Inhaled gene therapy of preclinical muco-obstructive lung diseases by nanoparticles capable of breaching the airway mucus barrier.

INTRODUCTION: Inhaled gene therapy of muco-obstructive lung diseases requires a strategy to achieve therapeutically relevant gene transfer to airway epithelium covered by particularly dehydrated and condensed mucus gel layer. Here, we introduce a synthetic DNA-loaded mucus-penetrating particle (DNA-MPP) capable of providing safe, widespread and robust transgene expression in in vivo and in vitro models of muco-obstructive lung diseases. METHODS: We investigated the ability of DNA-MPP to mediate reporter and/or therapeutic transgene expression in lung airways of a transgenic mouse model of muco-obstructive lung diseases (ie, Scnn1b-Tg) and in air-liquid interface cultures of primary human bronchial epithelial cells harvested from an individual with cystic fibrosis. A plasmid designed to silence epithelial sodium channel (ENaC) hyperactivity, which causes airway surface dehydration and mucus stasis, was intratracheally administered via DNA-MPP to evaluate therapeutic effects in vivo with or without pretreatment with hypertonic saline, a clinically used mucus-rehydrating agent. RESULTS: DNA-MPP exhibited marked greater reporter transgene expression compared with a mucus-impermeable formulation in in vivo and in vitro models of muco-obstructive lung diseases. DNA-MPP carrying ENaC-silencing plasmids provided efficient downregulation of ENaC and reduction of mucus burden in the lungs of Scnn1b-Tg mice, and synergistic impacts on both gene transfer efficacy and therapeutic effects were achieved when DNA-MPP was adjuvanted with hypertonic saline. DISCUSSION: DNA-MPP constitutes one of the rare gene delivery systems providing therapeutically meaningful gene transfer efficacy in highly relevant in vivo and in vitro models of muco-obstructive lung diseases due to its unique ability to efficiently penetrate airway mucus.

The evolution of pulmonary function in childhood onset Mucopolysaccharidosis type I.

Respiratory outcomes in Mucopolysaccharidosis Type I (MPS I), have mainly focused on upper airway obstruction, with the evolution of the restrictive lung disease being poorly documented. We report the long-term pulmonary function outcomes and examine the potential factors affecting these in 2 cohorts of MPS I patients, those who have undergone Haematopoietic Stem Cell Transplantation (HSCT) and those treated with Enzyme Replacement Therapy (ERT). The results were stratified using the American Thoracic Society (ATS) guidelines. 66 patients, capable of adequately performing testing, were identified by a retrospective case note review, 46 transplanted (45 Hurler, 1 Non-Hurler) and 20 having ERT (17 Non-Hurler and 3 Hurler diagnosed too late for HSCT). 5 patients died; 4 in the ERT group including the 3 Hurler patients. Overall 14% of patients required respiratory support (non-invasive ventilation (NIV) or supplemental oxygen)) at the end of follow up. Median length of follow-up was 12.2 (range = 4.9-32) years post HSCT and 14.34 (range = 3.89-20.4) years on ERT. All patients had restrictive lung disease. Cobb angle and male sex were significantly associated with more severe outcomes in the HSCT cohort, with 49% having severe to very severe disease. In the 17 Non-Hurler ERT treated patients there was no variable predictive of severity of disease with 59% having severe to very severe disease. During the course of follow up 67% of the HSCT cohort had no change or improved pulmonary function as did 52% of the ERT patients. However, direct comparison between therapeutic modalities was not possible. This initial evidence would suggest that a degree of restrictive lung disease is present in all treated paediatrically diagnosed MPS I and is still a significant cause of morbidity, though further stratification incorporating diffusing capacity for carbon monoxide (DLCO) is needed.

[Early outcomes following lung transplantation in patients aged 65 years and older]. / Résultats précoces de la transplantation pulmonaire chez les patients âgés de 65 ans et plus.

