Microbiol Spectr. 2023 Nov 15:e0273123. doi: 10.1128/spectrum.02731-23. Online ahead of print.

ABSTRACT

Burkholderia cenocepacia causes severe infections in cystic fibrosis (CF) patients. CF patients are prone to reoccurring infections due to the accumulation of mucus in their lungs, where bacteria can adhere and grow. Some of the antibiotics that inhibit B. cenocepacia in the laboratory are not effective for CF patients. A major contributor to poor clinical outcomes is that antibiotic testing in laboratories occurs under conditions that are different from those of sputum. CF sputum may be acidic and have increased concentrations of iron and zinc. Here, we used a medium that mimics CF sputum and found that acidic pH decreased the activity of many of the antibiotics used against B. cenocepacia. In addition, we assessed susceptibility to more than 500 antibiotics and found four active compounds against B. cenocepacia. Our findings give a better understanding of the lack of a relationship between susceptibility testing and the clinical outcome when treating B. cenocepacia infections.

PMID:37966209 | DOI:10.1128/spectrum.02731-23

J Clin Invest. 2023 Nov 15;133(22):e170500. doi: 10.1172/JCI170500.

ABSTRACT

Over the last decade, several organoid models have evolved to acquire increasing cellular, structural, and functional complexity. Advanced lung organoid platforms derived from various sources, including adult, fetal, and induced pluripotent stem cells, have now been generated, which more closely mimic the cellular architecture found within the airways and alveoli. In this regard, the establishment of novel protocols with optimized stem cell isolation and culture conditions has given rise to an array of models able to study key cellular and molecular players involved in lung injury and repair. In addition, introduction of other nonepithelial cellular components, such as immune, mesenchymal, and endothelial cells, and employment of novel precision gene editing tools have further broadened the range of applications for these systems by providing a microenvironment and/or phenotype closer to the desired in vivo scenario. Thus, these developments in organoid technology have enhanced our ability to model various aspects of lung biology, including pathogenesis of diseases such as chronic obstructive pulmonary disease, pulmonary fibrosis, cystic fibrosis, and infectious disease and host-microbe interactions, in ways that are often difficult to undertake using only in vivo models. In this Review, we summarize the latest developments in lung organoid technology and their applicability for disease modeling and outline their strengths, drawbacks, and potential avenues for future development.

PMID:37966116 | DOI:10.1172/JCI170500

Front Cell Infect Microbiol. 2023 Oct 26;13:1250339. doi: 10.3389/fcimb.2023.1250339. eCollection 2023.

ABSTRACT

Pseudomonas aeruginosa is a major human pathogen, particularly effective at colonizing the airways of patients with cystic fibrosis. Bacteriophages are highly abundant at infection sites, but their impact on mammalian immunity remains unclear. We previously showed that Pf4, a temperate filamentous bacteriophage produced by P. aeruginosa, modifies the innate immune response to P. aeruginosa infections via TLR3 signaling, but the underlying mechanisms remained unclear. Notably, Pf4 is a single-stranded DNA and lysogenic phage, and its production does not typically result in lysis of its bacterial host. We identified previously that internalization of Pf4 by human or murine immune cells triggers maladaptive viral pattern recognition receptors and resulted in bacterial persistence based on the presence of phage RNA. We report now that Pf4 phage dampens inflammatory responses to bacterial endotoxin and that this is mediated in part via bacterial vesicles attached to phage particles. Outer membrane vesicles (OMVs) are produced by Gram-negative bacteria and play a key role in host pathogen interaction. Recently, evidence has emerged that OMVs differentially package small RNAs. In this study, we show that Pf4 are decorated with OMVs that remain affixed to Pf4 despite of purification steps. These phages are endocytosed by human cells and delivered to endosomal vesicles. We demonstrate that short RNAs within the OMVs form hairpin structures that trigger TLR3-dependent type I interferon production and antagonize production of antibacterial cytokines and chemokines. In particular, Pf4 phages inhibit CXCL5, preventing efficient neutrophil chemotaxis in response to endotoxin. Moreover, blocking IFNAR or TLR3 signaling abrogates the effect of Pf4 bound to OMVs on macrophage activation. In a murine acute pneumonia model, mice treated with Pf4 associated with OMVs show significantly less neutrophil infiltration in BAL fluid than mice treated with purified Pf4. These changes in macrophage phenotype are functionally relevant: conditioned media from cells exposed to Pf4 decorated with OMVs are significantly less effective at inducing neutrophil migration in vitro and in vivo. These results suggest that Pf4 phages alter innate immunity to bacterial endotoxin and OMVs, potentially dampening inflammation at sites of bacterial colonization or infection.

