Elevated serum calprotectin (S100A8/A9) in patients with severe asthma.

OBJECTIVE: Asthma is a heterogeneous disease consisting of several inflammatory phenotypes of which neutrophilic asthma is associated with poorer responses to classic therapies, namely (inhaled) corticosteroids. The development of targeted therapies requires the identification of biomarkers to distinguish these phenotypes. Currently, we lack validated biomarkers for non-eosinophilic asthma. The aim of this study is to examine serum calprotectin (SC) in asthmatics and its potential as biomarker for neutrophilic asthma. METHODS: Hundred-seventeen severe asthmatics were referred for sputum induction and data were obtained from their medical records. To evaluate the association between SC and asthma phenotypes, patients were divided into subgroups based on sputum cell count (3% eosinophils and 61% neutrophils). Additionally, SC levels of asthmatics were compared with these of patients with chronic obstructive pulmonary disease, non-cystic fibrosis bronchiectasis and healthy controls. RESULTS: Asthmatics (n = 45) had significantly higher levels of SC than healthy controls. No significant differences were found between the different asthma phenotypes and in comparison with COPD patients. SC was significantly higher in asthmatics with a lower FEV1/FVC ratio (<70) and non-significantly elevated SC levels were seen in asthmatics with frequent exacerbations (>2 in the last year). CONCLUSION: In conclusion, there was no difference in SC levels between the different inflammatory subtypes in asthmatics. Nevertheless, severe asthmatics seemed to have higher SC levels suggesting that SC may be a marker of disease severity rather than a marker for specific inflammatory subtypes in asthmatics. Further research in larger cohorts is necessary to validate SC as biomarker in severe asthmatics.

Chronic oral corticosteroids use and persistent eosinophilia in severe asthmatics from the Belgian severe asthma registry.

BACKGROUND: Severe asthma (SA) may require frequent courses or chronic use of oral corticosteroids (OCS), inducing many known side effects and complications. Therefore, it is important to identify risk factors of chronic use of OCS in SA, considering the heterogeneity of clinical and inflammatory asthma phenotypes. Another aim of the present analysis is to characterize a subpopulation of severe asthmatics, in whom blood eosinophil counts (BEC) remain elevated despite chronic OCS treatment. METHODS: In a cross-sectional analysis of 982 SA patients enrolled in the Belgian Severe Asthma Registry (BSAR) between March 2009 and February 2019, we investigated the characteristics of the OCS treated patients with special attention to their inflammatory profile. RESULTS: At enrollment, 211 (21%) SA patients were taking maintenance OCS (median dose: 8 [IQR: 5-10]) mg prednisone equivalent). BEC was high (> 400/mm3) in 44% of the OCS treated population. Multivariable logistic regression analysis showed that risk factors for chronic use of OCS in SA were late-onset asthma (i.e. age of onset > 40 yr), frequent exacerbations (i.e. ≥2 exacerbations in the previous year) and non-atopic asthma. Late-onset asthma was also a predictor for persistently high BEC in OCS treated SA patients. CONCLUSION: These data showed a significant association between a persistently high BEC and late-onset asthma in OCS treated SA patients. Whether it is poor compliance to treatment or corticosteroid insensitivity the reasons for this association warrants further investigation.

Nasal symptoms, epithelial injury and neurogenic inflammation in elite swimmers.

BACKGROUND: A high burden of lower airway symptoms is found in elite swimmers. To what extent elite swimmers suffer from upper airway symptoms and how these associate with nasal inflammation is less clear. We here aimed to evaluate upper airway symptoms and nasal inflammation in elite athletes. METHODOLOGY: Elite swimmers, indoor athletes and age-matched controls were recruited. Upper airway symptoms were assessed by sino-nasal outcome test (SNOT)-22 questionnaire. Visual Analogue score (VAS) for nasal symptoms as well as neurogenic and inflammatory mediators in nasal fluid were assessed at baseline, immediately and 24-hours after sport-specific training. The effect of hypochlorite on nasal epithelial cells was evaluated in vitro. RESULTS: Baseline SNOT-22 and VAS for nasal itch and impaired smell were significantly higher in swimmers compared to controls. Nasal substance P and uric acid levels were increased in elite swimmers 24-hours after swimming compared to baseline. In elite swimmers, uric acid levels 24-hours post-exercise correlated with baseline SNOT-22. As increased symptoms and inflammation were found in swimmers but not in indoor athletes, we hypothesized that hypochlorite exposure might be the underlying mechanism. In vitro, the highest dose of hypochlorite decreased nasal epithelial cell integrity and induced release of uric acid. CONCLUSION: Upper airway symptoms are frequently reported in elite swimmers. Intensive swimming resulted in a delayed increase of epithelial injury and neurogenic inflammation.

