Use of a mobile application for self-management of pancreatic enzyme replacement therapy is associated with improved gastro-intestinal related quality of life in children with Cystic Fibrosis.

BACKGROUND: Most patients with cystic fibrosis (CF) suffer from pancreatic insufficiency (PI), leading to fat malabsorption, malnutrition, abdominal discomfort and impaired growth. Pancreatic enzyme replacement therapy (PERT) is effective, but evidence based guidelines for dose adjustment are lacking. A mobile app for self-management of PERT was developed in the context of the HORIZON 2020 project MyCyFAPP. It contains an algorithm to calculate individual PERT-doses for optimal fat digestion, based on in vitro and in vivo studies carried out in the same project. In addition, the app includes a symptoms diary, educational material, and it is linked to a web tool allowing health care professionals to evaluate patient's data and provide feedback. METHODS: A 6-month open label prospective multicenter interventional clinical trial was performed to assess effects of using the app on gastro-intestinal related quality of life (GI QOL), measured by the CF-PedsQL-GI (shortened, CF specific version of the Pediatric Quality of Life Inventory, Gastrointestinal Symptoms Module). RESULTS: One hundred and seventy-one patients with CF and PI between 2 and 18 years were recruited at 6 European CF centers. Self-reported CF-PedsQL-GI improved significantly from month 0 (M0) (84.3, 76.4-90.3) to month 6 (M6) (89.4, 80.35-93.5) (p< 0.0001). Similar improvements were reported by parents. Lower baseline CF-PedsQL-GI was associated with a greater improvement at M6 (p < 0.001). CONCLUSIONS: The results suggest that the MyCyFAPP may improve GI QOL for children with CF. This tool may help patients to improve self-management of PERT, especially those with considerable GI symptoms.

Effects of small airway dysfunction on the clinical expression of asthma: a focus on asthma symptoms and bronchial hyper-responsiveness.

BACKGROUND: The small airways are an important site of inflammation in asthma. However, the relation between small airway dysfunction and clinical expression of asthma has hardly been studied. AIM: To investigate the association of small and large airway dysfunction with asthma symptoms and bronchial hyper-responsiveness (BHR). METHODS: Fifty-eight patients with asthma were characterized with spirometry, body plethysmography, impulse oscillometry, alveolar and bronchial exhaled nitric oxide, and a methacholine provocation. Symptoms of nocturnal asthma, exercise-related symptoms, BHR symptoms, and respiratory symptoms were assessed with the Asthma Control Questionnaire and Bronchial Hyper-responsiveness Questionnaire. Perception of dyspnea was rated with the Borg score during the provocation test. RESULTS: Small and large airway dysfunction did not associate with higher scores for nocturnal, exercise-related, or BHR symptoms. Only higher scores on wheezing were significantly associated with higher values of difference between R5 and R20 (R5-R20) (r = 0.367, P < 0.01) and AX (r = 0.354, P < 0.01). Lower FEF25-75% (P = 0.024) and higher R5-R20 (P = 0.003) values were independently associated with more severe BHR to methacholine, but not FEV1 or R20 values. The increase in dyspnea during the methacholine provocation was strongly and independently correlated with the decrease in FEV1 and reactance of the respiratory system at 5 Hertz. CONCLUSION: Small and large airway dysfunction poorly associate with asthma symptoms in our patients. However, deteriorations in small airway dysfunction are strongly related to an increase in dyspnea during bronchial provocation with methacholine. Small airway dysfunction contributes also independently to the clinical expression of asthma, as reflected by the severity of BHR.

Less small airway dysfunction in asymptomatic bronchial hyperresponsiveness than in asthma.

BACKGROUND: Bronchial hyperresponsiveness (BHR) can be present in subjects without any respiratory symptoms. Little is known about the role of the small airways in asymptomatic subjects with BHR. METHODS: We investigated small airway function assessed by spirometry and impulse oscillometry, as well as Borg dyspnea scores at baseline and during a methacholine provocation test in 15 subjects with asymptomatic BHR, 15 asthma patients, and 15 healthy controls. RESULTS: At baseline, small airway function (R5 -R20 and X5 ) was comparable between subjects with asymptomatic BHR and healthy controls, whereas asthma patients showed small airway dysfunction as reflected by higher R5 -R20 and lower X5 values. During methacholine provocation, small airway dysfunction was more severe in asthma patients than in subjects with asymptomatic BHR. Interestingly, a higher increase in small airway dysfunction during methacholine provocation was associated with a higher increase in Borg dyspnea scores in subjects with asymptomatic BHR, but not in asthma patients. CONCLUSION: Subjects with asymptomatic BHR may experience fewer symptoms in daily life because they have less small airway dysfunction.

Treatment of the bronchial tree from beginning to end: targeting small airway inflammation in asthma.