PMID:37965262 | PMC:PMC10641230 | DOI:10.3389/fcimb.2023.1250339

ERJ Open Res. 2023 Nov 13;9(6):00560-2023. doi: 10.1183/23120541.00560-2023. eCollection 2023 Nov.

ABSTRACT

Patients with severe asthma perceive beneficial effects of biologics and good self-reported adherence to treatment, even when self-administered at home https://bit.ly/48vP70w.

PMID:37965229 | PMC:PMC10641582 | DOI:10.1183/23120541.00560-2023

Ann Am Thorac Soc. 2023 Nov 14. doi: 10.1513/AnnalsATS.202306-576OC. Online ahead of print.

ABSTRACT

RATIONALE: Rates of viral respiratory infection (VRI) are similar in people with cystic fibrosis (CF) and the general population; however, the associations between VRI and CF pulmonary exacerbations (PEx) require further elucidation.

OBJECTIVES: To determine VRI prevalence during CF PEx and evaluate associations between VRI, clinical presentation, and treatment response.

METHODS: The Standardized Treatment of Pulmonary Exacerbations II (STOP2) study was a multicenter, randomized trial to evaluate different durations of intravenous antibiotic therapy for PEx. In this ancillary study, participant sputum samples from up to three study visits were tested for respiratory viruses using multiplex PCR. Baselines and treatment associated changes in mean lung function (percent predicted forced expiratory volume in one second; ppFEV1), respiratory symptoms (Chronic Respiratory Infection Symptom Score; CRISS), weight, and C-reactive protein (CRP) were compared as a function of virus detection. Odds of PEx retreatment within 30 days and future PEx hazard were modeled by logistic and Cox proportional hazards regression, respectively.

RESULTS: A total of 1,254 sputum samples from 621 study participants were analyzed. One or more respiratory viruses were detected in sputum samples from 245 participants (39.5%). Virus-positive participants were more likely to be receiving CF transmembrane conductance regulator (CFTR) modulator therapy (45% vs. 34%) and/or chronic azithromycin therapy (54% vs. 44%), and more likely to have received treatment for nontuberculous mycobacterium infection in the preceding two years (7% vs. 3%). At study visit 1, virus-positive participants were more symptomatic (mean CRISS score 53.8 vs. 51.1), had evidence of greater systemic inflammation (log10CRP concentration: 1.32 log10 mg/L vs. 1.23 log10 mg/L), and had a greater drop in ppFEV1 from the prior 6-month baseline (5.8 vs 3.6). Virus positivity was associated with reduced risk of future PEx (HR: 0.82, 95% CI: 0.69-0.99; p=0.034) and longer median time to next PEx (255 days vs. 172 days, p=0.021) compared to virus-negativity.

CONCLUSIONS: Over one-third of STOP2 participants treated for a PEx tested positive for a respiratory virus with more symptomatic initial presentation compared to virus-negative participants, but favorable long-term outcomes. More refined phenotyping of PEx, taking VRIs into account, may aid in optimizing personalized management of PEx.

CLINICAL TRIAL REGISTRATION: NCT02781610 Primary Source of Funding: Cystic Fibrosis Foundation.

