Mucus Clearance Research Articles

BASELINE CLINICAL CHARACTERISTICS OF ADULT NON-CYSTIC FIBROSIS BRONCHIECTASIS PATIENTS ON HIGH FREQUENCY CHEST WALL OSCILLATION AND OTHER AIRWAY CLEARANCE THERAPIES: ANALYSIS FROM THE UNITED STATES BRONCHIECTASIS RESEARCH REGISTRY

SESSION TITLE: Obstructive Lung Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Non-Cystic Fibrosis Bronchiectasis (NCFBE) is characterized by permanent dilatation of the airways and a vicious cycle of inflammation, leading to impaired mucous clearance, recurrent infection, and progressive airway damage. Use of Airway Clearance Therapies (ACTs) is part of clinical practice. In this study, we aimed to evaluate the characteristics of adults with NCFBE receiving High Frequency Chest Wall Oscillation (HFCWO) therapy and other ACTs, utilizing the U.S. Bronchiectasis Research Registry. METHODS: A retrospective cohort study was conducted. Adult patients seen clinically between 2008-2019 with NCFBE who were using ACTs were grouped into two mutually exclusive cohorts; HFCWO and other ACTs (positive expiratory pressure devices, chest percussion, postural drainage, directed cough, active cycle breathing, or others). Descriptive statistics of demographics and clinical characteristics were assessed in the 24-months prior to enrollment. RESULTS: A total of 992 patients met inclusion criteria. The mean age was 63.2 years (SD=14). Seventy-nine percent were female. The average BMI was 22.9 (SD=4). Of the total cohort, 266 (27%) were using HFCWO, while 726 (73%) were using other ACTs. Disease severity was based on the modified bronchiectasis severity index (BSI). Eighteen percent of patients using HFCWO had mild disease, vs. 26% in the other ACTs cohort. Thirty-six percent of patients in the HFCWO group had moderate disease, vs. 48% in the other ACTs group. Forty-six percent of patients using HFCWO had severe disease, vs. 25% in the other ACTs group. Eighty-four percent of patients in the HFCWO group had at least one exacerbation within the past two years, compared to 66% in the other ACTs group. In the HFCWO group, 29% of patients had one exacerbation, and 25% had more than three exacerbations in the prior two years. In the other ACTs group, 33% had one exacerbation, and 22% had more than three exacerbations. In the HFCWO group, 33% reported having at least one hospital admission within the past two years, vs. 19% in the other ACTs group. Fifty-eight percent of patients in the HFCWO group had one hospitalization, and 10% had more than three hospitalizations. In the other ACTs group, 64% had one hospitalization, while 4% had more than three hospitalizations. There was a statistically significant difference between the HFCWO and other ACT groups in severity of disease (p<.0001), incidence of acute exacerbations (p<.0001), and rate of hospitalizations (p<.0001). CONCLUSIONS: Patients with bronchiectasis using HFCWO had more severe disease than those using other ACTs, as characterized by higher BSI scores and a greater number of exacerbations and hospitalizations. Further analysis to control for potential confounders and to explore longitudinal trends is recommended. CLINICAL IMPLICATIONS: HFCWO therapy is more commonly used in bronchiectasis patients with moderate to severe disease. DISCLOSURES: No relevant relationships by Timothy Aksamit, source=Web Response Advisory Board relationship with Insmed Please note: $1001 - $5000 by Ashwin Basavaraj, source=Web Response, value=Honoraria Consultant relationship with Hill-Rom Please note: $1001 - $5000 by Ashwin Basavaraj, source=Web Response, value=Consulting fee Employee relationship with Hill-Rom Company Inc. Please note: >$100000 Added 06/01/2020 by Brian Becker, source=Web Response, value=Salary Stock Ownership relationship with Hill-Rom Company Inc. Please note: $20001 - $100000 Added 06/01/2020 by Brian Becker, source=Web Response, value=Stock Ownership No relevant relationships by Radmila Choate, source=Web Response Employee relationship with Hill-Rom Inc Please note: >$100000 Added 05/31/2020 by Missy Wanjala, source=Web Response, value=Salary

Performance Characteristics of Positive Expiratory Pressure Devices.

