Aging generates a variety of phenotypes in the lungs with increased alveolar airspaces or emphysema, decreased surface area, and increased disease susceptibility. Senescence, oxidative stress, and mitochondrial dysfunction are known contributory factors. However, the underlying mechanisms promoting unhealthy aging remain unclear. Adenine nucleotide Translocase 1 (ANT1), a mitochondrial ADP/ATP transporter, is important for mitochondrial metabolism. Loss of ANT1 has been implicated in the development of pulmonary fibrosis, a disease characterized by accelerated lung aging, through mitochondrial dysfunction and senescence. To determine the role of ANT1 in normal lung aging, we analyzed aged human lung data from the Human Lung Cell Atlas and evaluated the ANT1-related mechanism in an aged genetic mouse and in vitro models. Analysis of SLC25A4 (ANT1) gene expression in the Human Lung Cell Atlas data from healthy adults (ages 20-80) revealed an age-associated reduction in SLC25A4 in alveolar type 2 pneumocytes (AT2), and airway ciliated and basal cells. Using an Ant1-deficient mouse model, aged Ant1-null mice developed increased airway thickening and airway resistance on lung function testing compared to aged wildtype mice. In human airway epithelial cells, ANT1 knockdown resulted in upregulation of senescence and tissue remodeling genes, including COL8A1. Aged Ant1-null mice and aged human airways similarly had increased p21 expression in AT2 and airway club cells, increased SASP markers, and increased COL8A1 expression in the airways. We demonstrate for the first time that ANT1, an important multifunctional mitochondrial protein, plays a significant role in the pathogenesis of lung aging by regulating senescence and airway matrix remodeling.

Rationale: Aging brings about a variety of phenotypes in the lungs, including decreased lung size, increased alveolar airspaces or “senile emphysema,” and increased susceptibility to diseases. Senescence, oxidative stress, and mitochondrial dysfunction are known contributory factors. However, the mechanisms by which these adverse aging effects occur through these processes remain unclear. ANT1 is a mitochondrial ADP/ATP transporter protein that is important for mitochondrial metabolism. Previous work in our lab has established that loss of ANT1 promotes pulmonary fibrosis through mitochondrial dysfunction. Here, we aim to illuminate ANT1's specific role in normal lung aging and the mechanisms behind these changes. Methods: Gene expression data from healthy adults (ages 20-80) in the Human Lung Cell Atlas project was used to determine SLC25A4 (ANT1) gene expression in human lung epithelial cells. Mouse studies were completed using Wildtype (WT) and global Ant1 knockout mice (A1KO): Young WT vs. A1KO (2 months old), Old WT vs A1KO (22 months old). Mice underwent Pulmonary Function Testing (PFT), and lung tissue was processed for H&E staining, immunofluorescence, and western blotting. Beas-2b cells with Crispr knockout of ANT1 underwent Bulk RNA sequencing. Results: Analysis of SLC25A4 gene expression in human lung epithelial cells revealed an age-associated reduction in SLC25A4 (ANT1) in type II pneumocytes, ciliated, and basal cells. In mice, Ant1 knockout affected the phenotypes of old mice but not young. As expected, aged mice had increased emphysema, compared to young. Interestingly, old A1KO mice had less emphysema, suggesting that the loss of Ant1 may have protective effects on age-related alveolar remodeling. Old A1KO mice had higher total lung and ATII-specific levels of the senescent marker p21 by western blot and immunofluorescence, respectively. Old A1KO mice also had increased airway resistance on PFTs with corresponding thicker airways. Bulk RNA sequencing of bronchial epithelial cells (Beas-2b) with ANT1 knockout demonstrated upregulation of senescence and tissue remodeling pathways, including Col8a1 and HB-EGF, and tumor promoting pathways, like MAPK and PI3K-AKT. There was also a downregulation of key inflammatory pathways (Il-17, NF-kB, and TNF-α) with ANT1 knockout. Conclusions: We demonstrated that ANT1, a crucial protein for mitochondrial function, is reduced in lung epithelial cells of older adults. Further, loss of ANT1 increases senescence markers and airway remodeling in old but not young mice. Studies in progress aim to characterize the specific pathways involved with loss of ANT1 in the aged lung to inform future therapeutic avenues for preventing aging-related lung disorders.