Prophylactic Azithromycin Therapy After Lung Transplantation: Post hoc Analysis of a Randomized Controlled Trial.

Prophylactic azithromycin treatment has been demonstrated to improve freedom from bronchiolitis obliterans syndrome (BOS) 2 years after lung transplantation (LTx). In the current study, we re-evaluated the long-term effects of this prophylactic approach in view of the updated classification system for chronic lung allograft dysfunction (CLAD). A retrospective, intention-to-treat analysis of a randomized controlled trial comparing prophylactic treatment with placebo (n = 43) versus azithromycin (n = 40) after LTx was performed. Graft dysfunction (CLAD), graft loss (retransplantation, mortality), evolution of pulmonary function and functional exercise capacity were analyzed 7 years after inclusion of the last study subject. Following LTx, 22/43 (51%) patients of the placebo group and 11/40 (28%) patients of the azithromycin group ever developed CLAD (p = 0.043). CLAD-free survival was significantly longer in the azithromycin group (p = 0.024). No difference was present in proportion of obstructive versus restrictive CLAD between both groups. Graft loss was similar in both groups: 23/43 (53%) versus 16/40 (40%) patients (p = 0.27). Long-term pulmonary function and functional exercise capacity were significantly better in the azithromycin group (p < 0.05). Prophylactic azithromycin therapy reduces long-term CLAD prevalence and improves CLAD-free survival, pulmonary function, and functional exercise capacity after LTx.

Multidimensional severity assessment in bronchiectasis: an analysis of seven European cohorts.

INTRODUCTION: Bronchiectasis is a multidimensional disease associated with substantial morbidity and mortality. Two disease-specific clinical prediction tools have been developed, the Bronchiectasis Severity Index (BSI) and the FACED score, both of which stratify patients into severity risk categories to predict the probability of mortality. METHODS: We aimed to compare the predictive utility of BSI and FACED in assessing clinically relevant disease outcomes across seven European cohorts independent of their original validation studies. RESULTS: The combined cohorts totalled 1612. Pooled analysis showed that both scores had a good discriminatory predictive value for mortality (pooled area under the curve (AUC) 0.76, 95% CI 0.74 to 0.78 for both scores) with the BSI demonstrating a higher sensitivity (65% vs 28%) but lower specificity (70% vs 93%) compared with the FACED score. Calibration analysis suggested that the BSI performed consistently well across all cohorts, while FACED consistently overestimated mortality in 'severe' patients (pooled OR 0.33 (0.23 to 0.48), p<0.0001). The BSI accurately predicted hospitalisations (pooled AUC 0.82, 95% CI 0.78 to 0.84), exacerbations, quality of life (QoL) and respiratory symptoms across all risk categories. FACED had poor discrimination for hospital admissions (pooled AUC 0.65, 95% CI 0.63 to 0.67) with low sensitivity at 16% and did not consistently predict future risk of exacerbations, QoL or respiratory symptoms. No association was observed with FACED and 6 min walk distance (6MWD) or lung function decline. CONCLUSION: The BSI accurately predicts mortality, hospital admissions, exacerbations, QoL, respiratory symptoms, 6MWD and lung function decline in bronchiectasis, providing a clinically relevant evaluation of disease severity.

Combined or Serial Liver and Lung Transplantation for Epithelioid Hemangioendothelioma: A Case Series.

