Ania Carsin

Correction of CFTR function in nasal epithelial cells from cystic fibrosis patients predicts improvement of respiratory function by CFTR modulators

Clinical studies with modulators of the Cystic Fibrosis Transmembrane conductance Regulator (CFTR) protein have demonstrated that functional restoration of the mutated CFTR can lead to substantial clinical benefit. However, studies have shown highly variable patient responses. The objective of this study was to determine a biomarker predictive of the clinical response. CFTR function was assessed in vivo via nasal potential difference (NPD) and in human nasal epithelial (HNE) cultures by the response to Forskolin/IBMX and the CFTR potentiator VX-770 in short-circuit-current (∆IscF/I+V) experiments. CFTR expression was evaluated by apical membrane fluorescence semi-quantification. Isc measurements discriminated CFTR function between controls, healthy heterozygotes, patients homozygous for the severe F508del mutation and patients with genotypes leading to absent or residual function. ∆IscF/I+V correlated with CFTR cellular apical expression and NPD measurements. The CFTR correctors lumacaftor and tezacaftor significantly increased the ∆IscF/I+V response to about 25% (SEM = 4.4) of the WT-CFTR level and the CFTR apical expression to about 22% (SEM = 4.6) of the WT-CFTR level in F508del/F508del HNE cells. The level of CFTR correction in HNE cultures significantly correlated with the FEV1 change at 6 months in 8 patients treated with CFTR modulators. We provide the first evidence that correction of CFTR function in HNE cell cultures can predict respiratory improvement by CFTR modulators.

Bronchial epithelium in children: a key player in asthma

Bronchial epithelium is a key element of the respiratory airways. It constitutes the interface between the environment and the host. It is a physical barrier with many chemical and immunological properties. The bronchial epithelium is abnormal in asthma, even in children. It represents a key component promoting airway inflammation and remodelling that can lead to chronic symptoms. In this review, we present an overview of bronchial epithelium and how to study it, with a specific focus on children. We report physical, chemical and immunological properties from ex vivo and in vitro studies. The responses to various deleterious agents, such as viruses or allergens, may lead to persistent abnormalities orchestrated by bronchial epithelial cells. As epithelium dysfunctions occur early in asthma, reprogramming the epithelium may represent an ambitious goal to induce asthma remission in children. Bronchial epithelium is a morphological and functional dysregulated gatekeeper in asthmatic children http://ow.ly/Y4MaM

Aspergillus fumigatus components distinguish IgE but not IgG4 profiles between fungal sensitization and allergic broncho-pulmonary aspergillosis.

Aspergillus fumigatus is the causative agent of allergic broncho‐pulmonary aspergillosis. Prompt and accurate diagnosis may be difficult to achieve with current clinical and laboratory scores, which do not include immune responses to recombinant A. fumigatus allergens. We measured specific immunoglobulin E and G4 directed to recombinant A. fumigatus allergens in 55 cystic fibrosis patients without allergic broncho‐pulmonary aspergillosis but sensitized to A. fumigatus and in nine patients with allergic broncho‐pulmonary aspergillosis (two with cystic fibrosis and seven with asthma). IgG4 responses to recombinant A. fumigatus allergens were detected in all patients, but neither prevalence nor levels were different between the two patient groups. On the other hand, both prevalence and levels of IgE responses to Asp f 3, Asp f 4, and Asp f 6 helped distinguish allergic broncho‐pulmonary aspergillosis from A. fumigatus sensitization with good negative and positive predictive values.

Aspergillus fumigatus in cystic fibrosis: An update on immune interactions and molecular diagnostics in allergic bronchopulmonary aspergillosis

A wide spectrum of pathological conditions may result from the interaction of Aspergillus fumigatus and the immune system of its human host. Allergic bronchopulmonary aspergillosis is one of the most severe A. fumigatus‐related diseases due to possible evolution toward pleuropulmonary fibrosis and respiratory failure. Allergic bronchopulmonary aspergillosis occurs almost exclusively in cystic fibrosis or asthmatic patients. An estimated 8%‐10% of patients with cystic fibrosis experience this condition. The diagnosis of allergic bronchopulmonary aspergillosis relies on criteria first established in 1977. Progress in the understanding of host‐pathogen interactions in A. fumigatus and patients with cystic fibrosis and the ongoing validation of novel laboratory tools concur to update and improve the diagnosis of allergic bronchopulmonary aspergillosis.

Toxocariasis: An unusual cause of pleural effusion.

Toxocara canis, one of the most frequent parasites worldwide, rarely triggers respiratory symptoms. We report the case of a 5‐year‐old girl hospitalized for a unilateral eosinophilic pleural effusion due to Toxocara canis. Besides the fact that she was living in a squat, no other medical condition was reported. There was no other site of infection caused by the parasite and she was successfully treated with albendazole. This case report is obviously unique as very few cases of pleural effusion due to Toxocara canis are reported in literature, all in adult patients. Pediatr Pulmonol. 2015; 50:E35–E36.

