Respirology. 2022 Jan 10. doi: 10.1111/resp.14197. Online ahead of print.

ABSTRACT

Pulmonary functional MRI (PfMRI) using inhaled hyperpolarized, radiation-free gases (such as 3 He and 129 Xe) provides a way to directly visualize inhaled gas distribution and ventilation defects (or ventilation heterogeneity) in real time with high spatial (~mm3 ) resolution. Both gases enable quantitative measurement of terminal airway morphology, while 129 Xe uniquely enables imaging the transfer of inhaled gas across the alveolar-capillary tissue barrier to the red blood cells. In patients with asthma, PfMRI abnormalities have been shown to reflect airway smooth muscle dysfunction, airway inflammation and remodelling, luminal occlusions and airway pruning. The method is rapid (8-15 s), cost-effective (~$300/scan) and very well tolerated in patients, even in those who are very young or very ill, because unlike computed tomography (CT), positron emission tomography and single-photon emission CT, there is no ionizing radiation and the examination takes only a few seconds. However, PfMRI is not without limitations, which include the requirement of complex image analysis, specialized equipment and additional training and quality control. We provide an overview of the three main applications of hyperpolarized noble gas MRI in asthma research including: (1) inhaled gas distribution or ventilation imaging, (2) alveolar microstructure and finally (3) gas transfer into the alveolar-capillary tissue space and from the tissue barrier into red blood cells in the pulmonary microvasculature. We highlight the evidence that supports a deeper understanding of the mechanisms of asthma worsening over time and the pathologies responsible for symptoms and disease control. We conclude with a summary of approaches that have the potential for integration into clinical workflows and that may be used to guide personalized treatment planning.

PMID:35008127 | DOI:10.1111/resp.14197

Ann Allergy Asthma Immunol. 2022 Jan 7:S1081-1206(22)00003-5. doi: 10.1016/j.anai.2022.01.002. Online ahead of print.

ABSTRACT

BACKGROUND: Hazelnut oral immunotherapy (H-OIT), a promising alternative to hazelnut-free diet for patients with hazelnut allergy, has not been extensively studied.

OBJECTIVE: The primary objective was to investigate the effectiveness of H-OIT for hazelnut allergic children.

METHODS: Retrospective medical record review of children treated by H-OIT in the University Hospital of Lyon (France) was reported. Clinical and laboratory data were collected, and the satisfaction of the children treated by H-OIT was evaluated using a questionnaire.

RESULTS: A total of 70 patients treated by H-OIT for an IgE-mediated hazelnut allergy (94.3%) or an IgE sensitization to hazelnut (5.7%) were included. Among these, 22.9% entered the maintenance phase at one-year consultation and 60.0% entered the maintenance phase during the study period. At home, 57.1% of the patients experienced at least one side effect and 2.9% experienced severe systemic allergic reactions. Among the 212 OFCs conducted at hospital, 3.3% led to severe systemic reactions and epinephrine was used four times. A total of 21.4% of children discontinued treatment; aversion to hazelnut was main reason. Forty-two children aged 8 or more and their parents answered the questionnaire. H-OIT was considered a strain for children but effective, and they would recommend H-OIT to other allergic children.

CONCLUSION: H-OIT appeared effective and well accepted by children. This is counterbalanced by a high rate of H-OIT discontinuation, mainly due to aversion to hazelnut, and an important rate of adverse reactions, which are however mostly mild.

PMID:35007745 | DOI:10.1016/j.anai.2022.01.002

Adv Healthc Mater. 2022 Jan 10:e2102145. doi: 10.1002/adhm.202102145. Online ahead of print.

ABSTRACT

Genetic medicine has great potential to treat the underlying causes of many human diseases with exquisite precision, but the field has historically been stymied by delivery as the central challenge. Nanoparticles, engineered constructs the size of natural viruses, are being designed to more closely mimic the delivery efficiency of viruses, while enabling the advantages of increased safety, cargo carrying flexibility, specific targeting, and ease in manufacturing. The speed in which non-viral gene transfer nanoparticles are making progress in the clinic is accelerating, with clinical validation of multiple non-viral nucleic acid delivery nanoparticle formulations recently FDA approved for both expression and for silencing of genes. While much of this progress has been with lipid nanoparticle formulations, significant development is being made with other nanomaterials for gene transfer as well, with favorable attributes such as biodegradability, scalability, and cell targeting. This review highlights the state of the field, current challenges in delivery, and opportunities for engineered nanomaterials to meet these challenges, including enabling long-term therapeutic gene editing. Delivery technology utilizing different kinds of nanomaterials and varying cargos for gene transfer (DNA, mRNA and ribonucleoproteins) are discussed. Clinical applications are presented, including for the treatment of genetic diseases such as cystic fibrosis. This article is protected by copyright. All rights reserved.

