Sven Seys

Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis—PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology

In this consensus document we summarize the current knowledge on major asthma, rhinitis, and atopic dermatitis endotypes under the auspices of the PRACTALL collaboration platform. PRACTALL is an initiative of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology aiming to harmonize the European and American approaches to best allergy practice and science. Precision medicine is of broad relevance for the management of asthma, rhinitis, and atopic dermatitis in the context of a better selection of treatment responders, risk prediction, and design of disease-modifying strategies. Progress has been made in profiling the type 2 immune response-driven asthma. The endotype driven approach for non-type 2 immune response asthma, rhinitis, and atopic dermatitis is lagging behind. Validation and qualification of biomarkers are needed to facilitate their translation into pathway-specific diagnostic tests. Wide consensus between academia, governmental regulators, and industry for further development and application of precision medicine in management of allergic diseases is of utmost importance. Improved knowledge of disease pathogenesis together with defining validated and qualified biomarkers are key approachesxa0to precision medicine.

Mortality in non-cystic fibrosis bronchiectasis: A prospective cohort analysis

INTRODUCTIONnThere is limited data on mortality and associated morbidity in non-cystic fibrosis bronchiectasis (NCFB). Our aim was to analyze the overall mortality for all newly diagnosed patients from June 2006 onwards and to evaluate risk factors for mortality in this cohort.nnnMETHODSn245 patients who had a new diagnosis of NCFB between June 2006 and October 2012 at the University Hospital of Leuven, Belgium, were included in the analysis. Death was analyzed until end of November 2013. All patients had chest HRCT scan confirming the presence of bronchiectatic lesions and had symptoms of chronic productive cough. Univariate and multivariate Cox proportional hazard survival regression analysis was used to estimate hazard ratios (HR) and their 95% confidence intervals (CI) of variables possibly predicting mortality.nnnRESULTSnOverall mortality in NCFB patients who had a median follow-up of 5.18 years was 20.4%. Patients with NCFB and associated chronic obstructive pulmonary disease (COPD) had a mortality of 55% in that period. Univariate analysis showed higher mortality according to age, gender, smoking history, Pseudomonas aeruginosa status, spirometry, radiological extent, total number of sputum bacteria and underlying etiology. Multivariate analysis showed significant higher mortality with increasing age (HRxa0=xa01.045; pxa0=xa00.004), with increasing number of lobes affected (HRxa0=xa01.53; pxa0=xa00.009) and when patients had COPD associated NCFB (HRxa0=xa02.12; pxa0=xa00.038). The majority of the 50 deaths were respiratory related (nxa0=xa029; 58%).nnnCONCLUSIONnNCFB patients with associated COPD disease had the highest mortality rates compared to the other NCFB patients. Additional risk factors for lower survival were increasing age and number of lobes affected.

Impaired barrier function in patients with house dust mite–induced allergic rhinitis is accompanied by decreased occludin and zonula occludens-1 expression

BACKGROUNDnTight junction (TJ) defects have recently been associated with asthma and chronic rhinosinusitis. The expression, function, and regulation of nasal epithelial TJs remain unknown in patients with allergic rhinitis (AR).nnnOBJECTIVEnWe investigated the expression, function, and regulation of TJs in the nasal epithelium of patients with house dust mite (HDM)-induced AR and in an HDM-induced murine model of allergic airway disease.nnnMETHODSnAir-liquid interface cultures of primary nasal epithelial cells of control subjects and patients with HDM-induced AR were used for measuring transepithelial resistance and passage to fluorescein isothiocyanate-dextran 4 kDa (FD4). Ex vivo transtissue resistance and FD4 permeability of nasal mucosal explants were measured. TJ expression was evaluated by using real-time quantitative PCR and immunofluorescence. In addition, the effects of IL-4, IFN-γ, and fluticasone propionate (FP) on nasal epithelial cells were investigated in vitro. An HDM murine model was used to study the effects of allergic inflammation and FP treatment on transmucosal passage of FD4 in vivo.nnnRESULTSnA decreased resistance in vitro and ex vivo was found in patients with HDM-induced AR, with increased FD4 permeability and reduced occludin and zonula occludens-1 expression. AR symptoms correlated inversely with resistance in patients with HDM-induced AR. In vitro IL-4 decreased transepithelial resistance and increased FD4 permeability, whereas IFN-γ had no effect. FP prevented IL-4-induced barrier dysfunction in vitro. In an HDM murine model FP prevented the allergen-induced increased mucosal permeability.nnnCONCLUSIONnWe found impaired nasal epithelial barrier function in patients with HDM-induced AR, with lower occludin and zonula occludens-1 expression. IL-4 disrupted epithelial integrity in vitro, and FP restored barrier function. Better understanding of nasal barrier regulation might lead to a better understanding and treatment of AR.