Early Halt of a Randomized Controlled Study with 3% Hypertonic Saline in Acute Bronchiolitis

Background: Albeit not recommended because of contradictory results, nebulized 3% hypertonic saline is widely used for treating acute viral bronchiolitis. Whether clinical differences may be attributed to the type of nebulizer used has never been studied. Objectives: By modifying the amount of salt deposited into the airways, the nebulizer characteristics might influence clinical response. Methods: A prospective, randomized, controlled trial included infants hospitalized in a French university hospital for a first episode of bronchiolitis. Each child received 6 nebulizations of 3% hypertonic saline during 48 h delivered with 1 of the 3 following nebulizers: 2 jet nebulizers delivering large or small particles, with a low aerosol output, and 1 mesh nebulizer delivering small particles, with a high aerosol output. The primary endpoint was the difference in the Wang score at 48 h. Results: Only 61 children of 168 were recruited before stopping this study because of severe adverse events (n = 4) or parental requests for discontinuation due to discomfort to their child during nebulization (n = 2). One minor adverse event was noted in 91.8% (n = 56/61) of children. A high aerosol output induced 75% of the severe adverse events; it was significantly associated with the nebulization-induced cough between 24 and 48 h (p = 0.036). Decreases in Wang scores were not significantly different between the groups at 48 h, 9 recoveries out of 10 being obtained with small particles. Conclusion: No beneficial effects and possibly severe adverse events are observed with 3% hypertonic saline in the treatment of bronchiolitis.

Mast cell tryptase changes with Aspergillus fumigatus – Host crosstalk in cystic fibrosis patients

Pulmonary and systemic antifungal immunity influences quality of life and survival of people with cystic fibrosis. Aspergillus fumigatus (Af) induces specific IgG and IgE. Mast cells respond to IgE, IgG and direct interactions with Af. Mast cells are the source of the protease tryptase. We aimed at evaluating serum baseline tryptase as a potential biomarker of the Af-host interaction in cystic fibrosis patients. Serum baseline tryptase, IgE and IgG directed to Af extract and Af molecular allergens were measured in 76 cystic fibrosis patients. The main findings were (i) lower levels of serum baseline tryptase in patients displaying specific IgE to Af (p < 0.0001) and (ii) an association between tryptase levels and IgE or IgG responses to Af and ribotoxin (Asp f 1). These findings suggest that serum baseline tryptase is influenced by Af-host interactions and thus might be a marker for mast cell regulation and pulmonary immune defenses.

STAT3 Gain of Function: A New Kid on the Block in Interstitial Lung Diseases

A 5-year-old girl with failure to thrive and multiorgan disease was referred to our center for chronic hypoxemia. On evaluation, we noted tachypnea (respiratory rate 35/min), supraclavicular retractions, median diurnal oxygen saturation as measured by pulse oximetry (Sp O 2) = 91.7% at rest, percentage of time below Sp O 2 90% at 26% during sleep, and clubbing. A computed tomography scan showed diffuse interstitial lung disease (Figure 1). Spirometry was normal (TLC, 83% of predicted; FEV 1 , 83% of predicted; FEV 1 /FVC, 98%; and forced expiratory flow, midexpiratory phase, 142% of predicted), but it was not possible to measure DL CO .

When Christmas decoration goes hand in hand with bronchial aspiration

We report the case of a 14-month-old girl suffering from cough and wheeze around Christmas. She was treated with anti-asthmatic drugs with no success, and 3 weeks later a chest X-ray revealed a LED bulb in the left main bronchus. This LED bulb came from a Christmas light garland decorating the Christmas tree. We discuss the different Christmas objects that can be inhaled by young children, the challenge to diagnose bronchial inhalation during this winter period, and the emergence of new foreign bodies, such as LED bulbs, with a particularly aerodynamic shape.

Multivariate Analysis As a Support for Diagnostic Flowcharts in Allergic Bronchopulmonary Aspergillosis: A Proof-of-Concept Study

Molecular-based allergy diagnosis yields multiple biomarker datasets. The classical diagnostic score for allergic bronchopulmonary aspergillosis (ABPA), a severe disease usually occurring in asthmatic patients and people with cystic fibrosis, comprises succinct immunological criteria formulated in 1977: total IgE, anti-Aspergillus fumigatus (Af) IgE, anti-Af “precipitins,” and anti-Af IgG. Progress achieved over the last four decades led to multiple IgE and IgG(4) Af biomarkers available with quantitative, standardized, molecular-level reports. These newly available biomarkers have not been included in the current diagnostic criteria, either individually or in algorithms, despite persistent underdiagnosis of ABPA. Large numbers of individual biomarkers may hinder their use in clinical practice. Conversely, multivariate analysis using new tools may bring about a better chance of less diagnostic mistakes. We report here a proof-of-concept work consisting of a three-step multivariate analysis of Af IgE, IgG, and IgG4 biomarkers through a combination of principal component analysis, hierarchical ascendant classification, and classification and regression tree multivariate analysis. The resulting diagnostic algorithms might show the way for novel criteria and improved diagnostic efficiency in Af-sensitized patients at risk for ABPA.