Positive expiratory pressure (PEP) therapy imposes expiratory flow resistance to increase airway diameter and enhance mucus clearance. PEP is achieved several ways. Oscillatory PEP devices (OPEP) generate repeated occlusions that are known to reduce mucus viscosity. There are many marketed devices, but comparative performance is mostly unreported. The purpose of this study was to evaluate performance characteristics of many PEP/OPEP devices. For OPEP devices, we defined an optimal performance metric by creating an oscillation index that combines the OPEP performance characteristics. PEP devices (TheraPEP, EzPAP, VersaPAP, Resistex, AccuPEP, AccuPAP, and Threshold PEP) and OPEP devices (Acapella DH, Acapella DM, Acapella Choice, ShurClear, Aerobika, VibraPEP, vPEP, and PocketPEP with and without the Oxyjet attachment) were tested by adjusting simulated expiratory flow from 5 L/min to 30 L/min in increments of 5 L/min using a standard flow meter. All devices showed varying performance characteristics. As expiratory flow increased, mean PEP increased for most devices. The TheraPEP showed a mean PEP of 13 cm H2O across all settings. For OPEP devices, there was a major difference between pressure and flow waveforms. The Acapella DH, ShurClear, and Aerobika showed the highest flow amplitude, flow frequency, and oscillation index. PEP devices behaved similarly and as expected, with increased pressure with increased flow (flow resistors) or flow independence (threshold resistors). There was much greater variation in the performance of the OPEP devices. A higher oscillation index indicates better mechanical performance characteristics. Many devices have similar characteristics. However, the devices with the highest oscillation index have the highest flow amplitude and frequency, which may indicate better clinical performance.

Transient receptor potential channels in pulmonary chemical injuries and as countermeasure targets.

The lung is highly sensitive to chemical injuries caused by exposure to threat agents in industrial or transportation accidents, occupational exposures, or deliberate use as weapons of mass destruction (WMD). There are no antidotes for the majority of the chemical threat agents and toxic inhalation hazards despite their use as WMDs for more than a century. Among several putative targets, evidence for transient receptor potential (TRP) ion channels as mediators of injury by various inhalational chemical threat agents is emerging. TRP channels are expressed in the respiratory system and are essential for homeostasis. Among TRP channels, the body of literature supporting essential roles for TRPA1, TRPV1, and TRPV4 in pulmonary chemical injuries is abundant. TRP channels mediate their function through sensory neuronal and nonneuronal pathways. TRP channels play a crucial role in complex pulmonary pathophysiologic events including, but not limited to, increased intracellular calcium levels, signal transduction, recruitment of proinflammatory cells, neurogenic inflammatory pathways, cough reflex, hampered mucus clearance, disruption of the integrity of the epithelia, pulmonary edema, and fibrosis. In this review, we summarize the role of TRP channels in chemical threat agents-induced pulmonary injuries and how these channels may serve as medical countermeasure targets for broader indications.

Novel Therapy of Bicarbonate, Glutathione, and Ascorbic Acid Improves Cystic Fibrosis Mucus Transport.

Defective airway mucus clearance is a defining characteristic of cystic fibrosis lung disease, and improvements to current mucolytic strategies are needed. Novel approaches targeting a range of contributing mechanisms are in various stages of preclinical and clinical development. ARINA-1 is a new nebulized product comprised of ascorbic acid, glutathione, and bicarbonate. Using microoptical coherence tomography, we tested the effect of ARINA-1 on central features of mucociliary clearance in F508del/F508del primary human bronchial epithelial cells to assess its potential as a mucoactive therapy in cystic fibrosis. We found that ARINA-1 significantly augmented mucociliary transport rates, both alone and with CFTR (cystic fibrosis transmembrane conductance regulator) modulator therapy, whereas airway hydration and ciliary beating were largely unchanged compared with PBS vehicle control. Analysis of mucus reflectivity and particle-tracking microrheology indicated that ARINA-1 restores mucus clearance by principally reducing mucus layer viscosity. The combination of bicarbonate and glutathione elicited increases in mucociliary transport rate comparable to those seen with ARINA-1, indicating the importance of this interaction to the impact of ARINA-1 on mucus transport; this effect was not recapitulated with bicarbonate alone or bicarbonate combined with ascorbic acid. Assessment of CFTR chloride transport revealed an increase in CFTR-mediated chloride secretion in response to ARINA-1 in CFBE41o- cells expressing wild-type CFTR, driven by CFTR activity stimulation by ascorbate. This response was absent in CFBE41o- F508del cells treated with VX-809 and primary human bronchial epithelial cells, implicating CFTR-independent mechanisms for the effect of ARINA-1 on cystic fibrosis mucus. Together, these studies indicate that ARINA-1 is a novel potential therapy for the treatment of impaired mucus clearance in cystic fibrosis.