PMID:35006646 | DOI:10.1002/adhm.202102145

Front Mol Biosci. 2021 Dec 22;8:812101. doi: 10.3389/fmolb.2021.812101. eCollection 2021.

ABSTRACT

Cystic fibrosis (CF), the most common inherited disease in Caucasians, is caused by mutations in CFTR, the most frequent of which is F508del. F508del causes ER retention and degradation of the mutant CFTR protein, but also defective channel gating and decreased half-life at the plasma membrane. Despite the recent successes with small-molecule CFTR modulator drugs, the folding-corrector/gating-potentiator drug combinations approved for CF individuals carrying F508del-CFTR have sometimes produced severe side effects. Previously, we showed that a prolonged, 15-days treatment of polarized bronchial epithelial monolayers with the VX-809+VX-770 combination resulted in epithelial dedifferentiation effects that we found were caused specifically by VX-809. Moreover, prolonged VX-770 exposure also led to the destabilization of VX-809-rescued F508del-CFTR. Notably, co-treatment with the physiological factor HGF prevented VX-809-mediated epithelial differentiation and reverted the destabilizing effect of VX-770 on VX-809-rescued CFTR. Here, we show that prolonged treatment with VX-661, a second-generation corrector developed based on VX-809 structure, does not perturb epithelial integrity of polarized bronchial epithelial monolayers. Yet, its efficacy is still affected by co-exposure to VX-770, the potentiator present in all VX-661-containing combination therapies approved in the United States and Europe for treatment of F508del-CFTR carriers. Importantly, we found that co-treatment with HGF still ameliorated the impact of VX-770 in F508del-CFTR functional rescue by VX-661, without increasing cell proliferation (Ki-67) or altering the overall expression of epithelial markers (ZO-1, E-cadherin, CK8, CK18). Our findings highlight the importance of evaluating the cellular effects of prolonged exposure to CFTR modulators and suggest that the benefits of adding HGF to current combination therapies should be further investigated.

PMID:35004859 | PMC:PMC8727755 | DOI:10.3389/fmolb.2021.812101

Multidiscip Respir Med. 2021 Dec 3;16(1):791. doi: 10.4081/mrm.2021.791. eCollection 2021 Jan 15.

ABSTRACT

BACKGROUND: Currently, the prognosis of bronchiectasis is based on different prognostic indicators, like BSI and FACED score, founded on clinical-demographic, functional and radiological criteria. Both scoring systems include the number of lobes involved in bronchiectasis, which represents an adverse prognostic index. Our study aimed to investigate the prognostic role of the clinical-functional parameters and the number of involved lobes ratio in adult bronchiectasis.

METHODS: The study was conducted on 52 patients diagnosed with non-cystic fibrosis bronchiectasis (NCFB) between 2015 and 2017 who attended the Pneumology Unit of Monaldi Hospital in Naples, Italy. Correlations between clinical- functional parameters (BMI, smoking history, number of exacerbations in the previous year, spirometry, DLCO, ABG test, and 6MWT) and number of involved lobes were investigated.

RESULTS: At baseline, the number of exacerbations in the previous year had a statistically significant association with the number of involved lobes. Furthermore, at baseline, the radiological criterion was also negatively associated with some functional parameters (FEV1/FVC ratio e FEF25-75%). Statistical significance was lost during the follow up, demonstrating the effectiveness of the therapy.

CONCLUSIONS: Imaging extension represents a promising biomarker of disease severity as well as a helpful follow up tool for non-Cystic Fibrosis bronchiectasis (NCFB).

PMID:35003733 | PMC:PMC8672485 | DOI:10.4081/mrm.2021.791

Front Immunol. 2021 Dec 22;12:788705. doi: 10.3389/fimmu.2021.788705. eCollection 2021.