The mucociliary clearance (MC) system clears mucus, pathogens, and toxins from the airways. Whole lung MC rate can be measured using gamma camera imaging after the inhalation of radiolabeled particulate. We sought a means to evaluate the therapeutic effect of clearance enhancing therapies in different airway size groups. We developed a mathematical model of mucus transport in the right lung that, when informed by imaging data, estimates MC rate and unclearable activity at points across the airway tree. We fit the model to imaging studies from 11 healthy controls (HC), resulting in a per-point mean absolute error (MAE) of 0.085 ± 0.016% of the total particulate deposition. Using principal component analysis and hierarchical clustering, we reduced the number of fitted clearance rate coefficients from 114 to 5 with only an 8.7% increase in MAE. These 5 cluster groups were closely associated with specific regions of the lung and likely with specific airway size groups. Comparing the HC group to a cystic fibrosis (CF) group we found only one cluster with significantly depressed MC rates in CF corresponding to the lower lobe. The inhalation of 7% hypertonic saline (HS) by the CF group increased MC rate in all clusters and decreased unclearable activity in 4/5 clusters. The computational model described provides detailed regional estimates of MC rate when applied to clearance imaging studies. If further informed, this model may provide a valuable tool for studying small airways obstructive disease and evaluating mucus clearance-enhancing therapies in the lung.

Rationale: Chronic obstructive pulmonary disease (COPD) is an increasing health problem in people with HIV (PWH), and mechanisms of HIV-associated COPD are poorly understood. Translocation of microbes or microbial products into the circulation because of increased mucosal permeability occurs in PWH, stimulates systemic inflammation and leads to end-organ damage. We and others found that fungal translocation, defined by 1,3-beta-D-glucan (BDG), occurs in PWH, and high systemic BDG levels correlate with circulating inflammatory mediators and worse lung function in PWH. This study investigates the relationship of fungal translocation, inflammation and pulmonary function in PWH. Methods: Sixty-one PWH in the study were from the Pittsburgh HIV Lung Cohort. Pulmonary function tests (PFTs) were performed on all participants. Lung permeability was measured using a two-probe nuclear imaging method. Twenty-six biomarker plasma levels of pulmonary, intestinal damage and microbial translocation (RAGE, I-FABP, REG3α, Zonulin, sCD14, BDG) and inflammation (CRP, cytokines, chemokines, MMPs) at baseline were measured by Luminex and ELISA assays. The correlation analyses among plasma biomarker levels, PFT measures (FEV1%-predicted, FVC%-predicted, FEV1/FVC ratio, DLCO%-predicted) and lung permeability were performed using Pearson and Spearman correlation. Results: 85% of participants were male, 48% were Caucasian and the mean age was 59 years. RAGE plasma levels were positively associated with REG3α, I-FABP, CCL2 and TNFR1 levels. I-FABP levels were positively correlated with RAGE, REG3α, IL-17A, TNFR1 and MMP7 levels. REG3α levels were positively associated with RAGE, I-FABP, IL-17A, sCD163, TNFR1 and MMP7 levels. Zonulin levels were positively correlated with CRP, CCL2, CXCL10, TNFSF10, MMP1 and MMP7 levels, and inversely correlated with FEV1%-predicted, FVC%-predicted, DLCO%-predicted. sCD14 levels were positively associated with REG3α, TNF-α, CCL2, CXCL10, sCD163, TNFR1and MMP7 levels. BDG and MMP1 levels were positively associated with lung permeability. Plasma levels of CCL17, MMP1, MMP7 and MMP12, and lung permeability were negatively associated with FEV1%-predicted, FVC%-predicted, FEV1/FVC ratio and DLCO%-predicted. Conclusions: The biomarker plasma levels of pulmonary and intestinal damage and microbial translocation are positively associated with systemic inflammatory markers and worse pulmonary function, suggesting that lung and gut damage leading to increased permeability and microbial translocation could contribute to development of pulmonary dysfunction through pulmonary and systemic inflammation in PWH.

Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment.

INTRODUCTION:The deposition of inhaled medications is the first step in the pulmonary pharmacokinetic process to produce a therapeutic response. Not only lung dose but more importantly the distribution of deposited drug in the different regions of the lung determines local bioavailability, efficacy, and clinical safety. Assessing aerosol deposition patterns has been the focus of intense research that combines the fields of physics, radiology, physiology, and biology. AREAS COVERED:The review covers the physics of aerosol transport in the lung, experimental, and in-silico modeling approaches to determine lung dose and aerosol deposition patterns, the effect of asthma, chronic obstructive pulmonary disease, and cystic fibrosis on aerosol deposition, and the clinical translation potential of determining aerosol deposition dose. EXPERT OPINION:Recent advances in in-silico modeling and lung imaging have enabled the development of realistic subject-specific aerosol deposition models, albeit mainly in health. Accurate modeling of lung disease still requires additional refinements in existing imaging and modeling approaches to better characterize disease heterogeneity in peripheral airways. Nevertheless, recent patient-centric innovation in inhaler device engineering and the incorporation of digital technology have led to more consistent lung deposition and improved targeting of the distal airways, which better serve the clinical needs of patients.

EDITORIAL article Front. Cell. Infect. Microbiol., 23 April 2024Sec. Biofilms Volume 14 - 2024 | https://doi.org/10.3389/fcimb.2024.1416131

The mucociliary clearance (MC) system is a vital host defense against infection in the lung. MC system function is dependent on ciliary density, structure, and function and airway surface liquid (ASL) composition and hydration. Animal and human studies indicate that MC rate decreases with age which may contribute to the increased rates of pulmonary infection experienced by older people. The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene encodes an anion channel on epithelial surfaces that plays a key role in maintaining ASL hydration. Failure or dysfunction of CFTR could result in the dehydration of airway mucus, depressing MC. Here we use two available databases including bulk (GTEx) and single-cell (CELLxGENE) sequencing data from the lung to determine if CFTR expression decreases with age. Bulk expression data and single-cell expression data from goblet, club, and respiratory basal cells all demonstrated patterns of decreasing CFTR expression with age. Ciliated airway cells did not. Secretory cells (including club and goblet cells) and basal cells are the largest source of CFTR expression in the airway. This indicates that changes in CFTR expression and ASL dehydration may contribute to the decreasing MC associated with aging.

BACKGROUND:The cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) is highly effective clinically for those with at least one F508del-CFTR allele. The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport. METHODS:Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment. RESULTS:Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modeled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G', G") were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed. CONCLUSIONS:E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.

Background: Inhaled drug delivery can be limited by heterogeneous dose distribution. An additive that would disperse drug over the internal surfaces of the lung after aerosol deposition could improve dosing uniformity and increase the treated area. Our previous studies demonstrated that surfactant additives can produce surface tension-driven (Marangoni) flows that effectively dispersed aerosol-delivered drugs over mucus surfaces. Here we sought to determine whether the addition of a surfactant would increase transport of an aerosol between lung regions and also improve dosing uniformity in human lungs. Methods: We compared the deposition and postdeposition dispersion of surfactant (10 mg/mL dipalmitoylphosphatidylcholine; DPPC) and saline-based liquid aerosols, admixed with Technetium 99m (Tc99m) diethylenetriaminepentaacetic acid, using gamma scintigraphy. Deposition images were obtained ex vivo in eight pairs of ventilated human lungs. The trachea was intubated and the mainstem bronchi were alternately clamped so that saline was delivered to one lung and then DPPC to the other (sides alternated). The lungs were continually imaged for 15 minutes during delivery. We assessed transport of the deposited aerosol by quantifying the percentage of Tc99m in each of four lung quadrants over time. We quantified dose uniformity within each lung quadrant by measuring the coefficient of variation (CV = standard deviation of the pixel associated radioactive counts/mean of the counts within each quadrant). Results: There was no change in the percentage of Tc99m in each quadrant over time, indicating no improvement in transport with the addition of the surfactant. The addition of surfactant was associated with a statistically significant decrease in CV in the lower inner lung quadrant at each of the three time points, indicating an improvement in dosing uniformity. Conclusion: These preliminary results indicate the possible utility of adding surfactant to aerosols to improve drug distribution uniformity to lower inner lung regions.