Update on pharmacotherapy for adult bronchiectasis

Bronchiectasis refers to abnormal dilatation of the bronchi, which leads to the failure of mucus clearance and increased risk of infection. Pharmacotherapy for stable bronchiectasis includes oral or inhaled mucoactive agents, anti-inflammatory therapy, inhaled bronchodilators, long-term antibiotics, and long-term macrolide treatment. Among them, mucoactive agents are the most common adjunctive agents to airway clearance techniques. When patients with impaired lung function suffer from dyspnea, inhaled bronchodilators may be prescribed to relieve the symptom. Long-term macrolide treatment has been proven to prevent exacerbation in patients with frequent bronchiectasis exacerbation. If exacerbation occurs despite the above mentioned treatments, one or two weeks of antibiotics should be prescribed to cover respiratory bacteria that include &lt;i&gt;Pseudomonas aeruginosa&lt;/i&gt;. Because evidence supporting the use of pharmacotherapy for bronchiectasis is weak, further research is warranted.

Phenotypic features of ciliary dyskinesia among patients with congenital cardiovascular malformations.

Cilia are cell membrane-bound organelles responsible for airway mucus clearance, establishment of left-right organ asymmetry, cardiogenesis, and many other functions in utero. Phenotypic features suggestive of respiratory ciliary dyskinesia among patients with heterotaxy syndrome, defined as complex cardiovascular malformations (CVM) and situs ambiguus (SA), has not been adequately explored. We hypothesized that there is a greater incidence of phenotypic features consistent with ciliary dyskinesia among patients with heterotaxy syndrome compared to patients with other CVM and laterality defects without heterotaxy syndrome. Thirty six subjects were identified by medical record search and divided into four groups based on situs status and type of CVM as follows: SA and complex CVM (group 1); SA and simple CVM (group 2); situs solitus and complex CVM (group 3); and situs solitus and simple CVM (group 4). Phenotype was assessed with a clinical questionnaire, nasal nitric oxide (NO) level, and pulmonary function testing. Those with complex CVM underwent additional testing for variants in genes involved in ciliary structure and function. The mean nasal NO level was significantly lower among all subjects with complex CVM regardless of situs anomalies (groups 1 and 3). There was no significant difference in respiratory symptoms or lung function among the four groups. No bi-allelic genetic mutations were detected among patients with complex CVM. This study identified a relatively lower mean nasal NO level, suggestive of relative ciliary dyskinesia, among subjects with complex CVM. Pulmonary function and clinical symptoms did not reflect significant pulmonary disease among those with complex CVM.

Hyperglycaemia in cystic fibrosis adversely affects BK channel function critical for mucus clearance.

Large-conductance, Ca2+-activated, voltage-dependent K+ (BK) channel function is critical for adequate airway hydration and mucociliary function. In airway epithelia, BK function is regulated by its γ-subunit, leucine-rich repeat-containing protein 26 (LRRC26). Since patients with cystic fibrosis (CF)-related diabetes mellitus (CFRD) have worse lung function outcomes, this study determined the effects of hyperglycaemia on BK function in CF bronchial epithelial (CFBE) cells in vitro and evaluated the correlation between glycaemic excursions and mRNA expression of LRRC26 in the upper airways of CF and CFRD patients.CFBE cells were redifferentiated at the air-liquid interface (ALI) in media containing either 5.5 mM or 12.5 mM glucose. BK activity was measured in an Ussing chamber. Airway surface liquid (ASL) volume was estimated by meniscus scanning and inflammatory marker expression was measured by quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA). CF patients were assessed by 7 days of continuous glucose monitoring (CGM). LRRC26 mRNA expression was measured by quantitative real-time PCR from nasal cells obtained at the end of glucose monitoring.BK currents were significantly decreased in CFBE cells cultured under high glucose. These cells revealed significantly lower ASL volumes and increased inflammation, including the receptor for advanced glycation endproducts (RAGE), compared to cells cultured in normal glucose. In vivo, nasal cell expression of LRRC26 mRNA was inversely correlated with hyperglycaemic excursions, consistent with the in vitro results.Our findings demonstrate that hyperglycaemia induces inflammation and impairs BK channel function in CFBE cells in vitro These data suggest that declining lung function in CFRD patients may be related to BK channel dysfunction.

