Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis intracellular growth and translocation into the cytosol of alveolar epithelial cells.

The elderly population is highly susceptible to developing respiratory diseases, including tuberculosis, a devastating disease caused by the airborne pathogen Mycobacterium tuberculosis (M.tb) that kills one person every 18 seconds. Once M.tb reaches the alveolar space, it contacts alveolar lining fluid (ALF), which dictates host-cell interactions. We previously determined that age-associated dysfunction of soluble innate components in human ALF leads to accelerated M.tb growth within human alveolar macrophages. Here we determined the impact of human ALF on M.tb infection of alveolar epithelial type cells (ATs), another critical lung cellular determinant of infection. We observed that elderly ALF (E-ALF)-exposed M.tb had significantly increased intracellular growth with rapid replication in ATs compared to adult ALF (A-ALF)-exposed bacteria, as well as a dampened inflammatory response. A potential mechanism underlying this accelerated growth in ATs was our observation of increased bacterial translocation into the cytosol, a compartment that favors bacterial replication. These findings in the context of our previous studies highlight how the oxidative and dysfunctional status of the elderly lung mucosa determines susceptibility to M.tb infection, including dampening immune responses and favoring bacterial replication within alveolar resident cell populations, including ATs, the most abundant resident cell type within the alveoli.

The Aging Human Lung Mucosa: A Proteomics Study.

The older adult population, estimated to double by 2050, is at increased risk of respiratory infections and other pulmonary diseases. Biochemical changes in the lung alveolar lining fluid (ALF) and in alveolar compartment cells can alter local immune responses as we age, generating opportunities for invading pathogens to establish successful infections. Indeed, the lung alveolar space of older adults is a pro-inflammatory, pro-oxidative, dysregulated environment that remains understudied. We performed an exploratory, quantitative proteomic profiling of the soluble proteins present in ALF, developing insight into molecular fingerprints, pathways, and regulatory networks that characterize the alveolar space in old age, comparing it to that of younger individuals. We identified 457 proteins that were significantly differentially expressed in older adult ALF, including increased production of matrix metalloproteinases, markers of cellular senescence, antimicrobials, and proteins of neutrophilic granule origin, among others, suggesting that neutrophils in the lungs of older adults could be potential contributors to the dysregulated alveolar environment with increasing age. Finally, we describe a hypothetical regulatory network mediated by the serum response factor that could explain the neutrophilic profile observed in the older adult population.

Quality of the discussion of asthma on twitter.

IntroductionPatients obtain a large amount of medical information online. Much of this information may not be reliable or of high quality. We investigated what influences the discussion of asthma on Twitter by evaluating the most popular tweets and the quality of the links shared.MethodsWe used Symplur Signals to extract data from Twitter examining characteristics of the top 100 most shared tweets and the 50 most shared links that included the hashtag #asthma. Information on each site was assessed using an Asthma Content score, and validated DISCERN scores and HONCode criteria.ResultsThe top 100 asthma-related tweets were shared 10,169 times and had 16,044 likes. Healthcare organizations posted 49 of the top 100 tweets, non-healthcare individuals posted 20, non-healthcare organizations posted 16 and clinicians posted 14. Of the top 100 tweets, 62 were educational, 11 research-related, 10 political and 15 promotional. The top 50 links were shared 6009 times (median number of shares 92 per link (range 60-710)). Links most commonly (42%) led to educational content while 24% of links led to research articles, 22% to promotional websites, and 12% to political websites. Educational links had higher Asthma Content scores than other links (p < 0.005). Overall, all three scores were low for all types of links. Only 34% of sites met HONCode criteria, and 14% were assessed as high quality by DISCERN score.ConclusionThe top tweets using the hashtag #asthma were commonly educational. The majority of top links on Twitter scored poorly on asthma content, quality, and reliability.

A Safety and Tolerability Study of Thin Film Freeze-Dried Tacrolimus for Local Pulmonary Drug Delivery in Human Subjects.

