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Background: Cardiac asthma describes symptoms of airflow obstruction due to heart failure. Chronic heart failure is associated with decreased FEV 1 , and FEV 1 improves after heart transplantation. Fibrotic remodeling of the heart and airways is mediated, in part, through transforming growth factor (TGF)- β . Blood TGF- b 1 concentration correlates with ventricular remodeling in cardiac disease, and TGF- β decreases after repair.Methods: We established a coculture of normal human bronchial epithelial (NHBE) cells differentiated at air-liquid interface with submerged basal cardiomyoblasts. Airway cells were immunostained with cytokeratin, actin, and involucrin. TGF- β synthesis was assayed using enzyme-linked immunosorbent assay. Phosphorylation of Smad in NHBE cells was determined by Western blotting.Mice given doxorubicin developed cardiac failure, and their airways were histologically examined.Results: Coculture induced involucrin-positive squamous metaplasia of NHBE cells, and this was attenuated by TGF- β antibody. Total TGF- β 1 was increased in coculture conditioned medium( P < .001). After 14 days of exposure to recombinant TGF- β 1 , there was squamous transformation of NHBE cells. One week after removing cardiomyoblasts from culture, squamous metaplasia resolved into normal ciliated epithelia. Smad was phosphorylated in NHBE cells with cardiomyoblasts or with recombinant TGF- β 1 exposure. The airways of mice with heart failure also demonstrated involucrin-positive squamous transformation.Conclusions: TGF- β from cardiomyoblasts or from the failing heart can cause airway squamous metaplasia via Smad signaling, and this is blocked by anti-TGF- b antibody and reversed when cardiac cells are removed from culture. This appears to be an important mechanism for airflow obstruction with heart failure, sometimes described as cardiac asthma. [ABSTRACT FROM AUTHOR]

Background: IL-8 is an important activator and chemoattractant for neutrophils that is produced by normal human bronchial epithelial (NHBE) cells through mitogen-activated protein kinase (MAPK) and nuclear factor-κB (NF-κB) p65 pathways. Dapsone, a synthetic sulfone, is widely used to treat chronic neutrophil dermatoses. We investigated the effects of dapsone on polarized IL-8 secretion from lipopolysaccharide (LPS)-stimulated NHBE cells and further evaluated its ability to decrease LPS-induced inflammation in the ferret airway.Methods: NHBE cells were grown at air-liquid interface (ALI) to ciliated differentiation. Baseline and endotoxin (LPS)-stimulated IL-8 secretion was measured by enzyme-linked immunosorbent assay at air and basal sides with and without dapsone. Western blotting was used to determine signaling pathways. In vivo, ferrets were exposed to intratracheal LPS over a period of 5 days. Once inflammation was established, oral or nebulized dapsone was administered for 5 days. Intraepithelial neutrophil accumulation was analyzed histologically, and mucociliary transport was measured on the excised trachea.Results: Dapsone, 1 μg/mL, did not influence unstimulated (basal) IL-8 secretion. Apical LPS stimulation induced both apical and basolateral IL-8, but basolateral LPS increased only basolateral IL-8. Dapsone inhibited polarized IL-8 secretion from ALI-conditioned cells. Dapsone also decreased LPS-induced IL-8 mRNA level. LPS led to phosphorylation of extracellular signal-regulated kinase 1/2, but not p38 MAPK or c-Jun NH(2)-terminal kinase. LPS also induced NF-κB p65 phosphorylation, an effect that was inhibited by dapsone. Both oral and aerosol dapsone decreased LPS-induced intraepithelial neutrophil accumulation, but only treatment with aerosol dapsone restored mucociliary transport to normal.Conclusions: Dapsone, given either systemically or as an aerosol, may be useful in treating neutrophilic airway inflammation. [ABSTRACT FROM AUTHOR]