BackgroundHuman nasal epithelial (HNE) cells can be sampled noninvasively and cultured to provide a model of the airway epithelium that reflects cystic fibrosis (CF) pathophysiology. We hypothesised thatin vitromeasures of HNE cell physiology would correlate directly within vivomeasures of lung physiology and therapeutic response, providing a framework for using HNE cells for therapeutic development and precision medicine.MethodsWe sampled nasal cells from participants with CF (CF group, n=26), healthy controls (HC group, n=14) and single CF transmembrane conductance regulator (CFTR) mutation carrier parents of the CF group (CR group, n=16). Participants underwent lung physiology and sweat chloride testing, and nuclear imaging-based measurement of mucociliary clearance (MCC) and small-molecule absorption (ABS). CF participants completed a second imaging day that included hypertonic saline (HS) inhalation to assess therapeutic response in terms of MCC. HNE measurements included Ussing chamber electrophysiology, small-molecule and liquid absorption rates, and particle diffusion rates through the HNE airway surface liquid (ASL) measured using fluorescence recovery after photobleaching (FRAP).ResultsLong FRAP diffusion times were associated with increased MCC response to HS in CF. This implies a strong relationship between inherent factors affecting ASL mucin concentration and therapeutic response to a hydrating therapy. MCC decreased with age in the CR group, which had a larger range of ages than the other two groups. Likely this indicates a general age-related effect that may be accentuated in this group. Measures of lung ABS correlated with sweat chloride in both the HC and CF groups, indicating that CFTR function drives this measure of paracellular small-molecule probe absorption.ConclusionsOur results demonstrate the utility of HNE cultures for assessing therapeutic response for hydrating therapies.In vitromeasurements of FRAP were particularly useful for predicting response and for characterising important properties of ASL mucus that were ultimately reflected in lung physiology.