Due to the low and erratic bioavailability of oral tacrolimus (TAC), the long-term survival rate following lung transplantation remained low compared to other solid organs. TAC was reformulated and developed as inhaled formulations by thin film freezing (TFF). Previous studies reported that inhaled TAC combined with 50% w/w lactose (LAC) was safe and effective for the treatment of lung transplant rejection in rodent models. In this study, we aimed to investigate the safety and tolerability of TFF TAC-LAC in human subjects. The formulation can be delivered to the lung as colloidal dispersions after reconstitution and as a dry powder. Healthy subjects inhaled TAC-LAC colloidal dispersions at 3 mg TAC/dose via a vibrating mesh nebulizer in the first stage of this study and TAC-LAC dry powder at 3 mg TAC/dose via a single dose dry powder inhaler in the second stage. Our results demonstrated that oral inhalation of TAC-LAC colloidal dispersions and dry powder exhibited low systemic absorption. Additionally, they were well-tolerated with no changes in CBC, liver, kidney, and lung functions. Only mild adverse side effects (e.g., cough, throat irritation, distaste) were observed. In summary, pulmonary delivery of TFF TAC-LAC would be a safe and promising therapy for lung transplant recipients.

In COPD, prophylactic macrolides, but not tetracyclines or quinolones, reduce exacerbations, with fewer serious adverse events.

SOURCE CITATION: Janjua S, Mathioudakis AG, Fortescue R, et al. Prophylactic antibiotics for adults with chronic obstructive pulmonary disease: a network meta-analysis. Cochrane Database Syst Rev. 2021;1:CD013198. 33448349.

Niclosamide inhalation powder made by thin-film freezing: Multi-dose tolerability and exposure in rats and pharmacokinetics in hamsters.

In this work, we have developed and tested a dry powder form of niclosamide made by thin-film freezing (TFF) and administered it by inhalation to rats and hamsters to gather data about its toxicology and pharmacokinetics. Niclosamide, a poorly water-soluble drug, is an interesting drug candidate because it was approved over 60 years ago for use as an anthelmintic medication, but recent studies demonstrated its potential as a broad-spectrum antiviral with pharmacological effect against SARS-CoV-2 infection. TFF was used to develop a niclosamide inhalation powder composition that exhibited acceptable aerosol performance with a fine particle fraction (FPF) of 86.0% and a mass median aerodynamic diameter (MMAD) and geometric standard deviation (GSD) of 1.11 µm and 2.84, respectively. This formulation not only proved to be safe after an acute three-day, multi-dose tolerability and exposure study in rats as evidenced by histopathology analysis, and also was able to achieve lung concentrations above the required IC90 levels for at least 24 h after a single administration in a Syrian hamster model. To conclude, we successfully developed a niclosamide dry powder inhalation that overcomes niclosamide's limitation of poor oral bioavailability by targeting the drug directly to the primary site of infection, the lungs.

Inhaled nanoparticles-An updated review.

We are providing an update to our previously published review paper on inhaled nanoparticles, thus updating with the most recent reports in the literature. The field of nanotechnology may hold the promise of significant improvements in the health and well-being of patients, as well as in manufacturing technologies. The knowledge of the impact of nanomaterials on public health is limited so far. This paper reviews the unique size-controlled properties of nanomaterials, their disposition in the body after inhalation, and the factors influencing the fate of inhaled nanomaterials. The physiology of the lungs makes it an ideal target organ for non-invasive local and systemic drug delivery, especially for protein and poorly water-soluble drugs that have low oral bioavailability via oral administration. More recently, inhaled nanoparticles have been reported to improve therapeutic efficacies and decrease undesirable side effects via pulmonary delivery. The potential application of pulmonary drug delivery of nanoparticles to the lungs, specifically in context of published results reported on nanomaterials in environmental epidemiology and toxicology is reviewed in this paper. This article presents updated delivery systems, process technologies, and potential of inhaled nanoparticles for local and systemic therapies administered to the lungs. The authors acknowledge the contributions of Wei Yang in our 2008 paper published in this journal.

In spontaneous pneumothorax, initial needle aspiration and large- and narrow-bore chest tubes do not differ for success.

SOURCE CITATION: Mummadi SR, de Longpre' J, Hahn PY. Comparative effectiveness of interventions in initial management of spontaneous pneumothorax: a systematic review and a Bayesian network meta-analysis. Ann Emerg Med. 2020;76:88-102. 32115203.