Rationale: We identified a 6-year-old girl with pulmonary alveolar proteinosis (PAP), impaired granulocyte-macrophage colony-stimulating factor (GM-CSF) receptor function, and increased GM-CSF.Objectives: Increased serum GM-CSF may be useful to identify individuals with PAP caused by GM-CSF receptor dysfunction.Methods: We screened 187 patients referred to us for measurement of GM-CSF autoantibodies to diagnose autoimmune PAP. Five were children with PAP and increased serum GM-CSF but without GM-CSF autoantibodies or any disease causing secondary PAP; all were studied with family members, subsequently identified patients, and controls.Measurement and Main Results: Eight children (seven female, one male) were identified with PAP caused by recessive CSF2RA mutations. Six presented with progressive dyspnea of insidious onset at 4.8 ± 1.6 years and two were asymptomatic at ages 5 and 8 years. Radiologic and histopathologic manifestations were similar to those of autoimmune PAP. Molecular analysis demonstrated that GM-CSF signaling was absent in six and severely reduced in two patients. The GM-CSF receptor β chain was detected in all patients, whereas the α chain was absent in six and abnormal in two, paralleling the GM-CSF signaling defects. Genetic analysis revealed multiple distinct CSF2RA abnormalities, including missense, duplication, frameshift, and nonsense mutations; exon and gene deletion; and cryptic alternative splicing. All symptomatic patients responded well to whole-lung lavage therapy.Conclusions: CSF2RA mutations cause a genetic form of PAP presenting as insidious, progressive dyspnea in children that can be diagnosed by a combination of characteristic radiologic findings and blood tests and treated successfully by whole-lung lavage. [ABSTRACT FROM AUTHOR]

This paper reviews the history of aerosol therapy; discusses patient, drug, and device factors that can influence the success of aerosol therapy; and identifies trends that will drive the science of aerosol therapy in the future. Aerosol medication is generally less expensive, works more rapidly, and produces fewer side effects than the same drug given systemically. Aerosol therapy has been used for thousands of years by steaming and burning plant material. In the 50 years since the invention of the pressurized metered-dose inhaler, advances in drugs and devices have made aerosols the most commonly used way to deliver therapy for asthma and COPD. The requirements for aerosol therapy depend on the target site of action and the underlying disease. Medication to treat airways disease should deposit on the conducting airways. Effective deposition of airway particles generally requires particle size between 0.5 and 5 mum mass median aerodynamic diameter; however, a smaller particle size neither equates to greater side effects nor greater effectiveness. However, medications like peptides intended for systemic absorption, need to deposit on the alveolar capillary bed. Thus ultrafine particles, a slow inhalation, and relatively normal airways that do not hinder aerosol penetration will optimize systemic delivery. Aerosolized antimicrobials are often used for the treatment of cystic fibrosis or bronchiectasis, and mucoactive agents to promote mucus clearance have been delivered by aerosol. As technology improves, a greater variety of novel medications are being developed for aerosol delivery, including for therapy of pulmonary hypertension, as vaccines, for decreasing dyspnea, to treat airway inflammation, for migraine headache, for nicotine and drug addiction, and ultimately for gene therapy. Common reasons for therapeutic failure of aerosol medications include the use of inactive or depleted medications, inappropriate use of the aerosol device, and, most importantly, poor adherence to prescribed therapy. The respiratory therapist plays a key role in patient education, device selection, and outcomes assessment. [ABSTRACT FROM AUTHOR]

