Over the last years CFTR (cystic fibrosis transmembrane conductance regulator) modulators have shown the ability to improve relevant clinical outcomes in patients with cystic fibrosis (CF). This review aims at a systematic research of the current evidence on efficacy and tolerability of CFTR modulators for different genetic subsets of patients with CF. Two investigators independently performed the search on PubMed and included phase 2 and 3 clinical trials published in the study period 1 January 2005–31 January 2020. A final pool of 23 papers was included in the systematic review for a total of 4219 patients. For each paper data of interest were extracted and reported in table. In terms of lung function, patients who had the most beneficial effects from CFTR modulation were those patients with one gating mutation receiving IVA (ivacaftor) and patients with p.Phe508del mutation, both homozygous and heterozygous, receiving ELX/TEZ/IVA (elexacaftor/tezacaftor/ivacaftor) had the most relevant beneficial effects in term of lung function, pulmonary exacerbation decrease, and symptom improvement. CFTR modulators showed an overall favorable safety profile. Next steps should aim to systematize our comprehension of scientific data of efficacy and safety coming from real life observational studies.

A comprehensive approach to lung function in bronchiectasis ABSTRACT Background: International guidelines recommend simple spirometry for bronchiectasis patients. However, pulmonary pathophysiology of bronchiectasis is very complex and still poorly understood. Our objective was to characterize lung function in bronchiectasis and identify specific functional sub-groups. Methods:This was a multicenter, prospective, observational study enrolling consecutive adults with bronchiectasis during stable sate. Patients underwent body-plethysmography before and after acute bronchodilation testing, diffusing lung capacity (DL CO ) with a 3-year follow up. Air trapping and hyperinflation were a residual volume (RV)>120%predicted and a total lung capacity>120%predicted. Acute reversibility was: ΔFEV 1 ≥12% and 200 ml from baseline (FEV 1rev ) and ΔRV ≥10% reduction from baseline (RV rev ). Sensitivity analyses included different reversibility cutoffs and excluded patients with concomitant asthma or chronic obstructive pulmonary disease.Results: 187 patients were enrolled (median age: 68 years; 29.4% males).Pathophysiological abnormalities often overlapped and were distributed as follows: air trapping (70.2%), impaired DL CO (55.7%), airflow obstruction (41.1%), hyperinflation (15.7%) and restriction (8.0%). 9.7% of patients had normal lung function. RV rev (17.6%) was more frequent than FEV 1rev (4.3%). Similar proportions were found after multiple sensitivity analyses. Compared with non-reversible patients, patients with RV rev had more severe obstruction (mean(SD) FEV 1 %pred: 83.0% (24.4) vs 68.9% (26.2); P=0.02) and air trapping (RV%pred, 151.9% (26.6) vs 166.2% (39.9); P=0.028). Conclusions:Spirometry alone does not encompass the variety of pathophysiological characteristics in bronchiectasis. Air trapping and diffusion impairment, not airflow obstruction, represent the most common functional abnormalities. RV rev is related to worse lung function and might be considered in bronchiectasis' workup and for patients' functional stratification. Demographics

Bronchiectasis is a heterogeneous chronic disease. Heterogeneity characterises bronchiectasis not only in the stable state but also during exacerbations, despite evidence on clinical and biological aspects of bronchiectasis, exacerbations still remain poorly understood.Although the scientific community recognises that bacterial infection is a cornerstone in the development of bronchiectasis, there is a lack of data regarding other trigger factors for exacerbations. In addition, a huge amount of data suggest a primary role of neutrophils in the stable state and exacerbation of bronchiectasis, but the inflammatory reaction involves many other additional pathways. Cole's vicious cycle hypothesis illustrates how airway dysfunction, airway inflammation, infection and structural damage are linked. The introduction of the concept of a “vicious vortex” stresses the complexity of the relationships between the components of the cycle. In this model of disease, exacerbations work as a catalyst, accelerating the progression of disease. The roles of microbiology and inflammation need to be considered as closely linked and will need to be investigated in different ways to collect samples. Clinical and translational research is of paramount importance to achieve a better comprehension of the pathophysiology of bronchiectasis, microbiology and inflammation both in the stable state and during exacerbations.