Epithelioid hemangioendothelioma (EHE) is a rare vascular tumor with variable biological and clinical behavior. There is increasing experience with liver transplantation (LiTx) for hepatic EHE, even in cases of extrahepatic disease localization. Until now, no cases of lung transplantation (LuTx) had been reported for pulmonary EHE. This report describes three cases of EHE with multifocal disease in patients who underwent either serial or combined LiTx and LuTx.

Low cord blood Foxp3/CD3γ mRNA ratios: a marker of increased risk for allergy development.

BACKGROUND: Data from birth cohort studies suggest that increased cord blood total IgE and reduced cord blood regulatory T cells increase the risk of developing allergic sensitization and atopic dermatitis. OBJECTIVE: We here addressed whether serum total IgE and hen's egg-specific IgE levels at birth and at age 1 year differed between healthy and allergic children in a Belgian birth cohort (FONIA). We furthermore studied whether these parameters as well as cord blood Foxp3/CD3γ mRNA levels might predict the allergic outcome. METHODS AND RESULTS: Children (n = 84) were clinically assessed at the ages of 6, 12, 18, and 24 months and at 6 years. Cord blood total IgE levels above 0.35 kU/L predicted early (i.e. before or at the age of 2 years) allergy development. Presence of serum IgE antibodies to hen's egg (cut-off 0.05 Ua/mL) at the age of 1 year was associated with early as well as late (i.e. between the age of 2 and 6 years) allergy development. Cord blood Foxp3/CD3γ mRNA ratios were significantly lower in early allergic children and levels below 0.32 predicted the allergic outcome. CONCLUSIONS AND CLINICAL RELEVANCE: Low cord blood Foxp3/CD3γ mRNA ratios are highly predictive for early allergy development, whereas specific IgE levels to hen's egg white above 0.05 Ua/mL at age 1 year predict allergy development in general.

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

BACKGROUND: Daily intensive exercise by elite athletes can result in exercise-induced asthma especially in elite swimmers and this may be linked to epithelial damage. OBJECTIVE: To study airway epithelial damage and release of damage-associated molecular patterns (DAMPs) after intensive exercise in elite athletes and controls. METHODS: We recruited competitive swimmers (n = 26), competitive indoor athletes (n = 13) and controls (n = 15) without any history of asthma. Lung function was measured before, immediately after and 24 h after a 90-min intensive exercise protocol. Sputum induction was performed at baseline and 24 h after exercise. Exercise-induced bronchoconstriction (EIB) was assessed by the eucapnic voluntary hyperventilation test. RESULTS: Baseline sputum uric acid, high mobility group box-1, CXCL8 mRNA, sputum neutrophils and serum Clara cell protein-16 (CC-16) were significantly higher in competitive swimmers compared with controls. Intensive swimming for 90 min resulted in an increase of sputum IL-1ß, IL-6 and TNF mRNA in competitive swimmers, and of sputum IL-6 mRNA and sputum neutrophils in controls. Although all participants were asymptomatic, seven competitive swimmers, one indoor athlete and one control met the criteria for EIB. CONCLUSION: Our findings show that the intensive training combined with exposure to by-products of chlorination induces airway epithelial damage in competitive swimmers. This is associated with increased damage-associated molecular patterns, innate cytokine release and neutrophilic airway inflammation.

Azithromycin and the treatment of lymphocytic airway inflammation after lung transplantation.