INTRODUCTION: The number of lung transplantations performed is increasing worldwide. With an improved experience and outcomes, the age of the recipient on its own has ceased to be an absolute contra-indication. We report our first experience with lung transplantation in patients aged 65 years or older. METHODS: From January 2014 to March 2019, the files of patients aged 65 years or older undergoing lung transplantation were retrospectively reviewed. RESULTS: During the study period, 241 patients underwent lung transplantation in Bichat hospital (Paris, France), including 25 recipients aged 65 years or older. Underlying diagnoses were interstitial (72%) and obstructive (28%) disease. The rate of single lung transplantation was 80%. Sixteen patients required ECMO assistance during the procedure. Early complications were mostly grade III primary graft dysfunction (12%) and cellular rejection (20%). Overall one-year survival rate was 76%. CONCLUSION: After a careful selection of the recipients, the early results of our retrospective single center series are encouraging. We continue to consider lung transplantation in rigorously selected recipients of aged 65 years and more.

[Masterplan 2025 of the Austrian Society of Pneumology (ASP)-the expected burden and management of respiratory diseases in Austria]. / Masterplan 2025 der Österreichischen Gesellschaft für Pneumologie (ÖGP) ­ die erwartete Entwicklung und Versorgung respiratorischer Erkrankungen in Österreich.

Scientific Members of the Austrian Society of Pneumology describe the expected development in respiratory health and provide guidance towards patient-oriented and cost-efficient respiratory care in Austria.Methods: In November 2017, respiratory care providers (physicians, nurses, physiotherapists) together with patient's advocacy groups and experts in health development, collaborated in workshops on: respiratory health and the environment, bronchial asthma and allergy, COPD, pediatric respiratory disease, respiratory infections, sleep disorders, interventional pneumology, thoracic oncology and orphan diseases.Results: Respiratory disease is extremely prevalent and driven by ill-health behavior, i.e. cigarette smoking, over-eating and physical inactivity. For the majority of respiratory diseases increased prevalence, but decreased hospitalizations are expected.The following measures should be implemented to deal with future challenges:1. Screening and case-finding should be implemented for lung cancer and COPD.2. E-health solutions (telemedicine, personal apps) should be used to facilitate patient management.3. Regional differences in respiratory care should be reduced through E­health and harmonization of health insurance benefits across Austria.4. Patient education and awareness, to reduce respiratory health illiteracy should be increased, which is essential for sleep disorders but relevant also for other respiratory diseases.5. Respiratory care should be inter-professional, provided via disease-specific boards beyond lung cancer (for ILDs, sleep, allergy)6. Programs for outpatient's pulmonary rehabilitation can have a major impact on respiratory health.7. Increased understanding of molecular pathways will drive personalized medicine, targeted therapy (for asthma, lung cancer) and subsequently health care costs.

Outcome measures for airway clearance techniques in children with chronic obstructive lung diseases: a systematic review.

BACKGROUND: Airway clearance techniques (ACTs) are an important aspect of the treatment of children with chronic obstructive lung diseases. Unfortunately, a sound evidence base is lacking and airway clearance strategies are largely based on clinical expertise. One of the reasons for the limited evidence is the lack of appropriate outcome measures specifically related to the effectiveness of ACTs. This review discusses all outcome measures applied in previous research in the pediatric population to provide a baseline for future studies. DATA SOURCES: A systematic literature search was performed in PubMed, Web of Science and EMBASE databases. Search terms included chronic obstructive lung diseases and ACTs. STUDY SELECTION: Studies were independently selected by the investigators according to the eligibility criteria. After screening, 49 articles remained for further analysis. RESULTS AND CONCLUSIONS: Data are summarized according to the type of outcome measure. 48 (98%) studies performed pulmonary function tests, 19 (39%) assessed expectorated sputum, 10 (20%) parameters related to disease exacerbation, 8 (16%) oxygenation, 8 (16%) patient-reported outcomes, 5 (10%) exercise capacity and 5 (10%) applied imaging techniques. The synthesis of results showed a high discrepancy between studies due to differences in study design, population and the application of techniques. Since no 'gold standard' method could be identified, a combination of different outcome measures is recommended to gain a better understanding and to identify the potential effects of ACTs. An overview of important considerations has been provided to assist researchers in their choice of outcomes in future studies.