BACKGROUND: Cystic fibrosis (CF) patients commonly use a high-frequency chest-wall compression (HFCWC) device for airway clearance that generates oscillatory flow with a sine-wave configuration. Typical HFCWC settings combine a lower Vest inflation pressure setting (eg, 5 on the Vest's arbitrary 1-10 scale for the setting that controls the background pressure of the inflatable vest) with mid-range frequency (14-16 Hz) (lower-pressure/mid-frequency HFCWC). OBJECTIVE: To determine whether HFCWC with higher pressure settings (6-10 on the Hill-Rom Vest's arbitrary 1-10 scale) combined with variable mid-frequencies (8, 9, and 10 Hz, plus 18, 19, and 20 Hz) (higher-pressure/variable-frequency HFCWC) results in greater sputum expectoration than lower-pressure/mid-frequency HFCWC. METHODS: This was a controlled randomized crossover study. Sixteen clinically stable, adult CF patients participated. Patients performed airway clearance with HFCWC, once each with lower-pressure/mid-frequency HFCWC and higher-pressure/variable-frequency HFCWC, on separate occasions. All sputum produced during each session was collected. Patients completed pulmonary function tests before and after each session. RESULTS: Median sputum wet weight was greater with higher-pressure/variable-frequency HFCWC than with lower-pressure/mid-frequency HFCWC (6.4 g, range 0.49 -22.0 g, versus 4.8 g, range 0.24- 15.0 g, P = .02). Dry sputum weight differences did not reach statistical significance (higherpressure/variable-frequency HFCWC 0.20 g, range 0.009-0.62 g, lower-pressure/mid-frequency HFCWC 0.12 g, range 0.0001-1.0 g, P = .23). Higher-pressure/variable-frequency HFCWC and lower-pressure/mid-frequency HFCWC resulted in similar increases in FEV1 (70 mL vs 90 mL, P =.21) and forced vital capacity (80 mL vs 80 mL, P = .94). Post-therapy sputum viscoelastic properties did not differ. Patients perceived the 2 regimens as equally comfortable and effective (P = .35 and P= .35, respectively). CONCLUSIONS: In adult CF patients, single-session higherpressure/variable-frequency HFCWC resulted in greater sputum expectoration by wet weight, but not other differences, compared to the commonly used lower-pressure/mid-frequency settings. Longer-term comparisons are needed in a larger, more diverse population to determine whether sustained use of the higher-pressure/variable-frequency settings results in clinically important differences in outcomes. (Clinicaltrials.gov registration NCT00685035). [ABSTRACT FROM AUTHOR]

Rationale: Cystic fibrosis (CF) is believed to be associated with mucus hypersecretion; thus, the principal airway gel-forming mucins, MUC5AC and MUC5B, are also expected to be increased relative to non-CF secretions. However, we have shown that these mucins are decreased during stable CF disease. Objectives: In this study, we determine if these mucins increase during a pulmonary exacerbation of CF. Methods: Expectorated sputum was collected from 11 adults with CF during stable disease and then during a pulmonary exacerbation and from 12 healthy control subjects. MUC5AC and MUC5B proteins were measured by Western blot. DNA content was measured using microfluorimetry. Results: MUC5AC protein increased by 908% and MUC5B by 59% (p < 0.05 for both) during an exacerbation compared with periods of stable disease. During stable disease, the vol/vol quantity of MUC5AC protein was 89% less than normal mucus, and the mucin-associated sugars, measured using a lectin binding assay, were 46% less compared with normal mucus. The concentration of DNA in CF sputum did not increase during an exacerbation. Conclusions: During a CF exacerbation, concentration of secreted mucin increased to the amount found in mucus from normal subjects, suggesting that the capacity to secrete mucin in response to an infection or inflammatory stimulus is preserved in CF airways. This might help to protect the airway from injury. [ABSTRACT FROM AUTHOR]

INTRODUCTION: Tracheal suction catheters (TSCs) are used to clear mucus from an endotracheal tube (ETT). The clearance rate is critical because airway mucus stasis leads to obstruction, but prolonged catheter suctioning can lead to hypoxemia. The rate of mucus clearance from an ETT is thought to be influenced by the properties of the mucus, the pressure used to suction the mucus, and the diameter of the catheter. In this study, different adult TSCs were evaluated for their ability to suction mucus simulants that had properties similar to airway mucus. METHODS: Six different 14F TSC designs were evaluated. All catheters had the same end hole size, but the two side holes were sized at 3 mm, 4 mm, or 5 mm. A coagulant (Polyox Water Soluble Resin Coagulant NF; Dow Chemical Company; Cary, NC) was mixed with water at concentrations of 0.5%, 1.5%, and 3.0% to simulate mucus or sputum. Suction effectiveness was evaluated by the mass percentage of the coagulant suctioned over 10 s at 100 mm Hg from an 8.0 ETT. MEASUREMENTS AND RESULTS: The 1.5% and 3.0% simulants had properties comparable to human airway mucus and sputum. Suction effectiveness was less with the 3.0% coagulant simulant compared with the 1.5% and 0.5% simulants. Suction effectiveness was greater (p < 0.01) with TSCs that had nonparallel holes and a side hole diameter of 5 mm when tested with the 1.5% and 3.0% simulants. However, no best catheter could be identified among TSCs when tested with the more liquid-like 0.5% simulant. CONCLUSIONS: Greater TSC side hole diameter and nonparallel positioning was important for suctioning mucus simulants that are similar to mucus or sputum. The distance between side holes, end hole size, suction force, and duration of suctioning were not tested but could also have an effect on TSC performance. [ABSTRACT FROM AUTHOR]