Mucoactive agents for acute respiratory failure in the critically ill: a systematic review and meta-analysis

PurposeAcute respiratory failure (ARF) is a common cause of admission to intensive care units (ICUs). Mucoactive agents are medications that promote mucus clearance and are frequently administered in patients with...

Antisense Oligonucleotides Targeting Jagged 1 Reduce House Dust Mite-induced Goblet Cell Metaplasia in the Adult Murine Lung.

Goblet cell metaplasia, excessive mucus production, and inadequate mucus clearance accompany and exacerbate multiple chronic respiratory disorders, such as asthma and chronic obstructive pulmonary disease. Notch signaling plays a central role in controlling the fate of multiple cell types in the lung, including goblet cells. In the present study, we explored the therapeutic potential of modulating the Notch pathway in the adult murine lung using chemically modified antisense oligonucleotides (ASOs). To this end, we designed and characterized ASOs targeting the Notch receptors Notch1, Notch2, and Notch3 and the Notch ligands Jag1 (Jagged 1) and Jag2 (Jagged 2). Pulmonary delivery of ASOs in healthy mice or mice exposed to house dust mite, a commonly used mouse model of asthma, resulted in a significant reduction of the respective mRNAs in the lung. Furthermore, ASO-mediated knockdown of Jag1 or Notch2 in the lungs of healthy adult mice led to the downregulation of the club cell marker Scgb1a1 and the concomitant upregulation of the ciliated cell marker FoxJ1 (forkhead box J1). Similarly, ASO-mediated knockdown of Jag1 or Notch2 in the house dust mite disease model led to reduced goblet cell metaplasia and decreased mucus production. Because goblet cell metaplasia and excessive mucus secretion are a common basis for many lung pathologies, we propose that ASO-mediated inhibition of JAG1 could provide a novel therapeutic path for the treatment of multiple chronic respiratory diseases.

Effect of hypertonic saline on mucociliary clearance and clinical outcomes in chronic bronchitis.

BackgroundMucus dehydration and impaired mucus clearance are common features of cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). In CF, inhaled hypertonic saline (HS) improves lung function and produces sustained increases in mucociliary clearance (MCC). We hypothesised that administration of HS (7% NaCl) twice daily for 2 weeks would improve clinical outcomes and produce sustained increases in MCC in COPD subjects with a chronic bronchitis (CB) phenotype.MethodsTwenty-two CB subjects completed a double-blinded, crossover study comparing inhaled HS to a hypotonic control solution (0.12% saline) administered via nebuliser twice daily for 2 weeks. Treatment order was randomised. During each treatment period, symptoms and spirometry were measured. MCC was measured at baseline, shortly after initial study agent administration, and approximately 12 h after the final dose.ResultsHS was safe and well tolerated but overall produced no significant improvements in spirometry or patient-reported outcomes. CB subjects had slower baseline MCC than healthy subjects. The MCC rates over 60 min (Ave60Clr) in CB subjects following 2 weeks of HS were not different from 0.12% saline but were slower than baseline (Ave60Clr was 9.1±6.3% at baseline versus 5.3±6.9% after HS; p<0.05). Subgroup analyses determined that subjects with residual baseline central lung clearance (14 subjects) had improved spirometry and symptoms following treatment with HS, but not 0.12% saline, treatment.ConclusionsInhaled HS appeared to be safe in a general CB population. A specific phenotypic subgroup may benefit from HS but requires additional study.

Multi-scale spatial heterogeneity enhances particle clearance in airway ciliary arrays.