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Bronchiectasis represents the final pathway of several infectious, genetic, immunologic or allergic disorders. Accurate and prompt identification of the underlying cause is a key recommendation of several international guidelines, in order to tailor treatment appropriately. Primary ciliary dyskinesia (PCD) is a genetic cause of bronchiectasis in which failure of motile cilia leads to poor mucociliary clearance. Due to poor ciliary function in other organs, individuals can suffer from chronic rhinosinusitis, otitis media and infertility.This paper explores the current literature describing why, when and how to investigate PCD in adult patients with bronchiectasis. We describe the main PCD diagnostic tests and compare the two international PCD diagnostic guidelines. The expensive multi-test diagnostic approach requiring a high level of expertise and specialist equipment, make the multifaceted PCD diagnostic pathway complex. Therefore, the risk of late or missed diagnosis is high and has clinical and research implications.Defining the number of patients with bronchiectasis due to PCD is complex. To date, few studies outlining the aetiology of adult patients with bronchiectasis conduct screening tests for PCD, but they do differ in their diagnostic approach. Comparison of these studies reveals an estimated PCD prevalence of 1–13% in adults with bronchiectasis and describe patients as younger than their counterparts with moderate impairment of lung function and higher rates of chronic infection with Pseudomonas aeruginosa.Diagnosing PCD has clinical, socioeconomic and psychological implications, which affect patients’ life, including the possibility to have a specific and multidisciplinary team approach in a PCD referral centre, as well as a genetic and fertility counselling and special legal aspects in some countries.To date no specific treatments for PCD have been approved, standardized diagnostic protocols for PCD and recent diagnostic guidelines will be helpful to accurately define a population on which planning RCT studies to evaluate efficacy, safety and accuracy of PCD specific treatments.

Different steps and conditions for DNA extraction for microbiota analysis in sputum have been reported in the literature. We aimed at testing both dithiothreitol (DTT) and enzymatic treatments of sputum samples and identifying the most suitable DNA extraction technique for the microbiota analysis of sputum. Sputum treatments with and without DTT were compared in terms of their median levels and the coefficient of variation between replicates of both DNA extraction yield and real-time PCR for the 16S rRNA gene. Treatments with and without lysozyme and lysostaphin were compared in terms of their median levels of real-time PCR for S. aureus. Two enzyme-based and three beads-based techniques for DNA extraction were compared in terms of their DNA extraction yield, real-time PCR for the 16S rRNA gene and microbiota analysis. DTT treatment decreased the coefficient of variation between replicates of both DNA extraction yield and real-time PCR. Lysostaphin (either 0.18 or 0.36 mg/mL) and lysozyme treatments increased S. aureus detection. One enzyme-based kit offered the highest DNA yield and 16S rRNA gene real-time PCR with no significant differences in terms of alpha-diversity indexes. A condition using both DTT and lysostaphin/lysozyme treatments along with an enzymatic kit seems to be preferred for the microbiota analysis of sputum samples.

Bronchiectasis is a chronic respiratory disease characterised by a syndrome of productive cough and recurrent respiratory infections due to permanent dilatation of the bronchi. Bronchiectasis represents the final common pathway of different disorders, some of which may require specific treatment. Therefore, promptly identifying the aetiology of bronchiectasis is recommended by the European Respiratory Society guidelines. The clinical history and high-resolution computed tomography (HRCT) features can be useful to detect the underlying causes. Despite a strong focus on this aspect of treatment a high proportion of patients remain classified as "idiopathic". Important underlying conditions that are treatable are frequently not identified for prolonged periods of time.The European Respiratory Society guidelines for bronchiectasis recommend a minimal bundle of tests for diagnosing the cause of bronchiectasis, consisting of immunoglobulins, testing for allergic bronchopulmonary aspergillosis and full blood count. Other testing is recommended to be conducted based on the clinical history, radiological features and severity of disease. Therefore it is essential to teach clinicians how to recognise the "clinical phenotypes" of bronchiectasis that require specific testing.This article will present the initial investigation and management of bronchiectasis focussing particularly on the HRCT features and clinical features that allow recognition of specific causes.

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