PMID:37963297 | DOI:10.1513/AnnalsATS.202306-576OC

Expert Rev Clin Immunol. 2023 Nov 14. doi: 10.1080/1744666X.2023.2284226. Online ahead of print.

ABSTRACT

BACKGROUND: The pharmacokinetics and pharmacodynamics of biosimilar infliximab (IFX-BioS) in pediatric inflammatory bowel disease (IBD) are poorly investigated. The aim of this study was to investigate factors predicting IFX-BioS trough levels (TLs).

RESEARCH DESIGN AND METHODS: IBD children with an indication to start IFX-BioS were included in this prospective observational study (January 2021-June 2022). TLs were measured at the 4th and 6th infusions and correlated with several covariates.

RESULTS: A total of 110 TLs in 55 children were included. The multivariate linear regression model at the 4th infusion found a positive correlation between TLs and age at diagnosis (B:1.950, 95% CI: [0.019, 3.882], p = 0.048) and IFX-BioS dose/kg (B:1.962, 95% CI: [0.238, 3.687], p = 0.029), and a negative correlation with clinical scores (B:-0.401, 95% CI: [-0.738, -0.064], p = 0.023). At the 6th infusion, female gender (B:6.887, 95% CI: [0.861, 12.913], p = 0.029), hemoglobin (B:1.853, 95% CI: [0.501, 3.204], p = 0.011), and IFX-BioS dose/kg (B:1.792, 95% CI: [0.979, 2.605], p < 0.001) were found to be positively correlated to TLs. No association between combined clinical and biochemical remission and TLs was found.

CONCLUSIONS: This study discovered some predictors for IFX-BioS TLs in IBD children. Knowledge of predictive factors could help physicians choose the best dosing regimen.

PMID:37962991 | DOI:10.1080/1744666X.2023.2284226

Physiology (Bethesda). 2023 Nov 14. doi: 10.1152/physiol.00023.2023. Online ahead of print.

ABSTRACT

The Nedd4 family of E3 ubiquitin ligases, consisting of a C2-WW(n)-HECT domain architecture, include the closely related Nedd4/Nedd4-1 and Nedd4L/Nedd4-2, which play critical roles in human physiology and pathophysiology. This review focuses on the regulation of enzymatic activity of these Nedd4 proteins, as well as on their roles in regulating stability and function of membrane and other signaling proteins, such as ion channels, ion transporters and growth factor receptors. The diseases caused by impairment of such regulation are discussed, as well as opportunities and challenges for targeting these enzymes for therapy.

PMID:37962894 | DOI:10.1152/physiol.00023.2023

J Clin Microbiol. 2023 Nov 14:e0061423. doi: 10.1128/jcm.00614-23. Online ahead of print.

ABSTRACT

Standardized approaches to phage susceptibility testing (PST) are essential to inform selection of phages for study in patients with bacterial infections. There is no reference standard for assessing bacterial susceptibility to phage. We compared agreement between PST performed at three centers: two centers using a liquid assay standardized between the sites with the third, a plaque assay. Four Pseudomonas aeruginosa phages: PaWRA01ø11 (EPa11), PaWRA01ø39 (EPa39), PaWRA02ø83 (EPa83), PaWRA02ø87 (EPa87), and a cocktail of all four phages were tested against 145 P. aeruginosa isolates. Comparisons were made within measurements at the two sites performing the liquid assay and between these two sites. Agreement was assessed based on coverage probability (CP8), total deviation index, concordance correlation coefficient (CCC), measurement accuracy, and precision. For the liquid assay, there was satisfactory agreement among triplicate measurements made on different days at site 1, and high agreement based on accuracy and precision between duplicate measurements made on the same run at site 2. There was fair accuracy between measurements of the two sites performing the liquid assay, with CCCs below 0.6 for all phages tested. When compared to the plaque assay (performed once at site 3), there was less agreement between results of the liquid and plaque assays than between the two sites performing the liquid assay. Similar findings to the larger group were noted in the subset of 46 P. aeruginosa isolates from cystic fibrosis. Results of this study suggest that reproducibility of PST methods needs further development.