Mucus clearance constitutes the primary defence of the respiratory system against viruses, bacteria and environmental insults [1]. This transport across the entire airway emerges from the integrated activity of thousands of multiciliated cells, each containing hundreds of cilia, which together must coordinate their spatial arrangement, alignment and motility [2, 3]. The mechanisms of fluid transport have been studied extensively at the level of an individual cilium [4, 5], collectively moving metachronal waves [6-10], and more generally the hydrodynamics of active matter [11, 12]. However, the connection between local cilia architecture and the topology of the flows they generate remains largely unexplored. Here, we image the mouse airway from the sub-cellular (nm) to the organ scales (mm), characterising quantitatively its ciliary arrangement and the generated flows. Locally we measure heterogeneity in both cilia organisation and flow structure, but across the trachea fluid transport is coherent. To examine this result, a hydrodynamic model was developed for a systematic exploration of different tissue architectures. Surprisingly, we find that disorder enhances particle clearance, whether it originates from fluctuations, heterogeneity in multiciliated cell arrangement or ciliary misalignment. This resembles elements of 'stochastic resonance' [13-15], in the sense that noise can improve the function of the system. Taken together, our results shed light on how the microstructure of an active carpet [16, 17] determines its emergent dynamics. Furthermore, this work is also directly applicable to human airway pathologies [1], which are the third leading cause of deaths worldwide [18].

A Functional Respiratory Imaging Approach to the Effect of an Oscillating Positive Expiratory Pressure Device in Chronic Obstructive Pulmonary Disease.

PurposeChronic obstructive pulmonary disease (COPD) patients are prone to suffer from chronic bronchitis, which ultimately affects their quality of life and overall prognosis. Oscillating positive expiratory pressure (oPEP) devices are designed to aid in the mucus clearance by generating positive pressure pulses in the airways. The main aim of this study was to analyze the impact of a specific oPEP device – Aerobika® – on top of standard of care medication in COPD patients’ lung dynamics and drug deposition.Patients and MethodsIn this single-arm pilot study, patients were assessed using standard spirometry tests and functional respiratory imaging (FRI) before and after a period of 15±3 days of using the oPEP device twice daily (before their standard medication).ResultsThe utilization of the oPEP device led to a significant increase of 2.88% in specific airway volume after two weeks (1.44 (SE: 0.18) vs 1.48 (SE: 0.19); 95% CI = [0.03%,5.81%]; p=0.048). Moreover, the internal airflow distribution (IAD) was affected by the treatment: patients’ changes ranged from −6.74% to 4.51%. Furthermore, IAD changes at the lower lobes were also directly correlated with variations in forced expiratory volume in one second and peak expiratory flow; conversely, IAD changes at the upper lobes were inversely correlated with these clinical parameters. Interestingly, this change in IAD was significantly correlated with changes in lobar drug deposition (r2=0.30, p<0.001).ConclusionOur results support that the Aerobika device utilization leads to an improved airflow, which in turn causes a shift in IAD and impacts the drug deposition patterns of the concomitant medication in patients with COPD.

Enhancing Mucus Clearance by Cough Through Repeated Pulses

AbstractThe aim of this study is to investigate the potential increase in the efficiency of the mucus clearance by repeated pulses of the same maximum speed and total air volume compared to single pulse simulated cough and to explore the effect of mucus simulant rheology and duration between repeated pulses on it. Experiments are conducted to study the behavior and clearance of a mucus simulant through a D-shaped rigid plexiglass horizontal tracheal model by approximately rectangular pulses. Mucus simulants with viscoelastic properties like mucus of patients with chronic obstructive pulmonary disease (COPD) or similar illnesses, a moderate increase in elastic modulus, and a sharp decrease in viscosity with increasing frequency were prepared by locust bean gum and borax-de-ionized water solutions (Ragavan, A. J., Evrensel, C. A., and Krumpe, P., 2010, “Interactions of Airflow Oscillation, Tracheal Inclination, and Mucus Elasticity Significantly Improve Simulated Cough Clearance,” Chest, 137(2), pp. 355–361). Displacement of 0.3 ml mucus simulant aliquot is measured during single or repeated airflow pulses with a total air volume of about 1.1 L and the same maximum velocity. The desired flow pattern is generated by a compressor set at 4.5 bar and a computer-controlled on–off valve. Displacement of the same volume of mucus aliquot increases with the increasing number of pulses with the same total volume of air and maximum velocity and increasing of elasticity of mucus simulants. The increased maximum airflow velocity of repeated pulses affects the displacement of mucus aliquot positively. Moreover, when the duration length between the repeated pulses increased up to 100 ms, the displacement of aliquot increased up to but after 100 ms to 150 ms started to decrease.

