Candida species in cystic fibrosis: A road less travelled.

Candida species are isolated with high frequency from cystic fibrosis patients, yet their definitive role in the disease remains unclear. Previously considered to have minimal inherent virulence owing to their commensal ability, the last decade has heralded an increasing recognition of Candida infection among patients with cystic fibrosis. What has been more recently hypothesized is that the organism possesses virulence factors that play diverse roles at different body sites during varied stages of an infection. Currently, limited data is accessible in the area of cystic fibrosis. This review aims to provide an overview of the role of Candida species in cystic fibrosis as it is currently understood including the common local and systemic infections observed in clinical practice. The uncertain role of airway colonization and insight into emerging fields such as Candida-bacterial interactions are also addressed. Finally, we outline the current understanding of the innate, cellular and humoral immune responses associated with this genus which has been the major focus of work performed to date

Pulmonary Inflammation in Cystic Fibrosis: Impact of Innate Immunity and Estrogen

Cystic fibrosis (CF) is a multisystem disease, affecting many organs including the liver, intestines, respiratory and reproductive tracts, bone, heart, spleen, gall bladder, and pancreas (Table 1) [1]. It is the pulmonary manifestations that account for significant morbidity and mortality in patients with CF [2]. The CF transmembrane conductance regulator (CFTR) protein is central to CF disease. CFTR is a cyclic adenosine monophosphateactivated, adenosine triphosphate-binding cassette transporter protein (Figure 1). Expressed in submucosal glands and the apical membranes of epithelial cells in the liver, pancreas, intestines, reproductive tract, and lungs, the CFTR normally functions as a chloride channel. Individuals with CF have mutations in the CFTR gene. More than 1800 CFTR mutations have been identified to date. A subgroup of CFTR mutations are disease-causing and, as CF is an autosomal recessive disease, two alleles with such mutations are required to cause the disease. CFTR mutations can be grouped into six classes (I–VI) depending on whether they affect the expression, processing, or activity of CFTR, or a combination of these [3,4]. For example, the class III glycine to aspartic acid mutation at codon 551 (G551D) leads to a CFTR channel defect, whereas the class II deletion of phenylalanine mutation at codon 508 (ΔF508) results in a CFTR protein that is aberrantly folded and defectively processed in the endoplasmic reticulum. CFTR alleles with the ΔF508 mutation account for approximately 70% of mutated CFTR alleles worldwide; 64% of the Irish CF population is homozygous for ΔF508, while 94% carry the ΔF508 mutation on at least one chromosome [5]

Bronchiectasis:an emerging global epidemic

Abstract Bronchiectasis has an increasing profile within respiratory medicine. This chronic and irreversible airways disease is common but suffers from a lack of evidenced based therapy for patients and, a lack of understanding of its inherent heterogeneity. Research focused on bronchiectasis must therefore be prioritized if we are to adequately address this evolving clinical problem. This special issue on bronchiectasis focuses on its clinical, microbiological and therapeutic aspects. By bringing together a unique collection of original research and review articles, we hope this issue will showcase international research efforts, encourage future research collaborations and stimulate debate. In doing so, we hope to bring greater attention to the urgent need for sustained investment into focused, dedicated and collaborative research platforms in bronchiectasis, an emerging “global epidemic”

Pathogenesis, imaging and clinical characteristics of CF and non-CF bronchiectasis

Bronchiectasis is a common feature of severe inherited and acquired pulmonary disease conditions. Among inherited diseases, cystic fibrosis (CF) is the major disorder associated with bronchiectasis, while acquired conditions frequently featuring bronchiectasis include post-infective bronchiectasis and chronic obstructive pulmonary disease (COPD). Mechanistically, bronchiectasis is driven by a complex interplay of inflammation and infection with neutrophilic inflammation playing a predominant role. The clinical characterization and management of bronchiectasis should involve a precise diagnostic workup, tailored therapeutic strategies and pulmonary imaging that has become an essential tool for the diagnosis and follow-up of bronchiectasis. Prospective future studies are required to optimize the diagnostic and therapeutic management of bronchiectasis, particularly in heterogeneous non-CF bronchiectasis populations

miR-126 Is Downregulated in Cystic Fibrosis Airway Epithelial Cells and Regulates TOM1 Expression.

