Individualized aerosol medicine: Integrating device into the patient.

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.

Cough medicines for children- time for a reality check.

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.

Bronchiolitis therapies and misadventures.

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.

The effect of oral guaifenesin on pediatric chronic rhinitis: A pilot study.

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.

Polysulfated Hyaluronan GlycoMira-1111 Inhibits Elastase and Improves Rheology in Cystic Fibrosis Sputum.

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.

Neutrophil Extracellular Traps Increase Airway Mucus Viscoelasticity and Slow Mucus Particle Transit.

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.

Covid-19 and the impact on young athletes.

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.

Electronic cigarettes and e-cigarette/vaping product use associated lung injury (EVALI).

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.

COVID-19 and telehealth, education, and research adaptations.

For decades, there have been government funded services to provide healthcare telephonically to remote sites both on the earth and in the air. This capability has evolved into what we now know as telehealth. The use of telehealth dramatically accelerated as a result of concerns for patient and healthcare provider safety during the SARS-CoV2 pandemic. Similarly, concerns regarding transmission of infection have required medical schools to provide robust, easily accessible virtual education options. At short notice, faculties have had to develop new telehealth focused curriculum components. However, telehealth, online education, and internet enabled research should not be simply a new way to do traditional jobs but rather, an opportunity to take advantage of how technology can best be used to develop new and better ways to provide care, educate health care providers, and support research.

COVID-19 and respiratory support devices.

There are significant logistical challenges to providing respiratory support devices, beyond simple oxygen flow, when centres run out of supplies or do not have these devices at all, such as in low resource settings. At the peak of the COVID-19 crisis, it was extremely difficult to import medical equipment and supplies, because most countries prohibited the medical industry from selling outside of their own countries. As a consequence, engineering teams worldwide volunteered to develop emergency devices, and medical experts in mechanical ventilation helped to guide the design and evaluation of prototypes. Although regulations vary among countries, given the emergency situation, some Regulatory Agencies facilitated expedited procedures. However, laboratory and animal model testing are crucial to minimize the potential risk for patients when treated with a device that may worsen clinical outcome if poorly designed or misused.

Dry powder aerosol containing muco-inert particles for excipient enhanced growth pulmonary drug delivery.

Tenacious sputum poses a critical diffusion barrier for aerosol antibiotics used to treat cystic fibrosis (CF) lung infection. We conducted a proof-of-concept study using dense poly(ethylene glycol) coated polystyrene nanoparticles (PS-PEG NPs) as model muco-inert particles (MIPs) formulated as a powder using an excipient enhanced growth (EEG) strategy, aiming to minimize extrathoracic airway loss, maximize deposition in the airway and further overcome the sputum barrier in the CF lungs. The EEG aerosol formulation containing PS-PEG MIPs was prepared by spray drying and produced discrete spherical particles with geometric diameter of approximately 2 µm; and >80% of the powder dose was delivered from a new small-animal dry powder inhaler (DPI). The MIPs released from the EEG aerosol had human airway mucus and CF sputum diffusion properties comparable to the suspension formulation. These properties make this formulation a promising pulmonary drug delivery system for CF lung infections.

Molecular principles for heparin oligosaccharide-based inhibition of neutrophil elastase in cystic fibrosis.

Cystic fibrosis (CF) is a multifactorial disease in which dysfunction of protease-antiprotease balance plays a key role. The current CF therapy relies on dornase α, hypertonic saline, and antibiotics and does not address the high neutrophil elastase (NE) activity observed in the lung and sputum of CF patients. Our hypothesis is that variants of heparin, which potently inhibit NE but are not anticoagulant, would help restore the protease-antiprotease balance in CF. To realize this concept, we studied molecular principles governing the effectiveness of different heparins, especially 2-O,3-O-desulfated heparin (ODSH), in the presence of sputum components and therapeutic agents. Using sputa from CF patients and an NE activity assay, we found that heparins are ineffective if used in the absence of dornase. This is true even when mucolytics, such as DTT or N-acetylcysteine, were used. Computational modeling suggested that ODSH and DNA compete for binding to an overlapping allosteric site on NE, which reduces the anti-NE potential of ODSH. NE inhibition of both DNA and ODSH is chain length-dependent, but ODSH chains exhibit higher potency per unit residue length. Likewise, ODSH chains exhibit higher NE inhibition potential compared with DNA chains in the presence of saline. These studies suggest fundamental differences in DNA and ODSH recognition and inhibition of NE despite engaging overlapping sites and offer unique insights into molecular principles that could be used in developing antiprotease agents in the presence of current treatments, such as dornase and hypertonic saline.

Tiotropium inhibits mucin production stimulated by neutrophil elastase but not by IL-13.