Mucus clearance at rest and during exercise in patients with bronchial hypersecretion

The purpose of this study was to measure the effects on mucus clearance after physical exercise. We measured mucociliary clearance at rest and during exercise in eleven patients with mild or moderate bronchial hypersecretion. The subjects inhaled an aerosol containing 99mTc-labelled albumin millimicrospheres. Four sets of scintigraphic images were obtained with 15 minute intervals. The lung retention of radioactivity was quantified using a gamma camera and the clearance of particles from the lungs were calculated for each 15 min period. The first image was obtained directly after inhalation, the second after a period of 15 min rest, the third after a period of exercise on a bicycle ergometer and the final fourth image after another period of rest. We found no differences in the clearance rate at rest and after exercise.

Effects of the Lower Airway Secretions on Airway Opening Pressures and Suction Pressures in Critically Ill COVID-19 Patients: A Computational Simulation

Background: In patients with critically ill COVID-19 pneumonia, alveoli or small airways are filled with a large amount of highly viscous exudates or mucus, leading to airway occlusion. This is currently a difficult point in mechanical ventilation treatment of these patients. The estimation of airway opening pressures and effective mucus clearance are therefore two issues that clinicians are most concerned about. Methods: We retrospectively analyzed respiratory data from 24 critical ill patients with confirmed COVID-19 who received invasive mechanical ventilation and recruitment maneuver at Jinyintan Hospital in Wuhan, China, and found the extraordinarily high inspiratory plateau pressures. A computational model of airway opening was subsequently introduced to investigate possible fluid dynamic mechanisms. Using various types of fluids as lower airway secretions simulants, we further predicted airway opening pressures and suction pressures in critically ill patients with COVID-19. Findings: Among 24 critically ill patients in this retrospective study, the inspiratory plateau pressures ranged from 45 cmH2O to 60 cmH2O, and the mean was 52.4±4.4 cmH2O (mean±[SD]). Patients had low static compliance (23.1±7.3 ml/cmH2O), high alveolar dead space fraction (45±9 percent of tidal volume). Particularly, the capnograms presented a spike-like appearance with an upward slope during the expiratory plateau, indicting the existence of airway obstruction. Our simulation results showed that properties of airway secretions affected the airway opening pressures and suction pressures. When secretions simulants had viscosity similar to that of medicinal glycerin at room temperature or presented rheological properties like peanut butter, the airway opening pressures could be as high as 40~50 cmH2O; the negative pressure needed for secretions suctioning could exceed 20 kPa, likely causing the closures of the distal airways. Interpretation: In a proportion of critically ill patients with COVID-19, limiting plateau pressure to 30 cmH2O may not guarantee the opening of airways due to the presence of highly viscous lower airway secretions, not to mention spontaneous inspiratory efforts. Active airway humidification and effective expectorant drugs are therefore strongly recommended during airway management. Funding Statement: This work was supported by the National Natural Science Foundation of China (81971807, 11532003, 31670950) and Special Project of the National Natural Science Foundation of China (82041003). Declaration of Interests: The authors declare no competing interests. Ethics Approval Statement: The Ethics Committee of Jinyintan Hospital approved the study (KY-2020-56.01). Written informed consent was waived due to the retrospective manner of this study.