ABSTRACT

In epigenome-wide association studies analysing DNA methylation from samples containing multiple cell types, it is essential to adjust the analysis for cell type composition. One well established strategy for achieving this is reference-based cell type deconvolution, which relies on knowledge of the DNA methylation profiles of purified constituent cell types. These are then used to estimate the cell type proportions of each sample, which can then be incorporated to adjust the association analysis. Bronchoalveolar lavage is commonly used to sample the lung in clinical practice and contains a mixture of different cell types that can vary in proportion across samples, affecting the overall methylation profile. A current barrier to the use of bronchoalveolar lavage in DNA methylation-based research is the lack of reference DNA methylation profiles for each of the constituent cell types, thus making reference-based cell composition estimation difficult. Herein, we use bronchoalveolar lavage samples collected from children with cystic fibrosis to define DNA methylation profiles for the four most common and clinically relevant cell types: alveolar macrophages, granulocytes, lymphocytes and alveolar epithelial cells. We then demonstrate the use of these methylation profiles in conjunction with an established reference-based methylation deconvolution method to estimate the cell type composition of two different tissue types; a publicly available dataset derived from artificial blood-based cell mixtures and further bronchoalveolar lavage samples. The reference DNA methylation profiles developed in this work can be used for future reference-based cell type composition estimation of bronchoalveolar lavage. This will facilitate the use of this tissue in studies examining the role of DNA methylation in lung health and disease.

PMID:35003108 | PMC:PMC8727592 | DOI:10.3389/fimmu.2021.788705

Front Microbiol. 2021 Dec 23;12:711134. doi: 10.3389/fmicb.2021.711134. eCollection 2021.

ABSTRACT

Introduction: The airway microbiota has been linked to specific paediatric respiratory diseases, but studies are often small. It remains unclear whether particular bacteria are associated with a given disease, or if a more general, non-specific microbiota association with disease exists, as suggested for the gut. We investigated overarching patterns of bacterial association with acute and chronic paediatric respiratory disease in an individual participant data (IPD) meta-analysis of 16S rRNA gene sequences from published respiratory microbiota studies. Methods: We obtained raw microbiota data from public repositories or via communication with corresponding authors. Cross-sectional analyses of the paediatric (<18 years) microbiota in acute and chronic respiratory conditions, with >10 case subjects were included. Sequence data were processed using a uniform bioinformatics pipeline, removing a potentially substantial source of variation. Microbiota differences across diagnoses were assessed using alpha- and beta-diversity approaches, machine learning, and biomarker analyses. Results: We ultimately included 20 studies containing individual data from 2624 children. Disease was associated with lower bacterial diversity in nasal and lower airway samples and higher relative abundances of specific nasal taxa including Streptococcus and Haemophilus. Machine learning success in assigning samples to diagnostic groupings varied with anatomical site, with positive predictive value and sensitivity ranging from 43 to 100 and 8 to 99%, respectively. Conclusion: IPD meta-analysis of the respiratory microbiota across multiple diseases allowed identification of a non-specific disease association which cannot be recognised by studying a single disease. Whilst imperfect, machine learning offers promise as a potential additional tool to aid clinical diagnosis.

PMID:35002989 | PMC:PMC8733647 | DOI:10.3389/fmicb.2021.711134

Pediatric Health Med Ther. 2021 Dec 29;12:551-559. doi: 10.2147/PHMT.S332434. eCollection 2021.

ABSTRACT

Limited information and literature exist examining pulmonary infections caused by nontuberculous mycobacterial specifically in an infant population. The objective of our study was to summarize clinical characteristics and outcomes of infant patients with nontuberculous mycobacterial pulmonary infection via systematic literature review to identify common diagnostic and treatment regimens for this infection in infants. A search of MEDLINE and PubMed databases in October 2019 using MeSH search terms "infant," "NTM," "pulmonary," and "Mycobacterium abscessus" yielded 139 articles. Inclusion criteria were i) English-language studies including cases and case series with ii) established nontuberculous mycobacterial pulmonary infection in iii) a patient population of infants no older than 24 months. Patients with cystic fibrosis and any study which did not contain relevant information such as infection and age were excluded. This yielded data on 37 patients extracted from 28 studies analyzed. The most common strain was Mycobacterium avium complex, isolated in 56.8% of patient diagnoses. Bronchoscopy/thoracoscopy with a subsequent culture were the most common diagnostic techniques, utilized in 64.9% of cases. Drug therapeutic treatment was utilized in 86% of cases, with a median of three drugs administered. Notable limitations of this study are the small sample size and its retrospective nature, which relies on information reported in previous case studies. Although there is limited formal clinician consensus on the treatment of NTM pulmonary infection and how it may differ in an infant population, our findings indicate an informal consensus typically involving diagnostic lung specimen culture and antibiotic therapy.