Cystic fibrosis (CF) is one of the most common lethal genetic diseases in which the role of microRNAs has yet to be explored. Predicted to be regulated by miR-126, TOM1 (target of Myb1) has been shown to interact with Toll-interacting protein, forming a complex to regulate endosomal trafficking of ubiquitinated proteins. TOM1 has also been proposed as a negative regulator of IL-1beta and TNF-alpha-induced signaling pathways. MiR-126 is highly expressed in the lung, and we now show for the first time differential expression of miR-126 in CF versus non-CF airway epithelial cells both in vitro and in vivo. MiR-126 downregulation in CF bronchial epithelial cells correlated with a significant upregulation of TOM1 mRNA, both in vitro and in vivo when compared with their non-CF counterparts. Introduction of synthetic pre-miR-126 inhibited luciferase activity in a reporter system containing the full length 3\u27-untranslated region of TOM1 and resulted in decreased TOM1 protein production in CF bronchial epithelial cells. Following stimulation with LPS or IL-1beta, overexpression of TOM1 was found to downregulate NF-kappaB luciferase activity. Conversely, TOM1 knockdown resulted in a significant increase in NF-kappaB regulated IL-8 secretion. These data show that miR-126 is differentially regulated in CF versus non-CF airway epithelial cells and that TOM1 is a miR-126 target that may have an important role in regulating innate immune responses in the CF lung. To our knowledge, this study is the first to report of a role for TOM1 in the TLR2/4 signaling pathways and the first to describe microRNA involvement in CF

Recurring pulmonary hamartomas: cause for concern?

We report the case of a well-controlled female asthmatic who developed \u27multiple pulmonary hamartomas\u27 on three separate occasions over a period of 25 years that necessitated surgical resection. To our knowledge, this is the first report of recurrent hamartomas in a single individual necessitating multiple thoracotomies

A Phase 2 randomised study to establish efficacy, safety and dosing of a novel oral cathepsin C inhibitor, BI 1291583, in adults with bronchiectasis:Airleaf

New therapies are needed to prevent exacerbations, improve quality of life and slow disease progression in bronchiectasis. Inhibition of cathepsin C (CatC) activity has the potential to decrease activation of neutrophil-derived serine proteases in patients with bronchiectasis, thereby reducing airway inflammation, improving symptoms, reducing exacerbations and preventing further airway damage. Here we present the design of a phase 2 trial (Airleaf™; NCT05238675) assessing the efficacy and safety of a novel CatC inhibitor, BI 1291583, in adult patients with bronchiectasis. This multinational, randomised, double-blind, placebo-controlled, parallel-group, dose-finding study has a screening period of at least 6 weeks, a treatment period of 24–48 weeks and a follow-up period of 4 weeks. ∼240 adults with bronchiectasis of multiple aetiologies will be randomised to placebo once daily, or BI 1291583 1 mg once daily, 2.5 mg once daily or 5 mg once daily in a 2:1:1:2 ratio, stratified by Pseudomonas aeruginosa infection and maintenance use of macrolides. The primary efficacy objective is to evaluate the dose–response relationship for the three oral doses of BI 1291583 versus placebo on time to first pulmonary exacerbation up to Week 48 (the primary end-point). Efficacy will be assessed using exacerbations, patient-reported outcomes, measures of symptoms, sputum neutrophil elastase activity and pulmonary function testing. Safety assessment will include adverse event reporting, physical examination, monitoring of vital signs, safety laboratory parameters, 12-lead electrocardiogram, and periodontal and dermatological assessments. If efficacy and safety are demonstrated, results will support further investigation of BI 1291583 in phase 3 trials

Development and initial validation of the bronchiectasis exacerbation and symptom tool (BEST)

BACKGROUND: Recurrent bronchiectasis exacerbations are related to deterioration of lung function, progression of the disease, impairment of quality of life, and to an increased mortality. Improved detection of exacerbations has been accomplished in chronic obstructive pulmonary disease through the use of patient completed diaries. These tools may enhance exacerbation reporting and identification. The aim of this study was to develop a novel symptom diary for bronchiectasis symptom burden and detection of exacerbations, named the BEST diary. METHODS: Prospective observational study of patients with bronchiectasis conducted at Ninewells Hospital, Dundee. We included patients with confirmed bronchiectasis by computed tomography, who were symptomatic and had at least 1 documented exacerbation of bronchiectasis in the previous 12\u2009months to participate. Symptoms were recorded daily in a diary incorporating cough, sputum volume, sputum colour, dyspnoea, fatigue and systemic disturbance scored from 0 to 26. RESULTS: Twenty-one patients were included in the study. We identified 29 reported (treated exacerbations) and 23 unreported (untreated) exacerbations over 6-month follow-up. The BEST diary score showed a good correlation with the established and validated questionnaires and measures of health status (COPD Assessment Test, r =\u20090.61, p =\u20090.0037, Leicester Cough Questionnaire, r =\u2009-\u20090.52,p =\u20090.0015, St Georges Respiratory Questionnaire, r =\u20090.61,p <\u20090.0001 and 6\u2009min walk test, r =\u2009-\u20090.46,p =\u20090.037). The mean BEST score at baseline was 7.1 points (SD 2.2). The peak symptom score during exacerbation was a mean of 16.4 (3.1), and the change from baseline to exacerbation was a mean of 9.1 points (SD 2.5). Mean duration of exacerbations based on time for a return to baseline symptoms was 15.3\u2009days (SD 5.7). A minimum clinically important difference of 4 points is proposed. CONCLUSIONS: The BEST symptom diary has shown concurrent validity with current health questionnaires and is responsive at onset and recovery from exacerbation. The BEST diary may be useful to detect and characterise exacerbations in bronchiectasis clinical trials