Lymphocytic airway inflammation is a major risk factor for chronic lung allograft dysfunction, for which there is no established treatment. We investigated whether azithromycin could control lymphocytic airway inflammation and improve allograft function. Fifteen lung transplant recipients demonstrating acute allograft dysfunction due to isolated lymphocytic airway inflammation were prospectively treated with azithromycin for at least 6 months (NCT01109160). Spirometry (FVC, FEV1 , FEF25-75 , Tiffeneau index) and FeNO were assessed before and up to 12 months after initiation of azithromycin. Radiologic features, local inflammation assessed on airway biopsy (rejection score, IL-17(+) cells/mm(2) lamina propria) and broncho-alveolar lavage fluid (total and differential cell counts, chemokine and cytokine levels); as well as systemic C-reactive protein levels were compared between baseline and after 3 months of treatment. Airflow improved and FeNO decreased to baseline levels after 1 month of azithromycin and were sustained thereafter. After 3 months of treatment, radiologic abnormalities, submucosal cellular inflammation, lavage protein levels of IL-1ß, IL-8/CXCL-8, IP-10/CXCL-10, RANTES/CCL5, MIP1-α/CCL3, MIP-1ß/CCL4, Eotaxin, PDGF-BB, total cell count, neutrophils and eosinophils, as well as plasma C-reactive protein levels all significantly decreased compared to baseline (p < 0.05). Administration of azithromycin was associated with suppression of posttransplant lymphocytic airway inflammation and clinical improvement in lung allograft function.

Pirfenidone: a potential new therapy for restrictive allograft syndrome?

This case report describes the evolution of pulmonary function findings (FVC, FEV1 and TLC) and CT features with pirfenidone treatment for restrictive allograft syndrome following lung transplantation. Furthermore, we herein report hypermetabolic activity on (18) F-FDG PET imaging in this setting, which could indicate active fibroproliferation and pleuroparenchymal remodeling. These findings may warrant further investigation.

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

BACKGROUND AND OBJECTIVE: 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. METHODS: Differential cell counts and cytokine mRNA (quantified by real-time PCR) were analysed on sputum from 40 controls and 66 asthmatic adults. A 'cytokine-high' profile was defined if mRNA levels for that particular cytokine exceeded the 90th percentile value in the control population. Radar graphs were used to visualize cytokine profiles. RESULTS: Sputum mRNA analysis confirmed heterogeneity of cytokine patterns among patients. Thirty-six patients (55%) had a Th2 cytokine pattern: 'IL-5-high' (n = 13), 'IL-4-high' (n = 17) or 'IL-4- and IL-5-high' (n = 6). The 'IL-5-high' asthma profile (n = 13) coincided with the 'IL-25-high' (10/13) and surprisingly also with the 'IL-17A-high' (11/13) profile. The 'IL-5-/IL-25-/IL-17A-high profile was different from the 'IL-4-high' pattern. Patients with the 'IL-5, IL-17A, IL-25-high' pattern had significantly worse lung function parameters. Uncontrolled asthmatics [Asthma Control Test (ACT) < 20] had higher sputum IL-5, IL-17A and IL-25 mRNA levels compared to controlled asthmatics (P = 0.002; P = 0.002; P = 0.066) and uncontrolled asthma is more common among 'IL-5- and IL-17A-high' asthmatics compared to 'IL-5-, IL-17A-low' asthmatics (χ(2) = 3.7, P = 0.027; relative risk (RR): 1.8, 95% CI = 1.1-3.1). CONCLUSIONS AND CLINICAL RELEVANCE: Patients with the 'IL-5, IL-17A, IL-25-high' airway inflammatory pattern are often uncontrolled asthmatics, despite daily treatment. It seems worthwhile to evaluate whether measuring sputum cytokine levels might be used to assess the response to increased doses of steroids in patients with asthma.

Lymphocytic bronchiolitis after lung transplantation is associated with daily changes in air pollution.

Acute rejection represents a major problem after organ transplantation, being a recognized risk for chronic rejection and mortality. Recently, it became clear that lymphocytic bronchiolitis (LB, B-grade acute rejection) is more important than previously thought, as it predisposes to chronic rejection. We aimed to verify whether daily fluctuations of air pollution, measured as particulate matter (PM) are related to histologically proven A-grade rejection and/or LB and bronchoalveolar lavage (BAL) fluid cellularity after lung transplantation. We fitted a mixed model to examine the association between daily variations in PM(10) and A-grade rejection/LB on 1276 bronchoscopic biopsies (397 patients, 416 transplantations) taken between 2001 and 2011. A difference of 10 µg/m(3) in PM(10) 3 days before diagnosis of LB was associated with an OR of 1.15 (95% CI 1.04-1.27; p = 0.0044) but not with A-grade rejection (OR = 1.05; 95% CI 0.95-1.15; p = 0.32). Variations in PM(10) at lag day 3 correlated with neutrophils (p = 0.013), lymphocytes (p = 0.0031) and total cell count (p = 0.024) in BAL. Importantly, we only found an effect of PM10 on LB in patients not taking azithromycin. LB predisposed to chronic rejection (p < 0.0001). The risk for LB after lung transplantation increased with temporal changes in particulate air pollution, and this was associated with BAL neutrophilia and lymphocytosis. Azithromycin was protective against this PM effect.