PMID:35002357 | PMC:PMC8721029 | DOI:10.2147/PHMT.S332434

Physiol Rev. 2022 Jan 10. doi: 10.1152/physrev.00004.2021. Online ahead of print.

ABSTRACT

The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na+ absorptive vs Cl- secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., CF, COPD, NCFB, and PCD. A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.

PMID:35001665 | DOI:10.1152/physrev.00004.2021

Epidemiol Prev. 2021 Nov-Dec;45(6):463-469. doi: 10.19191/EP21.6.122.

ABSTRACT

BACKGROUND: there is increasing concern that the COVID-19 pandemic has disproportionately affected the most vulnerable individuals.

OBJECTIVES: to determine whether education inequalities have widened during the first wave of the COVID-19 pandemic in Italy. DESIGN: historic cohort study based on administrative databases.

SETTING AND PARTICIPANTS: the study was based on subjects registered in the Base Register of Individuals on 01.01.2019, aged >=35 years, and followed-up until 30.06.2020.

MAIN OUTCOME MEASURES: education inequalities in mortality before, during the first phase (March-April), and during the second phase (May-June) of the first pandemic wave in Italy were measured through the mortality rate ratios (MRRs). MMRs were estimated through negative binomial models. The interaction term between period and education was tested through the likelihood ratio test.

RESULTS: the cohort included 37,976,670 individuals, and 719,665 of them died over the follow-up. In high pandemic areas, the MRR among less educated men were: 1.48 (95%CI 1.42-1.55) in the pre-pandemic period, 1.45 (95%CI 1.36-1.55) in the first phase and 1.42 (95%CI 1.30-1.56) in the second phase of the pandemic (p-value: 0.92). Corresponding figures among women were: 1.26 (95%CI 1.21-1.32), 1.39 (95%CI 1.30-1.49), and 1.35 (95%CI 1.23-1.48); p-value: 0.03. The MRRs substantially increased in the first pandemic phase among women aged 35-64 years (from 1.48 to 1.98; p-value; 0.011) and 65-79 years (from 1.22 to 1.51; p-value: 0.017). During the second phase, the MRRs returned to the values observed before the pandemic.

CONCLUSIONS: in Italy, education inequality in mortality widened during the COVID-19 pandemic among working-age women and those aged 65-79 years.

PMID:35001594 | DOI:10.19191/EP21.6.122

Georgian Med News. 2021 Dec;(321):36-41.

ABSTRACT

Objectives - the associations between vitamin D concentrations and respiratory diseases have been assessed in a large and rapidly expanding literature. Observational studies and numerous randomized trials. Data sources: - Medline, Embase, the Cochrane Central Register of Controlled Trials, Web of Science, ClinicalTrials.gov, and the International Standard Randomized Controlled Trials Number registry from 2011 to 2021. Vitamin D plays an essential role in maintaining bone health through regulating calcium concentrations in the body. The development of vitamin D deficiency is associated with deteriorating bone health and in severe cases, hypocalcemia, rickets, and osteomalacia in children and adults. Those at greatest risk of vitamin D deficiency include patients with chronic illnesses (e.g., chronic kidney disease, cystic fibrosis, asthma, and sickle cell disease), dark-pigmented skin, poor nutrition, and infants who are exclusively breastfed. The primary source of vitamin D is sunlight exposure with nutritional intake. However, the composite literature is often confusing and has led to heated debates about the optimal concentrations of vitamin D and related guidelines for supplementation. According to the last period of research, the impact of vitamin D is actively discussing the correct functioning of the immune system. It is established that it participates in the formation of the innate and adaptive immune response. In last years appeared data from controlled trials where there are confirmed D hypovitaminosis correlations with infections. The systemic review of the randomized controlled trials and meta analysis showed the effectiveness of vitamin D supplementation for reducing morbidity with respiratory diseases. In literary sources, the impact of Vitamin D is considered to influence the duration and severity of pneumonia. The authors note that in the cases of severe and complicated pneumonia, the concentrations of vitamin D was significantly lower than in control cases. It has been proposed that the activation of the vitamin D receptor (VDR) signaling pathway may generate beneficial effects in ARDS caused by SARS-CoV-2 with decreasing the cytokine/chemokine storm, regulating the renin‑angiotensin system, modulating neutrophil activity. The systemic review of the randomized controlled trials and meta analysis showed the effectiveness of vitamin D supplementation for reducing morbidity with respiratory diseases. But most of researchers have concluded that data remain uncertain and requires confirmation in farther well designed randomized controlled trials.