Transforming growth factor (TGF) beta plays an important role in normal pulmonary morphogenesis and function and in the pathogenesis of lung disease. The effect of TGFbeta is regulated via a selective pathway of TGFbeta synthesis and signaling that involves activation of latent TGFbeta, specific TGFbeta receptors, and intracellular signaling via Smad molecules. All three isoforms of TGFbeta are expressed at high levels during normal lung development, being particularly important for branching morphogenesis and epithelial cell differentiation with maturation of surfactant synthesis. Small amounts of TGFbeta are still present in the adult lung, and TGFbeta is involved in normal tissue repair following lung injury. However, in a variety of forms of pulmonary pathology, the expression of TGFbeta is increased. These include chronic lung disease of prematurity as well as several forms of acute and chronic adult lung disease. While TGFbeta1 appears to be the predominant isoform involved, elevated levels of all three isoforms have been demonstrated. The increase in TGFbeta precedes abnormalities in lung function and detectable lung pathology, but correlates with the severity of the disease. TGFbeta plays a key role in mediating fibrotic tissue remodeling by increasing the production and decreasing the degradation of connective tissue via several mechanisms. [ABSTRACT FROM AUTHOR]

The use of troleandomycin as adjunctive therapy for the treatment of patients with corticosteroid-dependent asthma first suggested an immunomodulatory effect of the macrolide antibiotics. This led to studies of the macrolides in other chronic airway diseases, such as diffuse panbronchiolitis (DPB), a disease occurring primarily in East Asia. The use of macrolides for the therapy of patients with DPB has led to dramatic improvements in pulmonary function and prolonged survival. Similar benefits have been documented in Japanese studies of bronchiectasis, chronic bronchitis, and sinobronchial syndrome. Clinical and pathologic similarities between DPB and cystic fibrosis (CF) led to the investigation of macrolides for the treatment of CF. Data now suggest that persons with CF will benefit from macrolide therapy. In vitro and in vivo studies suggest that macrolides may inhibit the pulmonary influx of neutrophils, inhibit the release of proinflammatory cytokines, protect the epithelium from bioactive phospholipids, and improve the transportability of airway secretions. The immunomodulatory effects of the macrolides also may be beneficial for the treatment of other chronic inflammatory conditions. [ABSTRACT FROM AUTHOR]

