There is accumulating evidence that the lower airway microbiota impacts lung health. However, the link between microbial community composition and lung homeostasis remains elusive. We combine ...amplicon sequencing and bacterial culturing to characterize the viable bacterial community in 234 longitudinal bronchoalveolar lavage samples from 64 lung transplant recipients and establish links to viral loads, host gene expression, lung function, and transplant health. We find that the lung microbiota post-transplant can be categorized into four distinct compositional states, 'pneumotypes'. The predominant 'balanced' pneumotype is characterized by a diverse bacterial community with moderate viral loads, and host gene expression profiles suggesting immune tolerance. The other three pneumotypes are characterized by being either microbiota-depleted, or dominated by potential pathogens, and are linked to increased immune activity, lower respiratory function, and increased risks of infection and rejection. Collectively, our findings establish a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant.
In lung transplant recipients, long-term graft survival relies on the control of inflammation and tissue remodeling to maintain graft functionality and avoid chronic lung allograft dysfunction. ...Although advances in clinical practice have improved transplant success, the mechanisms by which the balance between inflammation and remodeling is maintained are largely unknown.
To assess whether host-microbe interactions in the transplanted lung determine the immunologic tone of the airways, and consequently could impact graft survival.
Microbiota DNA and host total RNA were isolated from 203 bronchoalveolar lavages obtained from 112 patients post-lung transplantation. Microbiota composition was determined using 16S ribosomal RNA analysis, and expression of a set of genes involved in prototypic macrophage functions was quantified using real-time quantitative polymerase chain reaction.
We show that the characteristics of the pulmonary microbiota aligned with distinct innate cell gene expression profiles. Although a nonpolarized activation was associated with bacterial communities consisting of a balance between proinflammatory (e.g., Staphylococcus and Pseudomonas) and low stimulatory (e.g., Prevotella and Streptococcus) bacteria, "inflammatory" and "remodeling" profiles were linked to bacterial dysbiosis. Mechanistic assays provided direct evidence that bacterial dysbiosis could lead to inflammatory or remodeling profiles in macrophages, whereas a balanced microbial community maintained homeostasis.
The crosstalk between bacterial communities and innate immune cells potentially determines the function of the transplanted lung offering novel pathways for intervention strategies.
Drugs modulating the cystic fibrosis transmembrane conductance regulator (CFTR) protein, namely ivacaftor, lumacaftor, tezacaftor, and elexacaftor, are currently revolutionizing the management of ...patients with cystic fibrosis (CF), particularly those with at least one F508del variant (up to 85% of patients). These “caftor” drugs are mainly metabolized by cytochromes P450 3A, whose enzymatic activity is influenced by environmental factors, and are sensitive to inhibition and induction. Hence, CFTR modulators are characterized by an important interindividual pharmacokinetic variability and are also prone to drug–drug interactions. However, these CFTR modulators are given at standardized dosages, while they meet all criteria for a formal therapeutic drug monitoring (TDM) program that should be considered in cases of clinical toxicity, less-than-expected clinical response, drug or food interactions, distinct patient subgroups (i.e., pediatrics), and for monitoring short-term adherence. While the information on CFTR drug exposure–clinical response relationships is still limited, we review the current evidence of the potential interest in the TDM of caftor drugs in real-life settings.
Barriers and motives towards physical activity (PA) in lung transplant (LTx) recipients with cystic fibrosis (CF) are largely unknown. We aimed to explore perceptions towards PA in LTx recipients ...with CF to better understand individuals' needs and preferences.
Participants completed an online survey at two Swiss LTx and one follow-up shared care centre between June and December 2018.
One hundred and eleven individuals completed the survey (87.4% response rate). Overall, survey participants perceive PA as important for their daily life and health. Perceived motives of PA were improving muscle strength, endurance and quality of life (QoL), to feel better, fun, to achieve personal goals and having more energy for everyday life. Fatigue was the most common perceived barrier to PA and associated with poorer QoL (r = -0.43, p<0.001) and health status (r = -0.31, p = 0.001). Participants with lung allograft dysfunction (LAD, n = 20) reported lower habitual PA (p = 0.009) and health status (p = 0.011), and rated shortness of breath, bad weather and concerns regarding lung rejection higher than those without LAD (all p<0.05). When we asked how an optimal training programme should look like, the majority would prefer individual, non-supervised (60%), outdoor (77%), endurance training (90%), once or twice a week (47%) for 40-60 minutes (48%). Only a minority of patients (14%) would be willing to use exercise applications for their home-based training.