PMID:35000906

Chest. 2022 Jan;161(1):21-24. doi: 10.1016/j.chest.2021.06.018.

NO ABSTRACT

PMID:35000702 | DOI:10.1016/j.chest.2021.06.018

Chest. 2022 Jan;161(1):18-20. doi: 10.1016/j.chest.2021.05.070.

NO ABSTRACT

PMID:35000701 | DOI:10.1016/j.chest.2021.05.070

Int J Pharm. 2022 Jan 5:121445. doi: 10.1016/j.ijpharm.2021.121445. Online ahead of print.

ABSTRACT

Dry powder inhalers (DPI) are well established products for the delivery of actives via the pulmonary route. Various DPI products are marketed or developed for the treatment of local lung diseases such as chronic obstructive pulmonary disease (COPD), asthma or cystic fibrosis as well as systemic diseases targeted through inhaled delivery (i.e. Diabetes Mellitus). One of the key prerequisites of DPI formulations is that the aerodynamic size of the drug particles needs to be below 5 µm to enter deeply into the respiratory tract. These inherently cohesive inhalable size particles are either formulated as adhesive mixture with coarse carrier particles like lactose called carrier-based DPI or are formulated as free-flowing carrier-free particles (e.g. soft agglomerates, large hollow particles). In either case, it is common practice that drug and/or excipient particles of DPI formulations are obtained by processing API and API/excipients. The DPI manufacturing process heavily involves several particle and powder technologies such as micronization of the API, dry blending, powder filling and other particle engineering processes such as spray drying, crystallization etc. In this context, it is essential to thoroughly understand the impact of powder/particle properties and processing on the quality and performance of the DPI formulations. This will enable prediction of the processability of the DPI formulations and controlling the manufacturing process so that meticulously designed formulations are able to be finally developed as the finished DPI dosage form. This article is intended to provide a concise account of various aspects of DPI powder processing, including the process understanding and material properties that are important to achieve the desired DPI product quality. Various endeavors of model informed formulation/process design and development for DPI powder and PAT enabled process monitoring and control are also discussed.

PMID:34998921 | DOI:10.1016/j.ijpharm.2021.121445

J Cyst Fibros. 2022 Jan 5:S1569-1993(21)02176-7. doi: 10.1016/j.jcf.2021.12.016. Online ahead of print.

ABSTRACT

BACKGROUND: New modulator therapies have markedly improved the health of people with cystic fibrosis (CF), allowing an increased focus on quality-of-life improvements for men with CF, including those related to sexual and reproductive health (SRH). This study explored CF providers' attitudes and experiences with addressing men's health in CF.

METHODS: We interviewed geographically diverse adult and pediatric United States (U.S.) CF program directors via semi-structured telephone interviews exploring their perspectives and practices related to men's SRH in CF. Two coders analyzed transcribed interviews and created a codebook to identify key themes.

RESULTS: We interviewed 20 providers and identified the following themes: 1) Men's SRH is important to address within CF care, but there is no standardization around this aspect of care; 2) There is no consensus about the recommendation or utilization of semen analysis to assess men's infertility; 3) There are many barriers to men's SRH care provision in CF centers, including the low priority of SRH concerns and provider discomfort and lack of expertise in SRH; 4) Providers desire clear evidence-based guidelines and patient resources related to men's SRH in CF; and 5) Providers believe future research should focus on testosterone and the impact of modulators on men's SRH.