Bile acids aspiration reduces survival in lung transplant recipients with BOS despite azithromycin.

Azithromycin (AZM) improved bronchiolitis obliterans syndrome (BOS) and reduced aspiration in lung transplant (LTx) recipients. We hypothesize that AZM could improve graft and overall survival more efficiently in LTx patients with BOS who have bile acid (BA) aspiration by protecting against the aspiration-induced progression of BOS. The goal was to compare FEV(1) (% baseline), BOS progression and overall survival in LTx recipients treated with AZM for BOS, both with versus without BA aspiration. Therefore, LTx recipients treated with AZM for BOS were recruited and broncho-alveolar lavage (BAL) samples were analyzed for the presence of BA and neutrophilia before the start of AZM treatment. Short-term effect of AZM on FEV(1) and BAL neutrophilia was assessed, progression of BOS and survival were followed-up for 3 years and results were compared between patients with/without BA aspiration. 19/37 LTx patients had BA in BAL. BA aspiration predisposed to a significantly worse outcome, in terms of decline in FEV(1) , progression of BOS ≥ 1 and survival. AZM does not seem to protect against the long-term allograft dysfunction caused by gastroesophageal reflux (GER) and aspiration and an additional treatment targeting aspiration may be indicated in those LTx patients.

A randomised controlled trial of azithromycin to prevent chronic rejection after lung transplantation.

Azithromycin reduces airway inflammation and improves forced expiratory volume in 1 s (FEV1) in chronic rejection or bronchiolitis obliterans syndrome (BOS) after lung transplantation (LTx). Azithromycin prophylaxis might prevent BOS. A double-blind randomised controlled trial of azithromycin (n = 40) or placebo (n = 43), initiated at discharge and administered three times a week for 2 yrs, was performed in 2005-2009 at the Leuven University Hospital (Leuven, Belgium). Primary end-points were BOS-free and overall survival 2 yrs after LTx; secondary end-points were acute rejection, lymphocytic bronchiolitis and pneumonitis rate, prevalence of pseudomonal airway colonisation or gastro-oesophageal reflux, and change in FEV1, airway and systemic inflammation over time. Patients developing BOS were assessed for change in FEV1 with open-label azithromycin. BOS occurred less in patients receiving azithromycin: 12.5 versus 44.2% (p = 0.0017). BOS-free survival was better with azithromycin (hazard ratio 0.27, 95% CI 0.092-0.816; p = 0.020). Overall survival, acute rejection, lymphocytic bronchiolitis, pneumonitis, colonisation and reflux were comparable between groups. Patients receiving azithromycin demonstrated better FEV1 (p = 0.028), and lower airway neutrophilia (p = 0.015) and systemic C-reactive protein levels (p = 0.050) over time. Open-label azithromycin for BOS improved FEV1 in 52.2% patients. No serious adverse events were noted. Azithromycin prophylaxis attenuates local and systemic inflammation, improves FEV1 and reduces BOS 2 yrs after LTx.

Real life experience with mTOR-inhibitors after lung transplantation.