Asthma is a chronic respiratory disease, characterized by airway obstruction and inflammation. Increasing evidence shows that the small airways contribute significantly to the clinical expression and severity of asthma. Traditionally, high levels of disease activity are thought to be necessary before symptoms occur in the small airways because of their large reserve capacity. However, this concept is being challenged and increasing evidence shows small airway disease to be associated with symptoms, disease severity, and bronchial hyper-responsiveness. Particle size and distribution are of key importance when developing inhaled treatments for small airway disease. The availability of small-particle aerosols such as HFA-ciclesonide and HFA-beclomethasone dipropionate (HFA-BDP) enables a higher drug deposition into the peripheral lung and potentially provides additional clinical benefits compared with large-particle treatment. However, improved methods are needed to monitor and assess small airway disease and its response to treatment because conventional spirometry mainly reflects large airway function. This remains a challenging area requiring further research. The aim of the current manuscript is to review the clinical relevance of small airway disease and the implications for the treatment of asthma.

Bronchodilation in infants with malacia or recurrent wheeze.

BACKGROUND: Controversy remains regarding the effectiveness of bronchodilators in wheezy infants. AIMS: To assess the effect of inhaled beta(2) agonists on lung function in infants with malacia or recurrent wheeze, and to determine whether a negative effect of beta(2) agonists on forced expiratory flow (V'(maxFRC)) is more pronounced in infants with airway malacia, compared to infants with wheeze. METHODS: We retrospectively analysed lung function data of 27 infants: eight with malacia, 19 with recurrent wheeze. Mean (SD) age was 51 (18) weeks. Mean V'(maxFRC) (in Z score) was assessed before and after inhalation of beta(2) agonists. RESULTS: Baseline V'(maxFRC) was below reference values for both groups. Following inhalation of beta(2) agonists the mean (95% CI) change in mean V'(maxFRC) in Z scores was -0.10 (-0.26 to 0.05) and -0.33 (-0.55 to -0.11) for the malacia and wheeze group, respectively. CONCLUSIONS: In infants with wheeze, inhaled beta(2) agonists caused a significant reduction in mean V'(maxFRC). Infants with malacia were not more likely to worsen after beta(2) agonists than were infants with recurrent wheeze.

Heat-stable enterotoxin receptor/guanylyl cyclase C is an oligomer consisting of functionally distinct subunits, which are non-covalently linked in the intestine.

Guanylyl cyclase (GC) C is a heat-stable enterotoxin (STa) receptor with a monomeric M(r) of approximately 140,000. We calculated from its hydrodynamic parameters that an active GC-C complex has a M(r) of 393,000, suggesting that GC-C is a trimer under native conditions. Both trimeric and dimeric GC-C complexes were detected by 125I-STa binding and SDS-polyacrylamide gel electrophoresis under non-reducing conditions. The GC activity and STa binding from intestinal brush border membranes comigrated in gel filtration and velocity sedimentation with recombinant GC-C. However, 125I-STa cross-linking demonstrated that STa receptors with molecular masses of 52 and 74 kDa are non-covalently attached to GC in the intestine. Radiation inactivation revealed different functional sizes for basal GC activity, STa-stimulated GC activity, and STa binding (59, 210-240, and 32-52 kDa, respectively). At low radiation doses, basal GC activity was stimulated, suggesting that GC-C is inhibited by a relatively large, probably internal structure. These results suggest that STa may activate GC-C by promoting monomer-monomer interaction (internal "dimerization") within a homotrimeric GC-C complex, and that GC-C is proteolytically modified in the brush border membrane but retains its function.

Heat-stable enterotoxin activation of immunopurified guanylyl cyclase C. Modulation by adenine nucleotides.

We studied the activation and inactivation of recombinant guanylyl cyclase (GC) C stably expressed in human kidney 293 cells. Activation of GC-C by heat-stable enterotoxin (STa), Cd2+, hemin, or the detergent Triton X-100 was followed by a rapid inactivation of the enzyme. Adenine nucleotides were found to prevent the inactivation process in native membranes, as well as following enzyme solubilization and immunopurification. Inactivation of GC-C was not associated with dephosphorylation. However, the phosphorylation of GC-C was promoted by phorbol esters, known activators of protein kinase C. The activation of purified GC-C by STa required the presence of a nonspecific factor as exemplified by bovine serum albumin. When immunopurified GC-C, stabilized by ATP and bovine serum albumin, was analyzed by SDS-polyacrylamide gel electrophoresis under nonreducing conditions, proteins with almost twice the molecular mass (220 and 245 kDa) of the monomer were observed. The mobility of these high M(r) GC-C forms was reduced by STa, suggesting that STa induces a conformation change in a preexisting GC-C dimer. These results indicate that ATP interacts directly with GC-C, stabilizing its active conformation and that the activation of GC-C may occur in the absence of other specific regulatory factors.