Oscillating devices for airway clearance in people with cystic fibrosis.

BACKGROUND: Chest physiotherapy is widely prescribed to assist the clearance of airway secretions in people with cystic fibrosis. Oscillating devices generate intra- or extra-thoracic oscillations orally or external to the chest wall. Internally they create variable resistances within the airways, generating controlled oscillating positive pressure which mobilises mucus. Extra-thoracic oscillations are generated by forces outside the respiratory system, e.g. high frequency chest wall oscillation. This is an update of a previously published review. OBJECTIVES: To identify whether oscillatory devices, oral or chest wall, are effective for mucociliary clearance and whether they are equivalent or superior to other forms of airway clearance in the successful management of secretions in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. Latest search of the Cystic Fibrosis Trials Register: 29 July 2019. In addition we searched the trials databases ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Latest search of trials databases: 15 August 2019. SELECTION CRITERIA: Randomised controlled studies and controlled clinical studies of oscillating devices compared with any other form of physiotherapy in people with cystic fibrosis. Single-treatment interventions (therapy technique used only once in the comparison) were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria to publications, assessed the quality of the included studies and assessed the evidence using GRADE. MAIN RESULTS: The searches identified 82 studies (330 references); 39 studies (total of 1114 participants) met the inclusion criteria. Studies varied in duration from up to one week to one year; 20 of the studies were cross-over in design. The studies also varied in type of intervention and the outcomes measured, data were not published in sufficient detail in most of these studies, so meta-analysis was limited. Few studies were considered to have a low risk of bias in any domain. It is not possible to blind participants and clinicians to physiotherapy interventions, but 13 studies did blind the outcome assessors. The quality of the evidence across all comparisons ranged from low to very low. Forced expiratory volume in one second was the most frequently measured outcome and while many of the studies reported an improvement in those people using a vibrating device compared to before the study, there were few differences when comparing the different devices to each other or to other airway clearance techniques. One study identified an increase in frequency of exacerbations requiring antibiotics whilst using high frequency chest wall oscillation when compared to positive expiratory pressure (low-quality evidence). There were some small but significant changes in secondary outcome variables such as sputum volume or weight, but not wholly in favour of oscillating devices and due to the low- or very low-quality evidence, it is not clear whether these were due to the particular intervention. Participant satisfaction was reported in 13 studies but again with low- or very low-quality evidence and not consistently in favour of an oscillating device, as some participants preferred breathing techniques or techniques used prior to the study interventions. The results for the remaining outcome measures were not examined or reported in sufficient detail to provide any high-level evidence. AUTHORS' CONCLUSIONS: There was no clear evidence that oscillation was a more or less effective intervention overall than other forms of physiotherapy; furthermore there was no evidence that one device is superior to another. The findings from one study showing an increase in frequency of exacerbations requiring antibiotics whilst using an oscillating device compared to positive expiratory pressure may have significant resource implications. More adequately-powered long-term randomised controlled trials are necessary and outcomes measured should include frequency of exacerbations, individual preference, adherence to therapy and general satisfaction with treatment. Increased adherence to therapy may then lead to improvements in other parameters, such as exercise tolerance and respiratory function. Additional evidence is needed to evaluate whether oscillating devices combined with other forms of airway clearance is efficacious in people with cystic fibrosis.There may also be a requirement to consider the cost implication of devices over other forms of equally advantageous airway clearance techniques. Using the GRADE method to assess the quality of the evidence, we judged this to be low or very low quality, which suggests that further research is very likely to have an impact on confidence in any estimate of effect generated by future interventions.

Physical Illnesses Before Diagnosed as Schizophrenia: A Nationwide Case-Control Study.