Pilot Study of Nuclear Scintigraphy To Assess Cough Clearance in DMDTo the Editor:Respiratory muscle weakness as a consequence of neuromuscular disease results in ineffective cough, atelectasis, and pneumonia. Augmented airway clearance treatments such as mechanical in-exsufflation and high frequency chest compression have been shown to decrease morbidity and mortality in children with neuromuscular disease, although the evidence supporting these therapies in clearance of airway secretions is indirect.We sought to pilot the use of nuclear imaging of the clearance of pulmonary secretions before and after voluntary coughing and airway clearance treatment to explore the role of measures of pulmonary function to predict airway clearance. This technique has been used for some time in patients with cystic fibrosis but has not been applied to patients with neuromuscular disease or to assess the utility of airway clearance devices. To this end, we recruited 7 outpatient subjects (7.8-21 years of age) with Duchenne Muscular Dystrophy when clinically well and categorized as “Early Ambulatory” (requiring minimal assistive devices, n=4); “Early Non-ambulatory” (using wheelchair some of time, n=2); and “Late Non-Ambulatory” (always using wheelchair, n=1). This study was approved by local Institutional Review Board.Spirometry was performed according to ATS specifications and normalized using Global Lung Initiative equations. Peak cough flow was measured from total lung capacity (TLC) and data was normalized with previously published equations[1]. Maximal inspiratory pressure (MIP) and maximal expiratory pressure (MEP) were measured at the mouth using a hand-held pressure manometer and maximal pressure from FRC was also be measured at the nares (SNIP) during a sniff maneuver[2] using a small nasal occluder and handheld transducer Maximal static pressures and SNIP pressures were normalized using previously published data.For imaging of mucus clearance, 4 mCi of Technetium [Tc-99m] sulfur-colloid particles in 2 ml of normal saline were delivered by nebulizer using a defined breathing pattern for 2 minutes [3]. During continuous imaging, subjects were asked to voluntarily cough every 10 seconds for 1 minute using guidance from a metronome, and this sequence was repeated 3 times. The subject then received an airway clearance treatment for 30 minutes using a high frequency chest compression device with pressure adjusted between 80-100% of maximum, and compression frequencies cycled between 5Hz-15Hz. The device was paused every 10 minutes at which time the patient was asked to cough every 10 seconds over 1 minute.Image analysis was performed according to previously published methods. Measurements of radioactivity in the right lung were corrected for background and radioactive decay and normalized by starting radioactive counts. A single retention curve was generated from the initial cough clearance period and the period during which the high frequency chest compression device was operated. Cough clearance (CC) represents the percent of total deposited radioactivity cleared during the associated period. We designated the percentage cleared by 18 voluntary coughs over 3 minutes as CCvol, and the percentage cleared during three 10 min periods of HFCC and 18 voluntary coughs over 3 minutes as CCHFCC. CCvol and CCHFCCwere correlated with physiologic measures including peak cough flow (PCF), MIP/MEP, and SNIP using Spearman’s correlation.Pulmonary function was overall well preserved (FVC 92% ± 35%). Respiratory muscle strength (in cmH2O) decreased with disease severity (e.g. MIP EA 73.5 ± 26, ENA 62.5 ± 14.8, LNA 47). Peak cough flow (% predicted) decreased with severity (EA 94±11, ENA 79±9, LNA 46). Complete details are provided in the online supplement.Representative imaging of two subjects is shown (Figure 1). Significant intra-subject differences were seen in clearance with voluntary cough and with cough augmented with HFCC vest (Figure 2). Voluntary cough was responsible for 46-96% of the total clearance and HFCC-augmented clearance for 3-53% of total clearance. For most patients, the kinetics of clearance with HFCC-augmented cough did not appear very different than for voluntary cough.Statistical comparisons between disease stages were hampered by the small sample size in each group. Nonetheless, while there appeared to be a trend for decreasing CCvol with stage of disease (Figure 2), age, and PCF, we found no statistically significant correlations between voluntary cough clearance and measures of pulmonary function (FVC, r=0.39), respiratory muscle strength (PCF, r=-0.63; SNIP r=-0.12, MIP r=0.43, MEP r=0.29), age (r=-0.57), height (r=-0.49), weight (r=-0.37). Additionally, we did not find statistically significant correlations between augmented cough clearance and measures of pulmonary function (FVC, r=0.40), respiratory muscle strength (PCF, r=-0.08; SNIP r=-.02, MIP r=-0.07, MEP r=0.05), age (r=-0.39), height (r=-0.75), weight (r=-0.03).This study is the first we are aware of to directly examine cough clearance of secretions using nuclear scintigraphy in patients with DMD. Importantly, the measurements were well tolerated by subjects. We did not find a relationship between CPF, respiratory muscle strength, or spirometry and voluntary cough clearance. However, these results must be qualified based on the small number of enrolled subjects. We do note that many of the patients had good cough clearance. Additionally, HFCC did not consistently alter the rate of secretion clearance above noted with voluntary cough.While Bach et al[4] showed that PCF >160 L/min was a predictor of successful tracheal decannulation in adults with neuromuscular disease, Airen et al[5] found that the majority of healthy children <13 years old generated PCFs < 270 l/min despite having the ability to generate MEP > 60 cmH2O. This suggests that PCF may change with age and that an absolute threshold cannot be used across the age span. There are no studies specifically examining use of HFCC in patients with DMD. As patients with DMD are expected to have impairment in cough, mechanical in-exsufflation would be expected to assist with airway clearance by replacing the function of weak respiratory muscles in a way that HFCC does not. Lechtzin et al[6] showed that in adults with neuromuscular diseases, HFCC decreased inpatient costs and costs for treating pneumonia compared to the year prior to initiating HFCC. Measures of pulmonary function, including PCF, were not assessed. It would be of interest to examine secretion removal with in-exsufflation using this nuclear imaging method.While we were not able to demonstrate a relationship between cough clearance and measures of respiratory muscle strength, peak cough flow, or FVC, it is possible that this relationship exists and would be demonstrated in a larger population. However, the longstanding assumption that PCF is a reliable indicator of need for airway clearance, especially in children, is not supported by these data. The biggest limitation of our pilot study is the small sample size. We suspect enrollment was limited due to preference for interventional studies. Another limitation is that for our population, the impairment of respiratory muscle strength was mild for most subjects. Additional subjects with more advanced weakness may have helped clarify the relationship between respiratory muscle strength and airway clearance. Finally, there can be day-to-day variations of clearance.There are now a number of airway clearance technologies being proposed for patients with neuromuscular and airway diseases (e.g. cystic fibrosis, ciliary dyskinesia). These include high frequency chest compression vests, battery-powered vests, in-exsufflation devices (with or without oscillation), intrapulmonary percussive ventilation devices, and handheld oscillating positive expiratory pressure devices. We propose that the imaging methodology used in this study could be utilized to compare these different techniques, some of which are costly and with limited or no comparison data. In addition, there are patients that will be unable to cooperate with pulmonary function measurements and an imaging assessment of airway clearance may be useful to determine optimal strategies.In conclusion, we demonstrated that use of nuclear scintigraphy is a feasible technique to examine airway clearance for patients with respiratory muscle weakness, as it has been used for patients with cystic fibrosis. Additional studies will be needed to further examine the relationship between pulmonary function measures and secretion removal.Daniel J. Weiner MD1,Hoda Abdel Hamid MD2,Timothy E. Corcoran PhD3Divisions of Pediatric Pulmonology1 and Neurology2, Department of PediatricsUPMC Children’s Hospital of PittsburghDivision of Pulmonary, Allergy and Critical Care Medicine3, Department of MedicineUniversity of Pittsburgh School of Medicine