Risk factors for morbidity and death in non-cystic fibrosis bronchiectasis: a retrospective cross-sectional analysis of CT diagnosed bronchiectatic patients

IntroductionThere is a relative lack of information about the death rate and morbidity of non-cystic fibrosis bronchiectasis and most studies are limited due to referral bias. We wanted to assess death rate and morbidity in those patients at our hospital.MethodsAdult patients seen at our department between June 2006 and November 2009 were recruited if the key string bronchiect- was mentioned in electronic clinical records and if chest CT imaging was available. Clinical records of all patients with confirmed radiologic diagnosis of bronchiectasis were reviewed and clinical characteristics were analyzed.Results539 patients with a radiographic diagnosis of non-cystic fibrosis bronchiectasis were identified in a retrospective cross-sectional analysis giving a prevalence of 2.6% in our hospital population. A wide range of etiologies was found with idiopathic bronchiectasis in 26%. In the 41 months interval, 57 patients (10.6%) died. We found a median exacerbation rate of 1.94 per year. Bacterial colonization status was associated with more deaths, exacerbation rate, symptoms and reduced pulmonary function. Pulmonary hypertension was found in 48% of our patients.ConclusionsWe evaluated a large non-cystic fibrosis bronchiectasis population, and provided new epidemiological data on associations between clinical characteristics and deaths and morbidity in these patients.

Sputum cytokine mapping reveals an 'IL-5, IL-17A, IL-25-high' pattern associated with poorly controlled asthma

Asthma is a heterogeneous disease with various clinical, inflammatory and molecular phenotypes. We studied sputum cytokine mRNA expression patterns in an unselected group of adult asthma patients to characterize the underlying inflammatory process.

The Sputum Colour Chart as a predictor of lung inflammation, proteolysis and damage in non-cystic fibrosis bronchiectasis: a case-control analysis.

Non‐cystic fibrosis bronchiectasis (NCFB) is characterized by a vicious cycle of airway infection, inflammation and structural damage with inappropriate mucus clearance. Our aim was to relate the value of proteolytic enzymes, proteolytic enzyme activity and inflammatory markers to disease severity and symptoms in patients with NCFB.

Pepsin and bile acids in induced sputum of chronic cough patients

One of the theories which explain, why gastroesophageal reflux disease (GORD) may provoke cough, is the occurrence of aspiration of gastric content into the airways. The aim of the study was to assess the presence of aspiration markers: pepsin and bile acids (BA) in induced sputum in gastroesophageal reflux-related (GOR-related) chronic cough (CC) patients. Forty-one CC patients and 20 healthy controls were enrolled in the study. GORD as cause of CC was diagnosed by presence of GORD-related symptoms, gastroscopy and/or improvement of cough upon treatment with proton pump inhibitors (PPI). Patients were divided into two groups based on the response to PPI treatment. In all patients and healthy controls induced sputum was obtained and differential cell counts were calculated. Levels of pepsin and BA were measured in sputum supernatants. Pepsin was detectable in 48.8% samples in CC patients and in 60% healthy controls (pxa0=xa0NS). In pepsin positive samples no significant difference in pepsin concentration could be found between CC patients and control subjects. Pepsin levels in pepsin positive samples were significantly decreased in patients treated with PPI compared to non-treated patients. BA were detectable in 56% samples of CC patients and in 70% healthy controls (pxa0=xa0NS). BA concentration in BA positive samples in CC group was not different from healthy controls. There was also no difference when comparing patients who took PPI and those who did not. Patients characterized as PPI-responders and PPI-non-responders had similar pepsin and BA concentrations. Airway cellularity was not significantly different between groups of patients with or without pepsin or BA in induced sputum. Our results demonstrated the lack of differences in gastric content aspiration between patients with probable GOR-related CC and healthy control subjects. This might imply that the reflex cough theory may be more relevant than the reflux-associated aspiration theory in the pathophysiology of GORinduced chronic cough.