Background: Allergic rhinitis (AR) and acute non-allergic rhinosinusitis (ARS) often present with similar symptoms. While these are generally differentiated by history and occasionally by secretion cell counts, there are few data temporally comparing these conditions., Methods: A prospective, observational study was conducted to assess nasal mucus properties, nasal obstruction, nasal secretion cells, and health related QOL during the acute phase (Day 5) and during a later phase of illness (Day 14/28). We screened 280 patients and enrolled 42 subjects (ARS, n = 34; and AR, n = 8) who were otherwise healthy and met eligibility criteria. Nasal secretions for cell count and rheology, and acoustic rhinometry were measured on days 5 and 14 of symptoms. SNOT-20 was administered on Day 5, 14, 10 and 28., Results: In subjects with ARS, there was significantly improved SNOT-20 and major symptom score at day 28 in association with increased nasal cavity volume by acoustic rhinometry and decreased mast cells; all consistent with improvement. However, in subjects with AR there was no symptomatic improvement or change in nasal volume and although there were fewer mast cells and epithelial cells, there was no decrease in the number of eosinophils, neutrophils, or goblet cells in secretions. There was no change in in vitro secretion mucociliary clearability in either group, although values were normal at baseline., Conclusions: These results suggest that nasal symptoms in ARS are improved over 14-28 days with the reduction of mast cells, and increased nasal volume, while in AR, symptoms persist., Competing Interests: Declaration of competing interest There are no conflicts of interest associated with this publication., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Pulmonary drug delivery is complex due to several challenges including disease-, patient-, and clinicians-related factors. Although many inhaled medications are available in aerosol medicine, delivering aerosolized medications to patients requires effective disease management. There is a large gap in the knowledge of clinicians who select and provide instructions for the correct use of aerosol devices. Since improper device selection, incorrect inhaler technique, and poor patient adherence to prescribed medications may result in inadequate disease control, individualized aerosol medicine is essential for effective disease management and control. The components of individualized aerosol medicine include: (1) Selecting the right device, (2) Selecting the right interface, (3) Educating the patient effectively, and (4) Increasing patient adherence to therapy. This paper reviews each of these components and provides recommendations to integrate the device and interface into the patient for better clinical outcomes., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: AA received a research grant from the CHEST Foundation and a speaking fee from the American Association for Respiratory Care, and Aerogen Ltd. JF is Chief Science Officer for Aerogen Pharma Corp. BR consults for Boehringer Ingelheim, Regenerx, and EpiEndo. Other authors have no conflicts of interest to disclose., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Cough medicines have been in use for over a century to treat the common and troublesome, but often helpful, symptoms of cough in children. They contain various combinations of "anti-tussive" drugs including opioids, antihistamines, herbal preparations, mucolytics, decongestants and expectorants. Whilst theoretically attractive for symptom relief when children are suffering, as time has passed these popular over the counter medicines have been shown to lack efficacy, delay more serious underlying diagnoses, and can cause complications and sometimes death. This has resulted in clinician concerns, a citizen petition to the American Food and Drug Association in 2007, some self-regulation from manufacturers and escalating restrictions on their use from regulatory agencies across the world over the last twenty years. This article will review the protective role of cough, juxtapose the conflicting treatment goals of suppressing a dry cough and promoting expectoration for a wet cough, consider the evidence basis for prescribing cough medicines in comparison to other more specific treatments such as for asthma [beta agonists] or infection [antibiotics], regulatory interventions, and conclude with the view that over counter cough medicines should not be used in children, especially young children., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Both nasal obstruction and sleep disturbance are common in patients with cystic fibrosis (CF). In patients with obstructive sleep apnea (OSA), studies suggest that these conditions are related and that nasal congestion improves with CPAP therapy. We hypothesized that subjects admitted to hospital for therapy of an exacerbation of CF would have both nasal symptoms and sleep disturbance and that these would improve with the initiation of nocturnal high-flow nasal cannula therapy (HFNC)., Methods: Twenty-five subjects with an exacerbation of CF were enrolled to randomly receive either 5 d of nocturnal HFNC at 20 L/min in the treatment group or 5 L/min of nocturnal nasal cannula air at ambient temperature and humidity in the low-flow group. On the first and last day of the study, the Sino-Nasal Outcome Test (SNOT-20) was administered to evaluate nasal symptoms, and sleep quality was measured using the Actiwatch 2., Results: Fifteen subjects completed the study (6 HFNC, 9 low flow). We confirmed that subjects had significant sleep disturbance that did not improve over the 5 d of the study. Subjects also had disturbing nasal symptoms that significantly improved only in those receiving HFNC (pre 14 [20] vs post 6 [13], P = .027)., Conclusions: Similar to what has been reported in older subjects with OSA, nocturnal HFNC improves sinonasal symptoms in subjects with an exacerbation of CF. There was no measurable effect on sleep quality, which may be due to the short duration of the study, or to subjects being evaluated while being treated in a hospital setting., Competing Interests: Dr Davis is funded by NIH/NHLBI PO1 HL128192 and the Indiana CTSI UL 1 TR002529. Dr Davis is a patent holder of Optate. Dr Davis discloses a relationship with Airbase Breathing Company. The remaining authors have disclosed no conflicts of interest., (Copyright © 2023 by Daedalus Enterprises.)

Viral bronchiolitis, which is most commonly caused by an infection with the respiratory syncytial virus (RSV), can lead to respiratory difficulties in young children which may require hospitalization. Despite years of research and medical trials, the mainstay of bronchiolitis treatment remains supportive only. This review provides an overview of the history of different treatments for bronchiolitis, including those that failed, as well as new therapies that are under study. Future studies for the treatment of bronchiolitis should consider different age-groups, important subgroups (i.e., those with a prior history of wheezing, those with a family history of asthma and those with non-RSV viral etiologies) whose response to treatment may differ from that of the composite group., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: MSS: Participates on the speaker’s bureau for Sanofi Pasteur. BKR, RSNL: No conflicts of interest related to this manuscript to declare., (Copyright © 2022. Published by Elsevier Ltd.)