The efficient generation of high concentrations of fine-particle, pure surfactant aerosols provides the possibility of new, rapid, and effective treatment modalities for Acute Respiratory Distress Syndrome (ARDS). SUPRAER-CATM is a patented technology by Kaer BiotherapeuticsTM, which is a new class of efficient aerosol drug generation and delivery system using Compressor Air (CA). SUPRAER-CA is capable of aerosolizing relatively viscous solutions or suspensions of proteins and surfactants and of delivering them as pure fine particle dry aerosols. In this Computational Fluid Dynamics (CFD) study, we select a number of sites within the upper 17 generations of the human respiratory tract for calculation of the deposition of dry pulmonary surfactant aerosol particles. We predict the percentage of inhaled dry pulmonary surfactant aerosol arriving from the respiratory bronchioles to the terminal alveolar sacs. The dry pulmonary surfactant aerosols, with a Mass Median Aerodynamic Diameter (MMAD) of 2.6 µm and standard deviation of 1.9 µm, are injected into the respiratory tract at a dry surfactant aerosol flow rate of 163 mg/min to be used in the CFD study at an air inhalation flow rate of 44 L/min. This CFD study in the upper 17th generation of a male adult lung has shown computationally that the penetration fraction (PF) is approximately 25% for the inhaled surfactant aerosols. In conclusion, an ARDS patient might receive approximately one gram of inspired dry surfactant aerosol during an administration period of one hour as a possible means of further inflating partly collapsed alveoli.