PMID:37962552 | DOI:10.1128/jcm.00614-23

Lung India. 2023 Nov-Dec;40(6):527-536. doi: 10.4103/lungindia.lungindia_69_23.

ABSTRACT

BACKGROUND: The prevalence of allergic bronchopulmonary aspergillosis (ABPA) in Indian asthmatic patients remains unknown. We systematically reviewed the literature for estimating the prevalence of Aspergillus sensitization (AS) and ABPA in Indian subjects with bronchial asthma.

METHODS: We searched the PubMed and Embase databases for studies from India reporting the prevalence of AS or ABPA in at least 50 asthmatics. The primary outcome of our study was to assess the prevalence of ABPA. The secondary outcomes were to evaluate the prevalence of AS in asthma and ABPA in Aspergillus-sensitized asthma. We pooled the prevalence estimates using a random effects model and examined the factors influencing the prevalence using multivariate meta-regression.

RESULTS: Of the 8,383 records retrieved, 34 studies with 14,580 asthmatics met the inclusion criteria. All the studies were from tertiary centers. The pooled prevalence of ABPA in asthmatics (26 studies; 5,554 asthmatics) was 16.2% [95% confidence interval (CI), 12.5-20.4]. The pooled prevalence of AS in asthma (29 studies; 13,405 asthmatics) was 30.9% (95% CI, 25.3-36.6), while the prevalence of ABPA in AS (20 studies; 1,493 asthmatics) was 48.2% (95% CI, 39.6-56.8). Meta-regression identified studies published after 2009 (OR 1.14; 95% CI, 1.02-1.28) and studies with severe asthmatics (OR 1.12; 95% CI, 1.00-1.26) as the only factors associated with higher ABPA prevalence.

CONCLUSIONS: There is a high prevalence of ABPA in Indian asthmatic subjects at tertiary centers, underscoring the need for screening all asthmatic subjects in special asthma and chest clinics for ABPA.

PMID:37961961 | DOI:10.4103/lungindia.lungindia_69_23

Int J Mol Sci. 2023 Oct 30;24(21):15766. doi: 10.3390/ijms242115766.

ABSTRACT

Cystic Fibrosis is a chronic disease affecting multiple systems, including the GI tract. Clinical manifestation in patients can start as early as infancy and vary across different age groups. With the advent of new, highly effective modulators, the life expectancy of PwCF has improved significantly. Various GI aspects of CF care, such as nutrition, are linked to an overall improvement in morbidity, lung function and the quality of life of PwCF. The variable clinical presentations and management of GI diseases in pediatrics and adults with CF should be recognized. Therefore, it is necessary to ensure efficient transfer of information between pediatric and adult providers for proper continuity of management and coordination of care at the time of transition. The transition of care is a challenging process for both patients and providers and currently there are no specific tools for GI providers to help ensure a smooth transition. In this review, we aim to highlight the crucial features of GI care at the time of transition and provide a checklist that can assist in ensuring an effective transition and ease the challenges associated with it.

PMID:37958749 | DOI:10.3390/ijms242115766

Int J Mol Sci. 2023 Oct 30;24(21):15741. doi: 10.3390/ijms242115741.

ABSTRACT

The Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) is a large multi-spanning membrane protein that is susceptible to misfolding and aggregation. We have identified here the region responsible for this instability. Temperature-induced aggregation of C-terminally truncated versions of CFTR demonstrated that all truncations up to the second transmembrane domain (TMD2), including the R region, largely resisted aggregation. Limited proteolysis identified a folded structure that was prone to aggregation and consisted of TMD2 and at least part of the Regulatory Region R. Only when both TM7 (TransMembrane helix 7) and TM8 were present, TMD2 fragments became as aggregation-sensitive as wild-type CFTR, in line with increased thermo-instability of late CFTR nascent chains and in silico prediction of aggregation propensity. In accord, isolated TMD2 was degraded faster in cells than isolated TMD1. We conclude that TMD2 extended at its N-terminus with part of the R region forms a protease-resistant structure that induces heat instability in CFTR and may be responsible for its limited intracellular stability.