Although pressurized metered dose inhaler (pMDI) education is a routine part of childhood asthma management and encouraging 'optimal breathing patterns' (i.e. slowly, deeply, completely, and with a mouth seal on the mouthpiece) is an integral part of recommended pMDI education, there is currently no quantifiable way to determine if a child is inhaling their medication correctly or optimally through a valved holding chamber (VHC). The TipsHaler™ (tVHC) is a prototype VHC device that measures inspiratory time, flow, and volume without changing the properties of the medication aerosol. The measurements in vivo recorded by the tVHC can be downloaded and transferred to a spontaneous breathing lung model to simulate the inhalational patterns in vitro and also determine the deposition of inhaled aerosol mass with each pattern. We hypothesized that pediatric patients' inhalational patterns when using a pMDI would improve after active coaching via tVHC. This would increase the pulmonary deposition of inhaled aerosols in an in vitro model. To test this hypothesis, we conducted a single-site, prospective, pilot, pre-and-post intervention study paired with a bedside-to-bench experiment. Healthy, inhaler-naïve subjects used a placebo inhaler in conjunction with the tVHC before and after coaching and recorded inspiratory parameters. These recordings were then implemented into a spontaneous breathing lung model during albuterol MDI delivery, and pulmonary deposition of albuterol was quantified. In this pilot study, active coaching resulted in a statistically significant increase in inspiratory time ( n = 8, p = 0.0344, 95%CI: 0.082 to ∞). tVHC recorded inspiratory parameters obtained from patients were successfully implemented in the in vitro model, which demonstrated that both inspiratory time ( n = 8, r = 0.78, p < 0.001, 95%CI: 0.47-0.92) and volume ( n = 8, r = 0.58, p = 0.0186, 95%CI: 0.15-0.85) strongly correlate with pulmonary deposition of inhaled drugs., (© 2023 IOP Publishing Ltd.)