Fungal ball of the maxillary sinus and the risk of persistent sinus dysfunction after simple antrostomy

Maxillary sinus fungal ball is a common cause of unilateral maxillary sinusitis. Fungal balls or mycetomas are primarily treated with surgery to remove the fungus. However, this assumes the pre-fungal ball sinus cavity was normal and post-surgery patients may suffer from mucostasis in the sinus cavity with persistent symptoms. It is proposed that fungal balls are potentially a feature of impaired mucus clearance as they are a pathology in their own right. A case series of consecutive patients undergoing antrostomy for maxillary sinus fungal ball was performed. Patient factors including age, gender, smoking status, comorbidities (allergy, asthma, and reflux), disease specific factors including duration of symptoms, microbiology (bacterial co-infection, Gram-positive and/or Gram-negative) and preoperative radiologic findings (extent of sinus development, and neo-osteogenesis/bone thickness) were collected. The primary outcome was sinus function defined by evidence of a normal functioning maxillary sinus, with the absence of mucostasis or pooling, on endoscopic exam at three months, six months and last follow-up. Endoscopic evaluation of inflammation was also collected. 28 patients (age 58.5±15.5years, 64.3% female) were assessed. Mucostasis was present at three months in 39.3%, at six months in 32.1%, and 17.9% at last follow-up. There was no comorbidity or radiologic finding that was associated with failure to normalize. Those patients with mucostasis had a higher modified Lund-Mackay endoscopic score at last follow-up (5.0±0.7 v 0.2±0.6, p<0.01). Long term post-operative mucostasis occurred in 17.9% of patients following an adequate maxillary antrostomy for treatment of a fungal ball. Patients with mucostasis had persistent mucosal inflammation and a greater need for further surgery (modified medial maxillectomy).

Mucoactive agent use in adult UK Critical Care Units: a survey of health care professionals' perception, pharmacists' description of practice, and point prevalence of mucoactive use in invasively mechanically ventilated patients.

BackgroundMechanical ventilation for acute respiratory failure is one of the most common indications for admission to intensive care units (ICUs). Airway mucus clearance is impaired in these patients medication, impaired mucociliary motility, increased mucus production etc. and mucoactive agents have the potential to improve outcomes. However, studies to date have provided inconclusive results. Despite this uncertainty, mucoactives are used in adult ICUs, although the extent of use and perceptions about place in therapy are not known.Aims and ObjectivesWe aim to describe the use of mucoactive agents in mechanically ventilated patients in UK adult critical care units. Specifically, our objectives are to describe clinicians perceptions about the use of mucoactive agents, understand the indications and anticipated benefits, and describe the prevalence and type of mucoactive agents in use.MethodsWe conducted three surveys. Firstly, a practitioner-level survey aimed at nurses, physiotherapists and doctors to elucidate individual practitioners perceptions about the use of mucoactive agents. Secondly, a critical care unit-level survey aimed at pharmacists to understand how these perceptions translate into practice. Thirdly, a point prevalence survey to describe the extent of prescribing and range of products in use. The practitioner-level survey was disseminated through the UK Intensive Care Society for completion by a multi-professional membership. The unit-level and point prevalence surveys were disseminated cthrough the UK Clinical Pharmacy Association for completion by pharmacists.ResultsThe individual practitioners survey ranked ‘thick secretions’ as the main reason for commencing mucoactive agents determined using clinical assessment. The highest ranked perceived benefit for patient centred outcomes was the duration of ventilation. Of these respondents, 79% stated that further research was important and 87% expressed support for a clinical trial. The unit-level survey found that mucoactive agents were used in 83% of units. The most highly ranked indication was again ‘thick secretions’ and the most highly ranked expected patient centred clinical benefit being improved gas exchange and reduced ventilation time. Only five critical care units provided guidelines to direct the use of mucoactive agents (4%). In the point prevalence survey, 411/993 (41%) of mechanically ventilated patients received at least one mucoactive agent. The most commonly administered mucoactives were inhaled sodium chloride 0.9% (235/993, 24%), systemic carbocisteine (161/993, 16%) and inhaled hypertonic sodium cloride (127/993, 13%).ConclusionsMucoactive agents are used extensively in mechanically ventilated adult patients in UK ICUs to manage ‘thick secretions’, with a key aim to reduce the duration of ventilation. There is widespread support for clinical trials to determine the optimal use of mucoactive agent therapy in this patient population.

Bronchoscopic lung volume reduction with valves: What should the internist know?