Mammalian target of rapamycin inhibitors (mTORi) are increasingly used after lung transplantation as part of a calcineurin inhibitor sparing regimen, aiming to preserve renal function. The aim of our study was to determine whether immunosuppressive therapy using mTORi in lung transplant recipients (LTR) is feasible in practice, or limited by intolerance and adverse events. Data were retrospectively assessed for all LTR transplanted between July 1991 and January 2020. Patients ever receiving mTORi (monotherapy or in combination with calcineurin inhibitor) as treatment of physicians' choice were included. 149/1184 (13%) of the LTR ever received mTORi. Main reasons to start were renal insufficiency (67%) and malignancy (21%). In 52% of the patients, mTORi was stopped due to side effects or drug toxicity after a median time of 159 days. Apart from death, main reasons for discontinuation were infection (19%) and edema (14%). Early discontinuation (<90 days) was mainly due to edema or gastrointestinal intolerance. As mTORi was stopped due to adverse events or drug intolerance in 52% of LTR, cautious consideration of advantages and disadvantages when starting mTORi is recommended.

Follicular bronchiolitis: a rare cause of bronchiolitis obliterans syndrome after lung transplantation: a case report.

This case report is the first confirmed case of follicular bronchiolitis (FB), a rare bronchiolar disorder characterized by peribronchiolar lymphoid follicles, in a series of over 400 lung transplantations performed in our center. It is to our knowledge, the first publication describing FB after lung transplantation (LTx), presenting as chronic allograft dysfunction or bronchiolitis obliterans syndrome (BOS).

Azithromycin reduces gastroesophageal reflux and aspiration in lung transplant recipients.

Azithromycin (AZI) is a macrolide antibiotic that improves lung function in lung transplant recipients (LTx). Gastroesophageal reflux (GER) has been implicated in the pathogenesis of chronic rejection after LTx. Macrolide antibiotics may affect GER by modifying esophageal and gastric motility. The purpose of this study was to evaluate the effect of AZI on GER and gastric aspiration after LTx. Acid and weakly acidic GER was measured with 24-h pH-impedance monitoring in 47 LTx patients (12 patients "on" AZI). Gastric aspiration was assessed in a separate group of 30 LTx patients before and after AZI by measurements of pepsin and bile acid in bronchoalveolar lavage fluid (BALF). Patients "on" AZI had a significant lower total number of reflux events [41 (30-61) vs. 22.5 (7-37.5)], number of acid reflux events [24 (16-41) vs. 8 (4-18)], esophageal acid exposure [2.9% (0.7-7.3) vs. 0.2% (0.1-2.0)], bolus exposure [0.73% (0.5-1.4) vs. 0.21% (0.12-0.92)], and proximal extent of reflux [14 (9-24) vs. 5 (2-7)]. AZI reduced the concentration of bile acids in BALF without affecting levels of pepsin. LTx patients "on" AZI have less GER and bile acids aspiration. This effect might be due to enhanced esophageal motility and accelerated gastric emptying.

Plasma C-reactive protein levels correlate with markers of airway inflammation after lung transplantation: a role for systemic inflammation in bronchiolitis obliterans syndrome?

OBJECTIVE: Plasma C-reactive protein (CRP) concentration has been associated with allograft dysfunction in cardiac and renal transplantation; data in lung transplantation (LTx), however, are lacking. We hypothesized that in Ltx, systemic inflammation may be associated with airway inflammation, which has an important role in the development of chronic allograft dysfunction or bronchiolitis obliterans syndrome after LTx. METHODS: In this retrospective, longitudinal, cohort study, plasma CRP concentration, bronchoalveolar lavage (BAL) inflammatory markers (interleukin [IL]-6 and IL-8 protein levels and cell differentials), and pulmonary function (forced expiratory volume in 1 second) were evaluated in 100 LTx recipients at discharge and at 3-, 6-, and 12-month follow-up. The Spearman rank test was used to determine a possible relationship between these parameters at each routine follow-up visit. RESULTS: Plasma CRP concentration positively correlated with BAL total cell count and neutrophilia, whereas there was a negative correlation with pulmonary function at discharge and at 3 and 6 months after LTx. A correlation between plasma CRP concentration and BAL interleukin levels was present at discharge (IL-6 and IL-8) and at 6 months (IL-8) after LTx. CONCLUSION: Systemic inflammation and IL-8-mediated neutrophilic airway inflammation seem to be associated after LTx. Therefore, systemic inflammation has a possible role in the development of bronchiolitis obliterans syndrome after LTx.