Long-term evaluation of response to omalizumab therapy in real life by a novel multimodular approach: The Real-life Effectiveness of Omalizumab Therapy (REALITY) study.

BACKGROUND: The evidence on long-term real-life response measures to omalizumab therapy in moderate to severe asthma is limited. A universal assessment tool is needed to adequately evaluate response to omalizumab in these patients. OBJECTIVE: To design a multimodular response assessment tool and use it to measure and define response to omalizumab therapy in real-world settings. METHODS: The Real-life Effectiveness of Omalizumab Therapy (REALITY) study is a retrospective, long-term, real-life clinical study that evaluates response in individuals with allergic asthma who received omalizumab between 2004 and 2011. The Standardized Measure to Assess Response to Therapy (SMART) tool was designed to define response (1 year before to after treatment) by 3 modules: (1) physician's subjective assessment of asthma symptoms and control; (2) objective assessment of 6 parameters: improvement by 50% or more for asthma exacerbation, steroid bursts, emergency department visits, and hospitalizations; increase in forced expiratory volume in 1 second of 200 mL or greater; and improved Asthma Control Test score of 3 or higher; -and (3) true responders (patient meeting both module 1 and 2 criteria). Response was assessed and compared for 3 modules at desired time points. RESULTS: A total of 198 patients (mean age, 31.7 years [range, 3-77 years]; 98 [49%] female; mean omalizumab therapy duration, 2.49 years [range, 3 months to 8 years]; mean omalizumab dosage, 473 mg every 4 weeks; median baseline IgE level, 433 IU/mL) were included in this analysis. Overall visit adherence was 78%, although the adherence rate decreased annually by 20%. Response rates assessed by SMART modules were 61.3%, 60.8%, and 41.8% at 16 weeks, 84.8%, 72.2%, and 64.6% at 1 year, 82.4%, 71.2%, and 63.2% at 2 years, and 95.1%, 87.8%, and 85.4% at 5 years for modules 1, 2, and 3, respectively. There were no significant adverse reactions. CONCLUSION: The REALITY study has demonstrated long-term effectiveness of omalizumab therapy in individuals with allergic asthma in real-life settings. The SMART tool is promising as a potential standard assessment tool to measure and define response to asthma therapy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01776177.

Clinical Approach to the Therapy of Asthma-COPD Overlap.

Over the last few years, there has been a renewed interest in patients with characteristics of both asthma and COPD. Although the precise definition of asthma-COPD overlap (ACO) is still controversial, patients with overlapping features are frequently encountered in clinical practice, and may indeed have worse clinical outcomes and increased health-care utilization than those with asthma or COPD. Therefore, there is a critical need to set a framework for the therapeutic approach of such patients. There are key distinctions in the therapy between asthma and COPD, particularly regarding the initial choice of therapy. However, there is considerable overlap in the use of existing medications for both diseases. Furthermore, novel therapies approved for asthma, such as monoclonal antibodies, may have a role in patients with COPD and ACO. The use of biomarkers, such as peripheral blood eosinophils, exhaled nitric oxide, and serum IgE, may help in selecting appropriate therapies for ACO. In this review, we provide an overview of available treatments for both asthma and COPD and explore their potential role in the treatment of patients with ACO.

Benralizumab, an add-on treatment for severe eosinophilic asthma: evaluation of exacerbations, emergency department visits, lung function, and oral corticosteroid use.

There are now multiple monoclonal antibodies targeting different inflammatory pathways of severe asthma. Benralizumab is a recently approved monoclonal antibody indicated for the treatment of severe eosinophilic asthma by targeting a subunit of the IL-5 receptor. Treatment with benralizumab results in significant reductions of blood and tissue eosinophils. Early studies report that this therapy has an adequate safety profile, and this was confirmed in later trials. Phase III studies have shown that benralizumab is effective in reducing the rate of exacerbations and improving asthma symptoms and quality of life in patients with severe eosinophilic asthma. Additionally, treatment with benralizumab has resulted in important reductions in the use of chronic oral corticosteroids. In this review, we evaluate the evidence up to date on the efficacy of benralizumab in severe eosinophilic asthma and explore the implications of this therapy in the ever-growing landscape of therapies for severe asthma.