Airway mucus is a complex viscoelastic gel that provides a defensive physical barrier and shields the airway epithelium by trapping inhaled foreign pathogens and facilitating their removal via mucociliary clearance (MCC). In patients with respiratory diseases, such as chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), non-CF bronchiectasis, and asthma, an increase in crosslinking and physical entanglement of mucin polymers as well as mucus dehydration often alters and typically reduces mucus mesh network pore size, which reduces neutrophil migration, decreases pathogen capture, sustains bacterial infection, and accelerates lung function decline. Conventional aerosol particles containing hydrophobic drugs are rapidly captured and removed by MCC. Therefore, it is critical to design aerosol delivery systems with the appropriate size and surface chemistry that can improve drug retention and absorption with the goal of increased efficacy. Biodegradable muco-adhesive particles (MAPs) and muco-penetrating particles (MPPs) have been engineered to achieve effective pulmonary delivery and extend drug residence time in the lungs. MAPs can be used to target mucus as they get trapped in airway mucus by steric obstruction and/or adhesion. MPPs avoid muco-adhesion and are designed to have a particle size smaller than the mucus network, enhancing lung retention of particles as well as transport to the respiratory epithelial layer and drug absorption. In this review, we aim to provide insight into the composition of airway mucus, rheological characteristics of airway mucus in healthy and diseased subjects, the most recent techniques to study the flow dynamics and particle diffusion in airway mucus (in particular, multiple particle tracking, MPT), and the advancements in engineering MPPs that have contributed to improved airway mucus penetration, lung distribution, and retention., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: The EEG aerosol technologies described in this publication have been filed as patent applications through Virginia Commonwealth University (VCU). Michael Hindle and Worth Longest are the co-inventors, which are subject to certain rules and restrictions under VCU policy. The terms of this arrangement are being managed by VCU in accordance with its conflict of interest policies., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: To investigate the effectiveness of guaifenesin in the relief of nasal symptoms in children with chronic rhinitis (CR). We hypothesized that guaifenesin use over a 14-day study period would improve subjective nasal complaints in pediatric patients with chronic rhinitis, as measured by the SinoNasal-5 (SN-5) survey. We also hypothesized improvement in nasal volume and cross-sectional area with guaifenesin., Study Design: Randomized, placebo-controlled, parallel group, masked clinical trial., Methods: The study consisted of a 14-day, randomized, placebo-controlled, parallel group, masked clinical trial of oral guaifenesin for CR in children aged 7-18 years. A 2:1 ratio of subjects on active medication to placebo was used. The study was approved by the Western Institutional Review Board. On initial enrollment and at the conclusion of therapy, the SN-5 was completed by parents, acoustic rhinometry measurements performed, and mucus sampling for rheology was obtained., Results: 30 subjects were enrolled in the study, with 20 receiving guaifenesin and 10 placebo. Treatment with guaifenesin for 14 days produced a significant mean change towards clinical improvement in SN-5 scores compared with placebo (p = 0.013). There was no significant difference in quality of life assessment scores between the two groups or in any of the acoustic rhinometry parameters. Many of the study subjects had difficulty producing a mucus sample sufficient for analysis., Conclusions: Based upon our pilot data, it appears that guaifenesin treatment may produce objective improvements in pediatric patients with CR. Further research with larger samples sizes, inclusion of children younger than 6, and biophysical mucus analyses is warranted., Level of Evidence: Level 2b., Competing Interests: Declaration of competing interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Cough characteristics vary between patients, and this can impact clinical diagnosis and care. The purpose of part two of this state-of-the-art review is to update the American College of Chest Physicians (CHEST) 2006 guideline on global physiology and pathophysiology of cough., Study Design and Methods: A review of the literature was conducted using PubMed and MEDLINE databases from 1951 to 2019 using prespecified search terms., Results: We describe the demographics of typical patients with cough in the clinical setting, including how cough characteristics change across age. We summarize the effect of common clinical conditions impacting cough mechanics and the physical properties of mucus on airway clearance., Interpretation: This is the second of a two-part update to the 2006 CHEST cough guideline; it complements part one on basic phenomenology of cough by providing an extended clinical picture of cough along with the factors that alter cough mechanics and efficiency in patients. A greater understanding of the physiology and pathophysiology of cough will improve clinical management., (Copyright © 2021. Published by Elsevier Inc.)

The Covid-19 pandemic has disrupted organised sport in the community as authorities cancelled, greatly modified or postponed sporting participation as part of a strategy to reduce transmission of the virus. This had a significant impact on young athletes and their families in relation to their psycho-social, physical and career progression considerations. The disruption is likely to continue for some years, considering the constraints of lockdowns, the need to overcome dysfunctional national logistics for delivery of medical care, fund and implement an efficacious vaccine programme locally, nationally and worldwide, develop sufficient herd immunity and create an environment of confidence in the safety of returning to sports for participants, coaches, umpires, administrators and observers. This article will consider the interim challenges regarding the physical and psychosocial importance of maintaining an active sporting programme for young athletes, reflect on safety measures for modifying sporting equipment and environmental protections to allow safest participation in training and competition and provide advice on protocols for a gradual return to sport for the young athlete after infection with Covid-19., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Erector spinae muscle (ESM) size has been reported as a predictor of prognosis in patients with some respiratory diseases. This study aimed to assess the association of ESM size on all-cause in-hospital mortality among elderly patients with pneumonia. We retrospectively included patients (age: ≥ 65 years) admitted to hospital from January 2015 to December 2017 for community-acquired pneumonia who underwent chest computed tomography (CT) on admission. The cross-sectional area of the ESM (ESMcsa) was measured on a single-slice CT image at the end of the 12th thoracic vertebra and adjusted by body surface area (BSA). Cox proportional hazards regression models were used to assess the influence of ESMcsa/BSA on in-hospital mortality. Among 736 patients who were admitted for pneumonia, 702 patients (95%) underwent chest CT. Of those, 689 patients (98%) for whom height and weight were measured to calculate BSA were included in this study. Patients in the non-survivor group were significantly older, had a greater frequency of respiratory failure, loss of consciousness, lower body mass index, hemoglobin, albumin, and ESMcsa/BSA. Multivariate analysis showed that a lower ESMcsa/BSA independently predicted in-hospital mortality after adjusting for these variables. In elderly patients with pneumonia, quantification of ESMcsa/BSA may be associated with in-hospital mortality.