Traditional therapies for emphysema such as bronchodilators and anti-inflammatory drugs have limited value due to permanent structural changes in the emphysematous lung that result in hyperinflation. Surgical lung volume reduction partially corrects hyperinflation by removing emphysematous lung and is an option in selected patients, but it carries a risk of morbidity and death. Valve therapy is a less-invasive option that involves bronchoscopic implantation of 1-way valves in emphysematous lung segments to allow air flow and mucus clearance in the direction of central airways. The authors review the rationale, evidence, and applications of valve therapy.

MP49: Does reduced cough capacity in minor thoracic trauma leads to more atelectasis development?

Introduction: Minor thoracic trauma (MTI) accounts for approximately 15% of all injuries treated in the emergency department (ED). Many of which are minor and will be handle on an outpatient basis. MTI and rib fractures especially cause non-negligible pain. The pain experienced by patients can lead to reduce pulmonary function, decrease mucous clearance and decrease cough capacity leading in infectious problems and atelectasis. To our knowledge, there is no study of atelectasis development caused by reduced cough capacity in the setting of MTI. Objective: Evaluate if a variation in cough capacity leads to atelectasis development. Evaluate if there was a difference in cough capacity perception between the nurse, the physician and the patient himself. Methods: A prospective observational cohort study (2006-2012) in 4 ED recruited patients with a chief complaint of MTI, ≥ 16 years old, discharged home from the ED. Exclusion criteria: 1) a confirmed hemothorax, pneumothorax, fail chest, lung contusion or any other important thoracic or abdominal internal injury at the initial visit or unable to attend follow-up visits. Patients were assessed at 7- and 14- days. For each patient, age, sex, mechanism of injury, dyspnea, COPD/asthma and smoking status were collected. Chest x-ray was done at each visit; pulmonary complications were assessed by a blind radiologist. Cough capacity was assessed on a scale of 0 to 10 by a nurse, physician and patient himself at 0, 7- and 14- days. Pain was scored on a scale of 0 to 10. Chi -squared and odds ratio (IC: 95%. p ≤ 0.05) were assessed to determine if the cough capacity variation leads to atelectasis development. A Pearson correlation test was assessed the correlation in cough capacity among participants. Results: 1474 patients were recruited. Initial visit: 9% had atelectasis, 7 days: 7% and 4.6% at 14 days. 1105 patients were retained for analysis after exclusion of missing data. The median initial pain score was 7-8 for all patient categories. At 7 days, the odds ratio of atelectasis development were (score (0-3) 1.18 (0.42-3.34); score (4-7) 1.20 (0.48-3.03); p&lt;=0.05). The Pearson correlation of cough capacity assessment, in patients without atelectasis were (0.53 nurse vs. patient; 0.37 physician vs. patient; 0.51 nurse vs. physician p&lt;=0.05). As for the cough capacity perception correlation in patients with atelectasis were (0.62 nurse vs. patient; 0.40 physician vs. patient; 0.51 nurse vs. physician; p&lt;=0.05). Conclusion: There is no statistically significant difference in atelectasis development depending on cough capacity and there is poor correlation regarding the perception of cough capacity except for the nurse. It would be interesting to develop a patient reported outcome measure questionnaire which targets minor thoracic trauma as it is a common emergency department complaint and it could help us improve medical management and patient quality of life

Conditional deletion of Nedd4-2 in lung epithelial cells causes progressive pulmonary fibrosis in adult mice

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease characterized by patchy scarring of the distal lung with limited therapeutic options and poor prognosis. Here, we show that conditional deletion of the ubiquitin ligase Nedd4-2 (Nedd4l) in lung epithelial cells in adult mice produces chronic lung disease sharing key features with IPF including progressive fibrosis and bronchiolization with increased expression of Muc5b in peripheral airways, honeycombing and characteristic alterations in the lung proteome. NEDD4-2 is implicated in the regulation of the epithelial Na+ channel critical for proper airway surface hydration and mucus clearance and the regulation of TGFβ signaling, which promotes fibrotic remodeling. Our data support a role of mucociliary dysfunction and aberrant epithelial pro-fibrotic response in the multifactorial disease pathogenesis. Further, treatment with the anti-fibrotic drug pirfenidone reduced pulmonary fibrosis in this model. This model may therefore aid studies of the pathogenesis and therapy of IPF.