Medication Regimens for Managing Acute Asthma.

Asthma exacerbation is defined as a progressive increase in symptoms of shortness of breath, cough, or wheezing sufficient to require a change in therapy. After ruling out diagnoses that mimic an asthma exacerbation, therapy should be initiated. Short-acting ß2 agonists and short-acting muscarinic antagonists are effective as bronchodilators for asthma in the acute setting. Systemic corticosteroids to reduce airway inflammation continue to be the mainstay therapy for asthma exacerbations, and, unless there is a contraindication, the oral route is favored. Based on the current evidence, nebulized magnesium should not be routinely used in acute asthma. The evidence favors the use of intravenous magnesium sulfate in selected cases, particularly in severe exacerbations. Methylxanthines have a minimum role as therapy for asthma exacerbations but may be considered in refractory cases of status asthmaticus with careful monitoring of toxicity. Current guidelines recommend the use of helium-oxygen mixtures in patients who do not respond to standard therapies or those with severe disease.

The Immunopathologic Effects of Mycoplasma pneumoniae and Community-acquired Respiratory Distress Syndrome Toxin. A Primate Model.

Mycoplasma pneumoniae infection has been linked to poor asthma outcomes. M. pneumoniae produces an ADP-ribosylating and vacuolating toxin called community-acquired respiratory distress syndrome (CARDS) toxin that has a major role in inflammation and airway dysfunction. The objective was to evaluate the immunopathological effects in primates exposed to M. pneumoniae or CARDS toxin. A total of 13 baboons were exposed to M. pneumoniae or CARDS toxin. At Days 7 and 14, BAL fluid was collected and analyzed for cell count, percent of each type of cell, CARDS toxin by PCR, CARDS toxin by antigen capture, eosinophilic cationic protein, and cytokine profiles. Serum IgM, IgG, and IgE responses to CARDS toxin were measured. All animals had a necropsy for analysis of the histopathological changes on lungs. No animal developed signs of infection. The serological responses to CARDS toxin were variable. At Day 14, four of seven animals exposed to M. pneumoniae and all four animals exposed to CARDS toxin developed histological "asthma-like" changes. T cell intracellular cytokine analysis revealed an increasing ratio of IL-4/IFN-γ over time. Both M. pneumoniae and CARDS toxin exposure resulted in similar histopathological pulmonary changes, suggesting that CARDS toxin plays a major role in the inflammatory response.

The efficacy of inhaled nanoparticle tacrolimus in preventing rejection in an orthotopic rat lung transplant model.

OBJECTIVE: The immunosuppressive efficacy of inhaled nanoparticle tacrolimus was compared with systemic tacrolimus in a rodent allogeneic lung transplant model. METHODS: Sixteen rats underwent allogeneic left orthotopic lung transplantation and were divided into 3 treatment groups: (1) inhaled nanoparticle tacrolimus: 6.4 mg tacrolimus/6.4 mg lactose twice per day; (2) intramuscular tacrolimus: 1 mg/kg tacrolimus once per day; and (3) inhaled lactose: 6.4 mg of lactose twice per day. Five days after transplant, the rats were necropsied and underwent histologic rejection grading and cytokine analysis. Trough levels of tacrolimus were measured in allograft, blood, and kidney. RESULTS: Both intramuscular (n = 6) and nanoparticle tacrolimus (n = 6) rats displayed lower histologic grades of rejection (mean scores 3.4 ± 0.6 and 4.6 ± 0.9, respectively) when compared with lactose rats (n = 4) (mean score 11.38 ± 0.5, P = .07). Systemic tacrolimus trough levels (median) were lower in nanoparticle tacrolimus-treated rats versus intramuscular-treated rats (29.2 vs 118.6 ng/g; P < .001 in kidney, and 1.5 vs 4.8 ng/mL; P = .01 in blood). CONCLUSIONS: Inhaled nanoparticle tacrolimus provided similar efficacy in preventing acute rejection when compared with systemic tacrolimus while maintaining lower systemic levels.