Effects of high altitude and cold air exposure on airway inflammation in patients with asthma

Aims Eighteen patients with asthma were evaluated during preparation to climb to extreme altitude in order to study the effects of low fractional inspired oxygen (FiO2), prolonged exposure to cold air and high altitude on lung function, asthma control and airway inflammation. Methods Spirometry and airway inflammation (fractional exhaled nitric oxide (FeNO) and induced sputum) were studied under different test conditions: hypoxic (FiO2=11%) exercise test, 24-hour cold exposure (−5°C) and before, during and after an expedition that involved climbing the Aconcagua mountain (6965u2005m). Results Forced expiratory volume in 1u2005s (FEV1) and FeNO values were slightly lower (p<0.04) after 1u2005h of normobaric hypoxia. FEV1 decreased (p=0.009) after 24-hour cold exposure, accompanied by increased sputum neutrophilia (p<0.01). During the expedition FEV1 and forced vital capacity decreased (maximum FEV1 decrease of 12.3% at 4300u2005m) and asthma symptoms slightly increased. After the expedition the Asthma Control Test score and prebronchodilator FEV1 were reduced (p<0.02), sputum neutrophil count was increased (p=0.04) and sputum myeloperoxidase levels, sputum interleukin 17 mRNA, serum and sputum vascular endothelial growth factor A levels were significantly higher compared with baseline. Patients with asthma with the lowest oxygen saturation during the hypoxic exercise test were more prone to develop acute mountain sickness. Conclusions Exposure to environmental conditions at high altitude (hypoxia, exercise, cold) was associated with a moderate loss of asthma control, increased airway obstruction and neutrophilic airway inflammation. The cold temperature is probably the most important contributing factor as 24-hour cold exposure by itself induced similar effects.

Restoring airway epithelial barrier dysfunction: a new therapeutic challenge in allergic airway disease

An intact functional mucosal barrier is considered to be crucial for the maintenance of airway homeostasis as it protects the host immune system from exposure to allergens and noxious environmental triggers. Recent data provided evidence for the contribution of barrier dysfunction to the development of inflammatory diseases in the airways, skin and gut. A defective barrier has been documented in chronic rhinosinusitis, allergic rhinitis, asthma, atopic dermatitis and inflammatory bowel diseases. However, it remains to be elucidated to what extent primary (genetic) versus secondary (inflammatory) mechanisms drive barrier dysfunction. The precise pathogenesis of barrier dysfunction in patients with chronic mucosal inflammation and its implications on tissue inflammation and systemic absorption of exogenous particles are only partly understood. Since epithelial barrier defects are linked with chronicity and severity of airway inflammation, restoring the barrier integrity may become a useful approach in the treatment of allergic diseases. We here provide a state-of-the-art review on epithelial barrier dysfunction in upper and lower airways as well as in the intestine and the skin and on how barrier dysfunction can be restored from a therapeutic perspective.

Damage-associated molecular pattern and innate cytokine release in the airways of competitive swimmers.

Daily intensive exercise by elite athletes can result in exercise‐induced asthma especially in elite swimmers and this may be linked to epithelial damage.