MS). Lung function was followed as FEV1 and airway inflammation as fraction of exhaled nitric oxide (FENO).
Results
Celecoxib treatment inhibited urinary excretion of PGEM by 50% or more in subjects with asthma and healthy controls, whereas there was no significant change in the excretion of PGDM. In comparison with the healthy controls, the subjects with asthma had higher baseline levels of urinary PGDM but not of PGEM. The 3‐day treatment did not cause significant changes in FEV1 or FENO.
Conclusion and Clinical Relevance
Biosynthesis of PGD2 was increased in subjects with asthma and its formation is catalysed predominantly by COX‐1. By contrast, COX‐2 contributes substantially to the biosynthesis of PGE2. The asymmetric impact of celecoxib on prostanoid formation raises the possibility of long‐term adverse consequences of COX‐2 inhibition on airway homeostasis by the decreased formation of bronchodilator PGs and maintained production of increased levels of bronchoconstrictor PGs in asthmatics.
Cite this as: K. Daham, W.‐ L. Song, J. A. Lawson, M. Kupczyk, A. Gülich, S.‐E. Dahlén, G. A. FitzGerald and B. Dahlén, Clinical & Experimental Allergy, 2011 (41) 36–45.
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