Some physical illnesses are potentially associated with the development of schizophrenia. However, few studies have investigated these associations. Here, we examined physical illnesses and medical utilization patterns existing before patients received a diagnosis of schizophrenia. We enrolled a large representative cohort of the general population in Taiwan (N = 1 000 000) and identified 1969 young patients with a new diagnosis of schizophrenia from January 1, 2000 to December 31, 2013. We conducted a nested case-control study based on risk-set sampling. Each case was age-matched and sex-matched with 4 controls selected from the general population. The case and control groups were compared on the basis of various clinical characteristics. Conditional logistic regression was used to estimate the magnitude of risk associated with newly diagnosed schizophrenia. Within the 1 year before the schizophrenia diagnosis, the cases were most likely to visit the psychiatry department, followed by internal medicine and family medicine departments. According to multivariate analysis, compared with the controls, the cases had substantially higher risk of physical conditions in the prodromal phase, including hypertension (adjusted risk ratio [aRR] = 1.93, P = .001), other forms of heart disease (aRR = 2.07, P < .001), cerebrovascular diseases (aRR = 2.96, P = .001), chronic obstructive pulmonary disease (aRR = 1.50, P = .005), asthma (aRR = 1.76, P = .003), and irritable bowel syndrome (aRR = 2.00, P < .001). A wide range of psychiatric diseases and concomitant use of medications were significantly associated with schizophrenia development. In conclusion, several physical illnesses were identified to be associated with schizophrenia development, indicating that people with these illnesses could be vulnerable to schizophrenia.

Intravital microscopic optical coherence tomography imaging to assess mucus-mobilizing interventions for muco-obstructive lung disease in mice.

Airway mucus obstruction is a hallmark of chronic lung diseases such as cystic fibrosis, asthma, and COPD, and the development of more effective mucus-mobilizing therapies remains an important unmet need for patients with these muco-obstructive lung diseases. However, methods for sensitive visualization and quantitative assessment of immediate effects of therapeutic interventions on mucus clearance in vivo are lacking. In this study, we determined whether newly developed high-speed microscopic optical coherence tomography (mOCT) is sensitive to detect and compare in vivo effects of inhaled isotonic saline, hypertonic saline, and bicarbonate on mucus mobilization and clearance in Scnn1b-transgenic mice with muco-obstructive lung disease. In vivo mOCT imaging showed that inhaled isotonic saline-induced rapid mobilization of mucus that was mainly transported as chunks from the lower airways of Scnn1b-transgenic mice. Hypertonic saline mobilized a significantly greater amount of mucus that showed a more uniform distribution compared with isotonic saline. The addition of bicarbonate-to-isotonic saline had no effect on mucus mobilization, but also led to a more uniform mucus layer compared with treatment with isotonic saline alone. mOCT can detect differences in response to mucus-mobilizing interventions in vivo, and may thus support the development of more effective therapies for patients with muco-obstructive lung diseases.

Mechanical Ventilation Strategies for the Patient with Severe Obstructive Lung Disease.

Patients with respiratory failure due to obstructive lung disease present a challenge to the emergency physician. These patients have physiologic abnormalities that prevent adequate gas exchange and lung mechanics which render them at increased risk of cardiopulmonary decompensation when managed with invasive mechanical ventilation. This article addresses key principles when managing these challenging patients: patient-ventilator synchrony, air trapping and auto-positive end-expiratory pressure, and airway pressures. This article provides a practical workflow for the emergency physician responsible for managing these patients.

Knowledge to action framework for home health monitoring.

Chronic disease management is a grand challenge, both to the patients for optimal management and to the overall health system with cost utilization. Emerging research evidence suggests that Home Health Monitoring (HHM) using home-based, remoting monitoring technologies can improve the patients' quality of life, self-management, and achieve cost-effectiveness for the health system. How should HHM be introduced and integrated appropriately into the current healthcare delivery pathways to improve patient care and collect evidence of benefits simultaneously? The Knowledge to Action (KTA) framework is an effective approach in the implementation science literature to methodically guide the translation of evidence-based research findings into practice, putting knowledge into practical use. This article examines the use of the seven-step KTA model to address implementation facilitators and barriers of applying HHM in chronic disease management and then focus on its applicability on chronic obstructive pulmonary disease as an example.