LTx recipients with CF value PA as important for their health. People with CF should be encouraged individually by their multidisciplinary transplant team to implement PA in their daily life, potential barriers should be identified and addressed. Overall, knowledge on perceived barriers and motives for PA should be considered in the development of future patient-centred PA programmes.
is the etiological agent of diphtheria, a disease caused by the presence of the diphtheria toxin. However, an increasing number of records report non-toxigenic
infections. Here, a
strain was ...recovered from a patient with a past history of bronchiectasis who developed a severe tracheo-bronchitis with multiple whitish lesions of the distal trachea and the mainstem bronchi. Whole-genome sequencing (WGS), performed in parallel with PCR targeting the toxin gene and the Elek test, provided clinically relevant results in a short turnaround time, showing that the isolate was non-toxigenic. A comparative genomic analysis of the new strain (CHUV2995) with 56 other publicly available genomes of
revealed that the strains CHUV2995, CCUG 5865 and CMCNS703 share a lower average nucleotide identity (ANI) (95.24 to 95.39%) with the
NCTC 11397
reference genome than all other
genomes (>98.15%). Core genome phylogeny confirmed the presence of two monophyletic clades. Based on these findings, we propose here two new
subspecies to replace the lineage denomination used in previous multilocus sequence typing studies:
subsp.
subsp. nov. (instead of lineage-2), regrouping strains CHUV2995, CCUG 5865, and CMCNS703, and
subsp.
subsp. nov, regrouping all other
in the dataset (instead of lineage-1). Interestingly, members of subspecies
displayed a larger genome size than subspecies
and were enriched in COG categories related to transport and metabolism of lipids (I) and inorganic ion (P). Conversely, they lacked all genes involved in the synthesis of pili (SpaA-type, SpaD-type and SpaH-type), molybdenum cofactor and of the nitrate reductase. Finally, the CHUV2995 genome is particularly enriched in mobility genes and harbors several prophages. The genome encodes a type II-C CRISPR-Cas locus with 2 spacers that lacks
or
, which could hamper the acquisition of new spacers and render strain CHUV2995 more susceptible to bacteriophage infections and gene acquisition through various mechanisms of horizontal gene transfer.
Lower respiratory tract infections lead to significant morbidity and mortality. They are increasingly caused by multidrug-resistant pathogens, notably in individuals with cystic fibrosis, ...hospital-acquired pneumonia and lung transplantation. The use of bacteriophages (phages) to treat bacterial infections is gaining growing attention, with numerous published cases of compassionate treatment over the last few years. Although the use of phages appears safe, the lack of standardisation, the significant heterogeneity of published studies and the paucity of robust efficacy data, alongside regulatory hurdles arising from the existing pharmaceutical legislation, are just some of the challenges phage therapy has to overcome. In this review, we discuss the lessons learned from recent clinical experiences of phage therapy for the treatment of pulmonary infections. We review the key aspects, opportunities and challenges of phage therapy regarding formulations and administration routes, interactions with antibiotics and the immune system, and phage resistance. Building upon the current knowledge base, future pre-clinical studies using emerging technologies and carefully designed clinical trials are expected to enhance our understanding and explore the therapeutic potential of phage therapy.
Fungal infections are estimated to be the main cause of death for more than 1.5 million people worldwide annually. However, fungal pathogenicity has been largely neglected. This is notably the case ...for pulmonary fungal infections, which are difficult to diagnose and to treat. We are currently facing a global emergence of antifungal resistance, which decreases the chances of survival for affected patients. New therapeutic approaches are therefore needed to face these life-threatening fungal infections. In this review, we will provide a general overview on respiratory fungal infections, with a focus on fungi of the genus
. Next, the immunological and microbiological mechanisms of fungal pathogenesis will be discussed. The role of the respiratory mycobiota and its interactions with the bacterial microbiota on lung fungal infections will be presented from an ecological perspective. Finally, we will focus on existing and future innovative approaches for the treatment of respiratory fungal infections.
We assessed for the first time the safety and efficacy of bronchoscopically inserted cs‐FM for CyberKnife® SBRT delivery. We show that this technique is safe and resulted in a very high PPL tracking ...rate enabling optimal SBRT delivery.