CFTR function is required for normal mucociliary clearance (MCC) and cough-assisted clearance (CC). Lumacaftor-ivacaftor is approved for use in people with cystic fibrosis (CF) carrying two copies of F508del-CFTR. In this observational study performed at four study sites, we characterized the effect of lumacaftor-ivacaftor on mucociliary and cough clearance and related this to other clinical and research endpoints after one month of treatment. Twenty-five adolescents and adults were enrolled. No effect on whole lung MCC was observed, but CC was significantly increased. Sweat chloride improved by 18 mEq/L in this group, indicating a modest restoration of CFTR activity, but no demonstrable change in FEV1 or lung clearance index was observed. We speculate that the modest effect of lumacaftor-ivacaftor on CFTR function was insufficient to yield an improvement in MCC.

HYPOTHESIS:Aerosols are generated during mastoidectomy and mitigation strategies may effectively reduce aerosol spread.BACKGROUND:An objective understanding of aerosol generation and the effectiveness of mitigation strategies can inform interventions to reduce aerosol risk from mastoidectomy and other open surgeries involving drilling.METHODS:Cadaveric and fluorescent three-dimensional printed temporal bone models were drilled under variable conditions and mitigation methods. Aerosol production was measured with a cascade impactor set to detect particle sizes under 14.1 μm. Field contamination was determined with examination under UV light.RESULTS:Drilling of cadaveric bones and three-dimensional models resulted in strongly positive aerosol production, measuring positive in all eight impactor stages for the cadaver trials. This occurred regardless of using coarse or cutting burs, irrigation, a handheld suction, or an additional parked suction. The only mitigation factor that led to a completely negative aerosol result in all eight stages was placing an additional microscope drape to surround the field. Bone dust was scattered in all directions from the drill, including on the microscope, the surgeon, and visually suspended in the air for all but the drape trial.CONCLUSIONS:Aerosols are generated with drilling the mastoid. Using an additional microscope drape to cover the surgical field was an effective mitigation strategy to prevent fine aerosol dispersion while drilling.

Background: Infants undergoing congenital cardiac surgery with cardiopulmonary bypass are at high risk for respiratory complications. As impaired airway mucociliary clearance (MCC) can potentially contribute to pulmonary morbidity, our study objective was to measure airway clearance in infants undergoing congenital cardiac surgery and examine correlation with clinical covariables that may impair airway clearance function.Materials and Methods: Airway clearance in infants was measured over 30 min using inhaled nebulized Technetium 99m sulfur colloid administered either via a nasal cannula or the endotracheal tube in intubated infants. This was conducted bedside with a portable gamma camera. No difficulty was encountered in positioning the gamma camera over the patient, and neither the camera nor the MCC scan interfered with routine medical care or caused any adverse events. Patient and perioperative variables were examined relative to the MCC measurements.Results: We prospectively enrolled 57 infants undergoing congenital cardiac surgery and conducted a single MCC scan per patient. MCC data from 42 patients were analyzable, including five pre-operative, 15 (40.5%) in the immediate post-operative period (days 1–2), and 22 (59.5%) were later post-operative (≥3 days). Pre-operative MCC was inversely proportional to days requiring post-operative mechanical ventilation (p = 0.006) and non-invasive positive pressure ventilation (p = 0.017). MCC was higher at later post-operative days (p = 0.002) with immediate post-operative MCC being lower (3%; 0–13%) than either pre-operative (21%; 4–25%) (p = 0.091) or later post-operative MCC (18%; 0–29%) (p = 0.054). Among the infants with low post-operative MCC, significantly more were pre-mature [5/19 (26%) vs. 0/18 (0%); p = 0.046], were intubated [14/19 (75%) vs. only 7/18 (39%); p = 0.033] and were receiving higher FiO2 (40%, 27–47% vs. 26%, 21–37%; p = 0.015).Conclusions: This is the first study to show that infants undergoing congenital cardiac surgery have impaired MCC. MCC appeared lowest in the immediate post-operative period. Worse MCC was associated with pre-maturity, mechanical ventilation, or receiving higher FiO2. These findings suggest MCC scans should be further explored for informing clinical decision making to improve post-surgical respiratory outcomes. The possible therapeutic benefit of airway clearance maneuvers for infants with poor MCC function should also be investigated.