Invasive Mechanical Ventilation.

Invasive mechanical ventilation is a potentially lifesaving intervention for acutely ill patients. The goal of this review is to provide a concise, clinically focused overview of basic invasive mechanical ventilation for the many clinicians who care for mechanically ventilated patients. Attention is given to how common ventilator modes differ in delivering a mechanical breath, evaluation of respiratory system mechanics, how to approach acute changes in airway pressure, and the diagnosis of auto-positive end-expiratory pressure. Waveform interpretation is emphasized throughout the review.

Emerging Concepts and Therapies for Mucoobstructive Lung Disease.

A spectrum of intrapulmonary airway diseases, for example, cigarette smoke-induced bronchitis, cystic fibrosis, primary ciliary dyskinesia, and non-cystic fibrosis bronchiectasis, can be categorized as "mucoobstructive" airway diseases. A common theme for these diseases appears to be the failure to properly regulate mucus concentration, producing mucus hyperconcentration that slows mucus transport and, importantly, generates plaque/plug adhesion to airway surfaces. These mucus plaques/plugs generate long diffusion distances for oxygen, producing hypoxic niches within adherent airway mucus and subjacent epithelia. Data suggest that concentrated mucus plaques/plugs are proinflammatory, in part mediated by release of IL-1α from hypoxic cells. The infectious component of mucoobstructive diseases may be initiated by anaerobic bacteria that proliferate within the nutrient-rich hypoxic mucus environment. Anaerobes ultimately may condition mucus to provide the environment for a succession to classic airway pathogens, including Staphylococcus aureus, Haemophilus influenzae, and ultimately Pseudomonas aeruginosa. Novel therapies to treat mucoobstructive diseases focus on restoring mucus concentration. Strategies to rehydrate mucus range from the inhalation of osmotically active solutes, designed to draw water into airway surfaces, to strategies designed to manipulate the relative rates of sodium absorption versus chloride secretion to endogenously restore epithelial hydration. Similarly, strategies designed to reduce the mucin burden in the airways, either by reducing mucin production/secretion or by clearing accumulated mucus (e.g., reducing agents), are under development. Thus, the new insights into a unifying process, that is, mucus hyperconcentration, that drives a significant component of the pathogenesis of mucoobstructive diseases promise multiple new therapeutic strategies to aid patients with this syndrome.

Fungi in Mucoobstructive Airway Diseases.

Asthma, chronic rhinosinusitis, and related incurable allergic afflictions of the upper and lower airways are medically important because of their association with the disabling symptom of dyspnea and, at least for asthma, the potential to cause fatal asphyxiation. Extensive research over the past two decades has uncovered both the physiological basis of airway obstruction in asthma and key governing molecular pathways. Exaggerated airway constriction in response to diverse provocative stimuli, termed airway hyperresponsiveness, is mediated through the cytokines interleukin 4 (IL-4) and IL-13 and the transcription factor signal transducer and activator of transcription 6 (STAT6). Overproduction of mucus has long been known to be an essential second component of airway obstruction and is also mediated in part through the IL-4/IL-13/STAT6 pathway. In this review, we discuss a second major signaling pathway which underlies mucus production that is mediated through proteinase-cleaved fibrinogen signaling through Toll-like receptor 4. Unexpectedly, our analysis of human sputum and paranasal sinus fluid indicates that in most cases of severe allergic airway disease, a unique type of airway fungal infection, termed airway mycosis, is pathogenically linked to these conditions. We further discuss how fungal and endogenous proteinases mediate the fibrinogenolysis that is essential to both Toll-like receptor 4 signaling and fibrin deposition that, together with mucus, contribute to airway obstruction.

Advancing the management of obstructive airways diseases through translational research.