CONCLUSIONS: CF center directors acknowledge the importance of addressing SRH with men with CF, but there is a lack of standardization and research in this aspect of care. Existing barriers to optimal SRH care and identified facilitators in this study can serve as targets for interventions in the CF care model.

PMID:34998704 | DOI:10.1016/j.jcf.2021.12.016

Paediatr Respir Rev. 2021 Dec 8:S1526-0542(21)00110-X. doi: 10.1016/j.prrv.2021.11.002. Online ahead of print.

ABSTRACT

There is now increased knowledge and experience of newborn screening around the world. There is also a better understanding of CF gene analysis, informed by international databases. This has resulted in a small number of children and adults having their diagnosis of CF reversed. This article illustrates this issue with three cases. It considers how best to tell children and adults with their families, and the reactions that may be encountered. It also discusses practical issues of removing the diagnosis.

PMID:34998674 | DOI:10.1016/j.prrv.2021.11.002

J Zoo Wildl Med. 2021 Dec;52(4):1205-1216. doi: 10.1638/2020-0049.

ABSTRACT

Unique among apes, orangutans (Pongo spp.) develop a chronic respiratory disease called orangutan respiratory disease syndrome (ORDS). The authors define ORDS as intermittent bacterial infection and chronic inflammation of any region or combination of regions of the respiratory tract, including the sinuses, air sacs, cranial bones, airways, and lung parenchyma. Infection in any of these areas can present acutely but then becomes recurrent, chronic, progressive, and ultimately fatal. The closest model to this disease is cystic fibrosis (CF) in people. We hypothesized that use of a 4-8-wk course of combined oral antibiotics used in the treatment of bronchiectasis in CF patients would lead to prolonged symptomatic and computed tomography (CT) scan improvement in orangutans experiencing early signs of ORDS. Nine adult Bornean orangutans (Pongo pygmaeus, eight males, one female, 18-29 yr of age) diagnosed with early ORDS-like respiratory disease underwent CT scan before initiation of treatment. Each animal received a combined course of azithromycin (400 mg 3/wk, mean 7 mg/kg) and levofloxacin (500 mg PO q24h, mean 8.75 mg/kg) for a period of 4-8 wk. CT scan was repeated 6-14 mon after completion of antibiotic treatment. Pretreatment CT showed that six of nine animals had lower respiratory pathology (airway disease, pneumonia, or both). All six orangutans had concurrent sinusitis, mastoiditis, airsacculitis, or a combination of these conditions. Upper respiratory disease alone was observed in three animals. CT showed improvement or resolution in four of five sinusitis cases, improvement in one of two instances of mastoiditis, resolution in five of six instances of airsacculitis, improvement or resolution in six of six instance of lower airway disease (P = 0.03, 95% CI 0.54-1.0], and resolution in five of five cases of pneumonia. Resolution of pretreatment clinical signs was observed in all nine animals. Two developed signs not present at pretreatment. These results show that combination antibiotic therapy with azithromycin and levofloxacin provides improvement in clinical signs and CT evidence of ORDS-related pathology, resulting in symptom-free status in some animals for up to 33 mon.

PMID:34998290 | DOI:10.1638/2020-0049

Respir Med. 2022 Jan 1;192:106728. doi: 10.1016/j.rmed.2021.106728. Online ahead of print.

ABSTRACT

BACKGROUND: Inhaled antibiotics have been incorporated into contemporary European and British guidelines for bronchiectasis, yet no inhaled antibiotics have been approved in the United States or Europe for the treatment of bronchiectasis not related to cystic fibrosis. Pseudomonas aeruginosa infection is common in patients with bronchiectasis, contributing to a cycle of progressive inflammation, exacerbations, and airway remodelling.

OBJECTIVE: The aim of the current study was to identify and evaluate published studies of inhaled tobramycin solution or powder in patients with bronchiectasis and P. aeruginosa infection not associated with cystic fibrosis.

METHODS: A literature review was conducted utilising the PubMed and Cochrane databases. Studies published in the English language that reported safety and/or efficacy outcomes of inhaled tobramycin either alone or in combination with other antibiotics were included.