PMID:37958724 | DOI:10.3390/ijms242115741

Healthcare (Basel). 2023 Oct 31;11(21):2873. doi: 10.3390/healthcare11212873.

ABSTRACT

BACKGROUND: Longitudinal data on changes in health-related quality of life (HRQoL) in adult people with cystic fibrosis (pwCF) and the longitudinal effects of Elexacaftor/Tezacaftor/Ivacaftor therapy (ETI) on HRQoL or HRQoL domains are currently scarce. This study aimed to investigate the effects of ETI on HRQoL and compare them with those of pwCF who did not receive highly effective CFTR modulators over a longer period.

METHODS: Baseline assessment and follow-up data for 5.6 years in pwCF with (n = 21) and 6.5 years in pwCF without (n = 6) ETI (≥18 years) were evaluated. The assessment of HRQoL and clinical parameters was identical at both time points. HRQoL was assessed using the CFQ-R, and clinical outcomes included BMI, ppFEV1, and FEV1 z-score.

RESULTS: ETI was found to improve all HRQoL domains at more than four points over time, and their increases were significant except for vitality, digestion, treatment burden, and social functioning (p < 0.05). Without ETI, psychosocial domains remained almost constant, whereas most physical domains decreased over time.

CONCLUSIONS: The results of the present study show that ETI therapy has a positive effect on HRQoL and clinical outcomes over time but not in pwCF without ETI treatment. Furthermore, our results suggest that disease progression over time affects the physical domains of HRQoL more than the psychosocial domains. Due to the small sample size and the heterogeneity of the study population (CFTR mutation genotype), the results should be interpreted with some caution.

PMID:37958017 | DOI:10.3390/healthcare11212873

Respir Res. 2023 Nov 13;24(1):278. doi: 10.1186/s12931-023-02593-1.

ABSTRACT

Several risk factors for Coronavirus-2019 (COVID-19) disease have been highlighted in clinical evidence. Among the various risk factors are advanced age, metabolic illness such as diabetes, heart disease, and diseases of the respiratory system. Cystic Fibrosis (CF) is a rare disease with autosomal recessive transmission, characterised by a lack of synthesis of the CFTR channel protein, and multi-organ clinical symptoms mainly affecting the respiratory tract with recurrent pulmonary exacerbations. In view of the pathophysiological mechanisms, CF disease should be in theory considered a risk factor for SARS-CoV2 or severe COVID-19. However, recent clinical evidence seems to point in the opposite direction, suggesting that CF could be a protective factor against severe COVID-19. Possibly, the lack of presence or function of the CFTR channel protein could be linked to the expression of the membrane glycoprotein ACE-2, a key enzyme for the endocellular penetration of SARS-CoV-2 and related to the pathophysiology of COVID-19 disease. Furthermore, CFTR channel modulating agents could indirectly influence the expression of ACE-2, playing an important role in restoring the proper functioning of mucociliary clearance and the pulmonary microbiome in the host response to SARS-CoV-2 infection. In this review, the authors attempt to shed light on these important associations of issues that are not yet fully elucidated.

PMID:37957647 | DOI:10.1186/s12931-023-02593-1

Therapie. 2023 Oct 31:S0040-5957(23)00170-1. doi: 10.1016/j.therap.2023.09.007. Online ahead of print.

ABSTRACT

The psychiatric risks associated with drugs are sometimes one of the few restrictions on the use of certain drug classes, such as corticosteroids in patients with a history of severe psychotic episodes associated with this drug class. In this non-exhaustive review, we propose to deal with the most recent issues concerning psychiatric disorders induced by drugs and encountered in doctors' clinical practice. Firstly, we look at depressive disorders and suicide risks, secondly at psychotic and manic disorders and thirdly at anxiety and sleep disorders. While lot of drugs are associated with psychiatric disorders, the confounding by indication represents an important methodological gap since information on the psychiatric profile of patients is not always available. This is particularly the case for serotonin reuptake inhibitors and esketamine used as antidepressants. Recent pharmacovigilance concerns of psychiatric disorders emerged with montelukast, orexin receptor antagonists or cystic fibrosis transmembrane regulator (CFTR) modulators.