Tiotropium, a muscarinic antagonist, is approved for the treatment of chronic obstructive pulmonary disease and poorly controlled asthma. Because mucus hypersecretion is characteristic of both of these diseases, and muscarinic agonists stimulate mucus secretion, we hypothesized that tiotropium would attenuate airway MUC5AC expression. We grew normal human bronchial epithelial (NHBE) cells to a goblet cell phenotype with 1 or 5 ng/mL of IL-13 and exposed these cells to 10 nM tiotropium or excipient for the full 14 days. Normally differentiated NHBE cells (without IL-13) were exposed to neutrophil elastase (NE) 1 × 10-7 or 5 × 10-7 M for 1 h. MUC5AC was measured by quantitative PCR and ELISA. Acetylcholine production by the epithelium was evaluated by quantitative PCR and by choline/acetylcholine quantification. Tiotropium had no effect on IL-13-stimulated MUC5AC, but attenuated MUC5AC stimulated by NE (p = 0.007 at 5 × 10-7 M). IL-13 increased CarAT mRNA (p < 0.001 at 5 ng/mL) and acetylcholine concentration in the medium (p = 0.018 at 5 ng/mL), while NE had no effect. Tiotropium had no direct effect on IL-13 or NE-induced CarAT or acetylcholine concentration. Tiotropium decreased MUC5AC stimulated by NE, but had no effect on MUC5AC stimulated by IL-13. These results may be due to IL-13, but not NE, increasing acetylcholine production.

Activating prostaglandin E2 receptor subtype EP4 increases secreted mucin from airway goblet cells.

Prostaglandin E2 (PGE2) is a ligand of the E-type prostanoid receptors, EP1-4. PGE2 secretion is increased in the airways of patients with asthma by secretory phospholipases A2, which also increases MUC5AC mucin in goblet cells. We hypothesized that PGE2 would also increase MUC5AC mRNA and secreted protein through specific EP receptor activation. We sought to assess the effect of specific EP receptor activation on MUC5AC secretion from ciliated-enriched cells or goblet-enriched cells induced by IL-13. We develop an enriched goblet cell epithelium by growing normal human bronchial epithelial cells at air liquid interface for 14 days in the presence of IL-13. We examined exposure to 4 specific EP receptor agonists at 24 h and 14 days in cells grown with or without IL-13 exposure, and measured MUC5AC mRNA and secreted protein, as well as airway culture morphology, and EP receptor expression. In ciliated-enriched cells grown in the absence of IL-13, the EP4 receptor agonist modestly increased both MUC5AC mRNA and secretion (p < 0.001, 241% increase of transcripts and p < 0.01, 86% increase of secreted protein) but did not visibly change cell morphology. In goblet-enriched cells grown in the presence of IL-13, the EP4 receptor agonist greatly increased both MUC5AC mRNA and protein (p < 0.001, 315% increase of transcripts and 92% increase of secreted protein). Specific activation of the other EP receptor had no effect on secreted mucin. EP4 receptor mRNA and protein were significantly increased in goblet-enriched cells, while the other receptor mRNA were decreased. We conclude that PGE2 stimulates airway mucin production predominantly by EP4 receptor activation in association with increased EP4 receptor expression. This may contribute to mucus hypersecretion as seen in severe asthma.

What do patients want from their asthma care doctors?

One of the most important causes of asthma morbidity, hospital admissions, and death is non-adherence to prescribed therapy. It is generally assumed that adherence rates can be increased with asthma education, although well conducted studies have not always supported this assumption. Education can be achieved, or can fail, in many ways and no two patients have the same needs or perceived needs. In order to better understand what children with asthma and their parents or caregivers would desire as support from their physician providers, we conducted a survey of nearly 1000 parents of asthmatic children affiliated with the Asthma and Allergy Network. Most of those who responded wanted convenient access to their doctor, more time spent in office visits with greater attention paid to the patient, help in navigating insurance and prescription costs and paperwork, and a partnership in developing care plans. Although most patients were well insured for medical coverage (not a given in the USA), half were dissatisfied with their self-reported asthma control, many were concerned about medication side effects, 60% were not cared for by an asthma specialist, and nearly half did not have an asthma action plan. These results are consistent with data from other published studies and suggest that we still can do much more to meet the needs of children for whom we provide asthma care.

Clarithromycin attenuates IL-13-induced periostin production in human lung fibroblasts.