Obstructive airways diseases (OAD) represent a huge burden of illness world-wide, and in spite of the development of effective therapies, significant morbidity and mortality related to asthma and COPD still remains. Over the past decade, our understanding of OAD has improved vastly, and novel treatments have evolved. This evolution is the result of successful translational research, which has connected clinical presentations of OAD and underlying disease mechanisms, thereby enabling the development of targeted treatments. The next challenge of translational research will be to position these novel treatments for OAD for optimal clinical use. At the same time, there is great potential in these treatments providing even better insights into disease mechanisms in OAD by studying the effects of blocking individual immunological pathways. To optimize this potential, there is a need to ensure that translational aspects are added to randomized clinical trials, as well as real-world studies, but also to use other trial designs such as platform studies, which allow for simultaneous assessment of different interventions. Furthermore, demonstrating clinical impact, that is research translation, is an increasingly important component of successful translational research. This review outlines concepts of translational research, exemplifying how translational research has moved management of obstructive airways diseases into the next century, with the introduction of targeted, individualized therapy. Furthermore, the review describes how these therapies may be used as research tools to further our understanding of disease mechanisms in OAD, through translational, mechanistic studies. We underline the current need for implementing basic immunological concepts into clinical care in order to optimize the use of novel targeted treatments and to further the clinical understanding of disease mechanisms. Finally, potential barriers to adoption of novel targeted therapies into routine practice and how these may be overcome are described.

Enhancement of lung gene delivery after aerosol: a new strategy using non-viral complexes with antibacterial properties.

The pathophysiology of obstructive pulmonary diseases, such as cystic fibrosis (CF), leads to the development of chronic infections in the respiratory tract. Thus, the symptomatic management of the disease requires, in particular, repetitive antibiotherapy. Besides these antibacterial treatments, certain pathologies, such as CF or chronic obstructive pulmonary disease (COPD), require the intake of many drugs. This simultaneous absorption may lead to undesirable drug interactions. For example, Orkambi® (lumacaftor/Ivacaftor, Vertex), a pharmacological drug employed to treat F508del patients, cannot be used with antibiotics such as rifampicin or rifabutin (rifamycin family) which are necessary to treat Mycobacteriaceae. As far as gene therapy is concerned, bacteria and/or biofilm in the airways present an additional barrier for gene transfer. Thus, aerosol administration of nanoparticles have to overcome many obstacles before allowing cellular penetration of therapeutic compounds. This review focusses on the development of aerosol formulations adapted to the respiratory tract and its multiple barriers. Then, formulations that are currently used in clinical applications are summarized depending on the active molecule delivered. Finally, we focus on new therapeutic approaches to reduce possible drug interactions by transferring the antibacterial activity to the nanocarrier while ensuring the transfection efficiency.

Towards Individualized Tracheobronchial Stents: Technical, Practical and Legal Considerations.

Stent placement has been established as a standard procedure for treating airway obstructions. Other indications are localized malacias and fistulas. Though many different stents with various diameters and lengths are available, the shapes are hardly ever ideal because of the distorted anatomy in patients with diseased airways. There are technical and legal limitations for customizing purchased airway stents. Individually tailored stents would be preferable. New techniques of additive manufacturing such as 3D printing make it possible to produce optimized stents for a particular patient. Using CT data and bronchoscopic images, stents can be constructed that match a particular anatomical situation and apply the optimized expansion force. We give an overview of the currently available manufacturing techniques for polymeric stents and report about our own experience. Direct on-site printing of polyurethane stents in a hospital and printing individual extrusion molds for silicone stents in a certified cleanroom are both feasible. Furthermore, there are promising attempts of combining mechanically customized stents with surface modifications, drug-eluting features, biodegradability, and time-dependent adaptation (4D printing). Truly optimized airway stents with the potential of solving the well-known stent problems such as granulation tissue formation, remodeling, mucostasis, and infections are in reach. The technical hurdles are probably easier to overcome than the legal constraints. The legal situations are discussed from a physician's and a manufacturer's perspective.

[New opportunities for inhaled therapy for inflammatory diseases of the respiratory system]. / Novye vozmozhnosti ingaliatsionnoi terapii pri vospalitel'nykh zabolevaniiakh respiratornoi sistemy.