Gastro-oesophageal reflux and aspiration of gastric contents in adult patients with cystic fibrosis.

BACKGROUND: Gastro-oesophageal reflux (GOR) is increased in cystic fibrosis (CF), but its prevalence, characteristics, association with gastric aspiration and respiratory impact are not well characterised. We investigated acid and weakly acidic reflux, aspiration and respiratory symptoms/function in adult CF patients. METHODS: Thirty-three CF patients [19 men; 29 (18-55) years, [10 post-lung transplant (LTx)] underwent impedance-pH monitoring for detection of acid (pH<4) and weakly acid GOR (pH 4-7). In 16 patients cough was objectively recorded with oesophageal manometry, and the symptom association probability (SAP) was calculated. Saliva and bronchoalveolar lavage fluid (BALF) were tested for bile acids. RESULTS: Twenty-eight patients had increased GOR (21 acid, 5 weakly acidic and 2 acid+weakly acidic) and 10 had a positive SAP for reflux cough. GOR parameters were similar in non-LTx and post-LTx CF patients. The sequence reflux cough was significantly more common than cough reflux. Sixteen of 38 patients had bile acids in saliva and 6/10 in BALF and this was almost exclusively observed in patients with genotype DF508/DF508. Only 12/28 with increased GOR and 9/22 with bile acids in saliva/BALF had typical reflux symptoms. There was a positive correlation (r = 0.53, p = 0.03) between oesophageal acid exposure and cough. SAP-positive patients with for reflux cough had a lower lung function than SAP-negative patients. CONCLUSION: Increased GOR is prevalent in CF and not secondary to cough. Acid GOR is common, but weakly acidic GOR may also occur. CF patients have a high risk of aspiration and reflux seems to be associated with more cough and poorer lung function. Outcome studies with intense anti-reflux therapy are needed to confirm the deleterious role of reflux in CF progression.

The role of the IL23/IL17 axis in bronchiolitis obliterans syndrome after lung transplantation.

Bronchiolitis obliterans syndrome (BOS) is the leading cause of death after lung transplantation. Treatment is challenging, as the precise pathophysiology remains unclear. We hypothesize that T(H)17 lineage plays a key role in the pathophysiology of BOS by linking T-cell activation to neutrophil influx and chronic inflammation. In a cross-sectional study, bronchoalveolar lavage (BAL) samples of 132 lung transplant recipients were analyzed. Patients were divided in four groups: stable or suffering from infection (INF), acute rejection (AR) or BOS. The upstream T(H)17 skewing (TGF-beta/IL1beta/IL6/IL23), T(H)17 counteracting (IL2), T(H)17 effector cytokine (IL17) and the principal neutrophil-attracting chemokine (IL8), were quantified at the mRNA or protein level in combination with the cell profiles. The BOS group (n = 36) showed an increase in IL1beta protein (x1.5), IL6 protein (x3), transforming growth factor-beta (TGF-beta) mRNA (x3), IL17 mRNA (x20), IL23 mRNA (x10), IL8 protein (x2), IL8 mRNA (x3) and a decrease in IL2 protein (x0.8). The infection group (n = 11) demonstrated an increase in IL1beta protein (x5), IL6 protein (x20), TGF-beta mRNA (x10), IL17 mRNA (x300), IL23 mRNA (x200) and IL8 protein (x6). The acute rejection group (n = 43) only revealed an increase in IL6 protein (x6) and IL8 protein (x2) and a decrease in IL2 protein (x0.7). Lymphocytes and neutrophils were increased in all groups compared to the stable (n = 42). Our findings demonstrate the IL23/IL17 axis to be involved in the pathophysiology of BOS potentially triggering the IL8-mediated neutrophilia. IL6, IL1beta and IL23 seem to be skewing cytokines and IL2 a counteracting cytokine for T(H)17 alignment. The involvement of TGF-beta could not be confirmed, either as T(H)17 steering or as counteracting cytokine.