BACKGROUND: Periostin is a biomarker indicating the presence of type 2 inflammation and submucosal fibrosis; serum periostin levels have been associated with asthma severity. Macrolides have immunomodulatory effects and are considered a potential therapy for patients with severe asthma. Therefore, we investigated whether macrolides can also modulate pulmonary periostin production. METHODS: Using quantitative PCR and ELISA, we measured periostin production in human lung fibroblasts stimulated by interleukin-13 (IL-13) in the presence of two 14-member-ring macrolides-clarithromycin or erythromycin-or a 16-member-ring macrolide, josamycin. Phosphorylation of signal transducers and activators of transcription 6 (STAT6), downstream of IL-13 signaling, was evaluated by Western blotting. Changes in global gene expression profile induced by IL-13 and/or clarithromycin were assessed by DNA microarray analysis. RESULTS: Clarithromycin and erythromycin, but not josamycin, inhibited IL-13-stimulated periostin production. The inhibitory effects of clarithromycin were stronger than those of erythromycin. Clarithromycin significantly attenuated STAT6 phosphorylation induced by IL-13. Global gene expression analyses demonstrated that IL-13 increased mRNA expression of 454 genes more than 4-fold, while decreasing its expression in 390 of these genes (85.9%), mainly "extracellular," "plasma membrane," or "defense response" genes. On the other hand, clarithromycin suppressed 9.8% of the genes in the absence of IL-13. Clarithromycin primarily attenuated the gene expression of extracellular matrix protein, including periostin, especially after IL-13. CONCLUSIONS: Clarithromycin suppressed IL-13-induced periostin production in human lung fibroblasts, in part by inhibiting STAT6 phosphorylation. This suggests a novel mechanism of the immunomodulatory effect of clarithromycin in asthmatic airway inflammation and fibrosis.

A systematic review of diagnostic methods to differentiate acute lung injury/acute respiratory distress syndrome from cardiogenic pulmonary edema.

BACKGROUND: Discriminating acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) from cardiogenic pulmonary edema (CPE) is often challenging. This systematic review examines studies using biomarkers or images to distinguish ALI/ARDS from CPE. METHODS: Three investigators independently identified studies designed to distinguish ALI/ARDS from CPE in adults. Studies were identified from PubMed, and the Cochrane Central Register of Controlled Trials database until July 3, 2017. RESULTS: Of 475 titles and abstracts screened, 38 full texts were selected for review, and we finally included 24 studies in this systematic review: 21 prospective observational studies, two retrospective observational studies, and one retrospective combined with prospective study. These studies compared various biomarkers to differentiate subjects with ALI/ARDS and in those with CPE, and 13 calculated the area under the receiver operator characteristic curve (AUC). The most commonly studied biomarker (four studies) was brain natriuretic peptide (BNP) and the discriminatory ability ranged from AUC 0.67-0.87 but the timing of measurement varied. Other potential biomarkers or tools have been reported, but only as single studies. CONCLUSIONS: There were no identified biomarkers or tools with high-quality evidence for differentiating ALI/ARDS from CPE. Combining clinical criteria with validated biomarkers may improve the predictive accuracy.

Inhibition of IL-13-induced periostin in airway epithelium attenuates cellular protein expression of MUC5AC.

BACKGROUND AND OBJECTIVE: Serum periostin is increased in asthma and serves as a surrogate marker for IL-13 activity in the lung. Serum levels of periostin are the most robust biomarker predicting a favourable response to the anti-IL-13 drug, lebrikizumab. We investigated the mechanisms of IL-13 stimulation of periostin, the polarized secretion of periostin and whether periostin would have a direct effect on mucin secretion by airway cells. METHODS: Normal human bronchial epithelial (NHBE) cells were cultured at air-liquid interface (ALI) in the presence of IL-13, and we evaluated the effect of the specific inhibitors, leflunomide (Janus kinase (JAK)/signal transducer and activator of transcription factor 6 (STAT6) inhibitor) or PD98059 (MEK/extracellular regulated protein kinase (ERK) inhibitor), on periostin production. We examined MUC5AC secretion from NHBE cells exposed to recombinant human (rh) periostin or IL-13 in the presence and absence of OC-20, a periostin-neutralizing antibody. RESULTS: IL-13 induced periostin protein which was predominantly secreted towards the basal surface of the cells. Periostin production was much greater from goblet cells than ciliated cells (P < 0.001). Periostin production after exposure to IL-13 was attenuated by both leflunomide (P < 0.001) and PD98059 (P < 0.001). The addition of exogenous periostin modestly increased MUC5AC secretion (P < 0.01), but did not visibly change cell morphology. IL-13-induced MUC5AC secretion was attenuated by OC-20 (P < 0.01). CONCLUSION: Periostin production in differentiated airway cells is mediated by JAK/STAT6 and MEK/ERK pathways. Periostin secretion is much greater from immunologically active goblet cells. IL-13-driven mucin production is partially inhibited by OC-20.