See Cover Image
See related Editorial
ABSTRACT
Background and objective
SBRT is an alternative treatment for early‐stage inoperable lung cancer. Metallic FM allow to increase tumour tracking precision by CyberKnife®. Currently used techniques for FM placement have many limitations; transthoracic insertion has a high risk for pneumothorax, endovascular insertion requires expertise and dedicated angiography infrastructure and endobronchial linear‐gold FM dislocate frequently. This is the first study to assess the safety and efficacy of cs‐FM endobronchial insertion under fluoroscopy with or without R‐EBUS assessment.
Methods
We retrospectively evaluated all consecutive patients undergoing endobronchial cs‐FM placement for at least one PPL <25 mm between 10.2015 and 12.2019. TBB of the PPL were performed in case of a typical R‐EBUS signal. PPL tracking accuracy by CyberKnife, complications, cs‐FM migration rate and procedure duration were analysed.
Results
A total of 52 patients were treated during 55 procedures and 207 cs‐FM were placed in 70 PPL. Tracking was successful for 65 of 70 (93%) PPL. R‐EBUS was performed for 33 (47%) PPL and TBB for 9 (13%) PPL. Bronchospasm occurred once and any other complications were observed. Migration of cs‐FM occurred in 16 of 207 (8%) cs‐FM. Migration was more frequent when the target was in a previously irradiated area (P = 0.022). The median bronchoscopy duration was 31.5 min (n = 48 procedures).
Conclusion
Bronchoscopic cs‐FM placement is a rapid and safe procedure. It is associated with a low migration rate and allows precise SBRT delivery. Previous irradiation of the PPL was associated with a higher migration rate.
Idiopathic pulmonary fibrosis (IPF) has been associated with abnormal vascular remodeling. Bone marrow derived endothelial progenitor cells (EPCs) are considered to possess lung tissue repair and ...vascular remodeling properties.
The study aimed to assess early EPCs levels and EPCs endogenous vascular endothelial growth factor (VEGF) expression in IPF. In order to examine alterations in the mobilization of EPCs from the bone marrow we measured plasma VEGF.
Twenty-three patients with IPF and fifteen healthy subjects were included. The number of early EPCs colonies was markedly reduced in IPF patients vs controls (6.00±6.49 vs 49.68±16.73, respectively, p<0.001). EPCs were further decreased in patients presenting systolic pulmonary arterial pressure (sPAP)≥35 mmHg. The number of colonies per well correlated negatively with P((A-a))O(2) (r = -0.750, p<0.001). Additionally, VEGF mRNA levels were significantly increased in IPF patients. There were no differences observed in VEGF plasma levels in IPF patients when compared to controls.
The current data suggest that inadequate levels of early EPCs may potentially contribute to suppressed repair and recovery of the damaged pulmonary endothelium and thereby may drive the sequence of events in profibrogenic direction. Increased VEGFmRNA levels in the clinical context of IPF may represent a compensatory mechanism to overcome reduced EPCs levels.
Background Exacerbations of COPD (ECOPD) remain a major cause of mortality and morbidity. Despite advances in the understanding of their pathophysiology, their assessment relies primarily on clinical ...presentation, which can be variable and difficult to predict. A large number of biomarkers already have been assessed in this context, and some appear to be promising. Methods An online search for articles published until December 2010 was conducted using three terms for ECOPD, five terms for biomarkers, and five terms for the sampling method. Biomarkers were evaluated for their potential role in the establishment and confirmation of the diagnosis of ECOPD, the evaluation of etiology and severity, the prediction of prognosis, and the guidance of treatment decisions. Results Several systemic biomarkers have been measured in the context of ECOPD, and most have been found to increase at ECOPD onset and to subside during the course of exacerbations. Correlations have been reported among these biomarkers, but direct associations with clinical variables have been more difficult to establish. Although there are several limitations yet to be addressed, some of the biomarkers, most notably C-reactive protein for the identification of an ECOPD and procalcitonin for antibiotic guidance, may provide clinically relevant information. Conclusions So far, no single biomarker has been able to gain wide acceptance, but some provide clinically useful information. The evaluation of such biomarkers in large decision-making studies is expected to become an area of intense investigation in the near future.
PDF