RESULTS: Seven clinical trials published between 1999 and 2021 were identified that met inclusion criteria. Inhaled tobramycin therapy was effective in reducing P. aeruginosa microbial density in the sputum of patients with bronchiectasis. Several studies demonstrated favourable impacts on hospitalisations, number and severity of exacerbations, and symptoms. Other studies were underpowered for these clinical outcomes or were exploratory in nature. Although tobramycin was generally well tolerated, some evidence of treatment-associated wheezing was reported.

CONCLUSIONS: In patients with bronchiectasis and chronic P. aeruginosa infection, inhaled tobramycin was effective in reducing the density of bacteria in sputum, which may be associated with additional clinical benefits. Definitive phase 3 trials of inhaled tobramycin in patients with bronchiectasis are indicated to determine clinical efficacy and long-term safety.

PMID:34998112 | DOI:10.1016/j.rmed.2021.106728

Health Soc Care Community. 2022 Jan 8. doi: 10.1111/hsc.13714. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is Australia's most common life limiting genetic condition, characterised by declining health and quality of life (QoL) over time. Despite improvements in treatment, there remains no cure. Adolescents and young adults (AYAs) with CF experience broad impacts to psychosocial functioning and QoL, as well as major transitions in care, all at a time of significant developmental change. The importance of developmentally tailored approaches to youth health care and self-management for young people with CF are well understood. However, to date, models of youth specific self-management have been lacking and motivation for young people with CF has not been well explored. This qualitative study, based on a social constructionist epistemological framework, addresses this gap. A total of 21 AYAs aged 15-30 years were recruited through one paediatric and one adult Australian CF centre. Demographic, clinical and distress data were captured to describe health complexity. Semi-structured interviews were audio-recorded, transcribed and analysed using thematic analysis. Participants were representative of Australian AYAs with CF by demography and clinical status. Alarmingly, over a third reported clinically significant distress. Two themes emerged. The first Identified impacts to motivation and self-management resulting from the challenges of managing CF, life and care. These included time and competing priorities, changing health statis, mental health, social factors, unmet needs and health system complexity. The second identified factors that support motivation including: achievement, meaning and purpose; consequence avoidance; and accountability. These results illustrate the importance of AYA specific, theoretically founded, holistic self-management models which extend beyond current theoretical approaches that aim to understand behaviour change or address barriers, in isolation from motivation. Improved approaches to care based on these findings are essential to foster positive behavioural change, support self-management and foster the best health outcomes for young people living with CF.

PMID:34997788 | DOI:10.1111/hsc.13714

Eur Respir J. 2022 Jan 7:2101994. doi: 10.1183/13993003.01994-2021. Online ahead of print.

ABSTRACT

INTRODUCTION: Loss of function variants in both copies of the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF); however, there is evidence that reduction in CFTR function due to the presence of one deleterious variant can have clinical consequences. Here, we hypothesize that CFTR variants in individuals with a history of smoking are associated with COPD and related phenotypes.

METHODS: Whole genome sequencing was performed through the NHLBI TOPMed program in 8597 subjects from the COPDGene study, an observational study of current and former smokers. We extracted clinically annotated CFTR variants and performed single variant and variant-set testing for COPD and related phenotypes. Replication was performed in 2,118 subjects from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study.

RESULTS: We identified 301 coding variants within the CFTR gene boundary: 147 of these have been reported in individuals with CF, including 36 CF-causing variants. We found that CF causing variants were associated with chronic bronchitis in variant-set testing in COPDGene (one sided p-value=0.0025, OR=1.53) and in meta-analysis of COPDGene and ECLIPSE (one sided p-value=0.0060, OR=1.52). Single variant testing revealed that the F508del variant was associated with chronic bronchitis in COPDGene (one sided p-value=0.015, OR=1.47). In addition, we identified 32 subjects with two or more CFTR variants on separate alleles, and these subjects were enriched for COPD cases (p=0.010).

CONCLUSIONS: Cigarette smokers who carry one deleterious CFTR variant have higher rates of chronic bronchitis, while presence of two CFTR variants may be associated with COPD. These results indicate that genetically-mediated reduction in CFTR function contributes to COPD related phenotypes, in particular chronic bronchitis.

PMID:34996830 | DOI:10.1183/13993003.01994-2021