The paper considers current approaches to mucoregulatory therapy for various inflammatory diseases of the respiratory system. It gives the advantages and disadvantages of common drugs used in their treatment. Emphasis is laid on the use of inhaled hypertonic saline of NaCl in combination with hyaluronic acid (Hyaneb). Clinical examples of its use in chronic obstructive pulmonary disease, acute and chronic bronchitis, and severe asthma are considered.

Oscillating devices for airway clearance in people with cystic fibrosis.

BACKGROUND: Chest physiotherapy is widely prescribed to assist the clearance of airway secretions in people with cystic fibrosis. Oscillating devices generate intra- or extra-thoracic oscillations orally or external to the chest wall. Internally they create variable resistances within the airways, generating controlled oscillating positive pressure which mobilises mucus. Extra-thoracic oscillations are generated by forces outside the respiratory system, e.g. high frequency chest wall oscillation. This is an update of a previously published review. OBJECTIVES: To identify whether oscillatory devices, oral or chest wall, are effective for mucociliary clearance and whether they are equivalent or superior to other forms of airway clearance in the successful management of secretions in people with cystic fibrosis. SEARCH METHODS: We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Trials Register comprising references identified from comprehensive electronic database searches and hand searches of relevant journals and abstract books of conference proceedings. Latest search of the Cystic Fibrosis Trials Register: 27 April 2017.In addition we searched the trials databases ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform. Latest search of trials databases: 26 April 2017. SELECTION CRITERIA: Randomised controlled studies and controlled clinical studies of oscillating devices compared with any other form of physiotherapy in people with cystic fibrosis. Single-treatment interventions (therapy technique used only once in the comparison) were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently applied the inclusion criteria to publications and assessed the quality of the included studies. MAIN RESULTS: The searches identified 76 studies (302 references); 35 studies (total of 1138 participants) met the inclusion criteria. Studies varied in duration from up to one week to one year; 20 of the studies were cross-over in design. The studies also varied in type of intervention and the outcomes measured, data were not published in sufficient detail in most of these studies, so meta-analysis was limited. Few studies were considered to have a low risk of bias in any domain. It is not possible to blind participants and clinicians to physiotherapy interventions, but 11 studies did blind the outcome assessors.Forced expiratory volume in one second was the most frequently measured outcome. One long-term study (seven months) compared oscillatory devices with either conventional physiotherapy or breathing techniques and found statistically significant differences in some lung function parameters in favour of oscillating devices. One study identified an increase in frequency of exacerbations requiring antibiotics whilst using high frequency chest wall oscillation when compared to positive expiratory pressure. There were some small but significant changes in secondary outcome variables such as sputum volume or weight, but not wholly in favour of oscillating devices. Participant satisfaction was reported in 15 studies but this was not specifically in favour of an oscillating device, as some participants preferred breathing techniques or techniques used prior to the study interventions. The results for the remaining outcome measures were not examined or reported in sufficient detail to provide any high level evidence. AUTHORS' CONCLUSIONS: There was no clear evidence that oscillation was a more or less effective intervention overall than other forms of physiotherapy; furthermore there was no evidence that one device is superior to another. The findings from one study showing an increase in frequency of exacerbations requiring antibiotics whilst using an oscillating device compared to positive expiratory pressure may have significant resource implications. More adequately-powered long-term randomised controlled trials are necessary and outcomes measured should include frequency of exacerbations, individual preference, adherence to therapy and general satisfaction with treatment. Increased adherence to therapy may then lead to improvements in other parameters, such as exercise tolerance and respiratory function. Additional evidence is needed to evaluate whether oscillating devices combined with other forms of airway clearance is efficacious in people with cystic fibrosis.There may also be a requirement to consider the cost implication of devices over other forms of equally advantageous airway clearance techniques. Using the GRADE method to assess the quality of the evidence, we judged this to be low or very low quality, which suggests that further research is very likely to have an impact on confidence in any estimate of effect generated by future interventions.