Cystic fibrosis (CF) lung disease is marked by high concentrations of neutrophil elastase (NE) and DNA polymers; both factors contribute to airway disease. Although inhaled recombinant human dornase alfa reduces the frequency of CF pulmonary exacerbations, it also increases free NE activity in the sputum. There are no approved anti-NE therapies for patients with CF. We investigated whether synthetic, low-molecular weight polysulfated hyaluronan GlycoMira-1111 (GM-1111) would be effective as an anti-NE drug using ex vivo CF sputum. Anti-NE activity of GM-1111 was tested in CF sputum in the presence or absence of dornase alfa and/or hypertonic saline using a spectrophotometric assay specific for human NE and was compared with unfractionated heparin. We tested whether GM-1111 disaggregated DNA from CF sputum (using gel electrophoresis analysis) or modified CF sputum viscoelastic properties (using a dynamic rheometer). GM-1111 and unfractionated heparin had near equivalent anti-NE activity in CF sputum in the presence of dornase alfa. Both GM-1111 and unfractionated heparin retained anti-NE activity in hypertonic saline but with decreased activity. GM-1111 increased the release of soluble DNA in CF sputum, resulting in improved depolymerization efficacy of dornase alfa. GM-1111 decreased CF sputum elasticity. GM-1111 inhibited NE activity, enhanced DNA depolymerization by deoxyribonuclease, and decreased viscoelastic properties of CF sputum, similar to effects reported previously for unfractionated heparin. Unlike heparins, GM-1111 is synthetic, with minimal anticoagulant activity, and is not derived from animal products. These key attributes provide advantages over unfractionated heparin as a potential therapeutic for CF.

Mucus obstruction is a key feature of many inflammatory airway diseases. Neutrophil extracellular traps (NETs) are released upon neutrophil stimulation and consist of extracellular chromatin networks studded with cytotoxic proteins. When released in the airways, these NETs can become part of the airway mucus. We hypothesized that the extracellular DNA and/or oxidative stress (e.g., by the release of reactive oxygen species and myeloperoxidase during NETs formation in the airways) would increase mucus viscoelasticity. We collected human airway mucus from endotracheal tubes of healthy patients admitted for elective surgery and coincubated these samples with NETs from phorbol 12-myristate 13-acetate-stimulated neutrophils. Unstimulated neutrophils served as controls, and blocking experiments were performed with dornase alfa for extracellular DNA and the free radical scavenger dimethylthiourea for oxidation. Compared with controls, the coincubation of mucus with NETs resulted in 1 ) significantly increased mucus viscoelasticity (macrorheology) and 2 ) significantly decreased mesh pore size of the mucus and decreased movement of muco-inert nanoparticles through the mucus (microrheology), but 3 ) NETs did not cause visible changes in the microstructure of the mucus by scanning EM. Incubation with either dornase alfa or dimethylthiourea attenuated the observed changes in macrorheology and microrheology. This suggests that the release of NETs may contribute to airway mucus obstruction by increasing mucus viscoelasticity and that this effect is not solely due to the release of DNA but may in part be due to oxidative stress.

Electronic cigarettes (e-cigarettes) are noncombustible tobacco products that have been promoted as safer alternatives to conventional cigarettes and beneficial tools for smoking cessation. However, e-cigarettes have been shown to produce aerosols with high concentrations of propylene glycol, glycerol, volatile organic compounds, and free radicals, which can lead to lung damage. Furthermore, e-cigarettes can deliver nicotine at concentrations higher than traditional combustibles, making them highly addictive. As delivery devices became smaller, less expensive, and refillable, the use of e-cigarettes dramatically increased, especially among adolescents and young adults in the United States. This rise in popularity of noncombustible products led to an outbreak of e-cigarette or vaping product use-associated lung injury (EVALI) in the fall of 2019. In this article, we review the history of e-cigarettes and its prevalence among American youth, the EVALI outbreak and clinical presentation of EVALI patients, and recent legislative efforts to regulate e-cigarette use., (Copyright © 2020 Elsevier Ltd. All rights reserved.)