PMID:37957053 | DOI:10.1016/j.therap.2023.09.007

Lancet Respir Med. 2023 Nov 10:S2213-2600(23)00303-X. doi: 10.1016/S2213-2600(23)00303-X. Online ahead of print.

ABSTRACT

BACKGROUND: Dupilumab efficacy and safety in children aged 6-11 years with uncontrolled, moderate-to-severe asthma were shown in the VOYAGE study-a 52-week, multinational, multicentre, phase 3 randomised, double-blind, placebo-controlled trial. We aimed to evaluate the long-term safety and efficacy of dupilumab in children with moderate-to-severe asthma who previously participated in the VOYAGE study.

METHODS: 365 of 408 children with moderate-to-severe asthma from VOYAGE enrolled in EXCURSION, a 52 week, open-label extension study conducted at 70 centres across 17 countries. 240 children continued with add-on dupilumab (dosed according to bodyweight: 100 mg for those weighing ≤30 kg and 200 mg for those weighing more than 30 kg at EXCURSION baseline) once every 2 weeks administered by subcutaneous injection (dupilumab/dupilumab group) and 125 children on placebo during VOYAGE initiated dupilumab (100 or 200 mg, according to bodyweight), once every 2 weeks administered by subcutaneous injection (placebo/dupilumab group). Following a protocol amendment, for a subset of children weighing 30 kg or less, the dose was changed to 300 mg once every 4 weeks. The primary endpoint for the open-label extension study was the number and proportion of patients with any treatment-emergent adverse event (TEAE) during the 52-week study period in the overall population (defined as children aged 6-11 years old with moderate-to-severe asthma who previously completed VOYAGE). Statistical analyses were descriptive. This study is registered with ClinicalTrials.gov (NCT03560466; EXCURSION).

FINDINGS: Children who completed VOYAGE were eligible to enrol in EXCURSION between June 21, 2018 and Aug 18, 2020. During EXCURSION, the safety profile and proportion of patients reporting TEAEs were consistent with those observed during the parent study (VOYAGE). In the overall population, 232 (63·6%) of 365 patients experienced at least one TEAE (dupilumab/dupilumab: 147 [61·3%]; placebo/dupilumab: 85 [68·0%]). The most frequently reported TEAEs were nasopharyngitis, pharyngitis, and upper respiratory tract infections.

INTERPRETATION: In EXCURSION, long-term treatment with dupilumab was well tolerated with an acceptable safety profile.

FUNDING: Sanofi and Regeneron Pharmaceuticals.

PMID:37956679 | DOI:10.1016/S2213-2600(23)00303-X

Proc Natl Acad Sci U S A. 2023 Nov 21;120(47):e2312995120. doi: 10.1073/pnas.2312995120. Epub 2023 Nov 13.

ABSTRACT

A model for antibiotic accumulation in bacterial biofilm microcolonies utilizing heterogenous porosity and attachment site profiles replicated the periphery sequestration reported in prior experimental studies on Pseudomonas aeruginosa PAO1 biofilm cell clusters. These P. aeruginosa cell clusters are in vitro models of the chronic P. aeruginosa infections in cystic fibrosis patients which display recalcitrance to antibiotic treatments, leading to exacerbated morbidity and mortality. This resistance has been partially attributed to periphery sequestration, where antibiotics fail to penetrate biofilm cell clusters. The physical phenomena driving this periphery sequestration have not been definitively established. This paper introduces mathematical models to account for two proposed physical phenomena driving periphery sequestration: biofilm matrix attachment and volume-exclusion due to variable biofilm porosity. An antibiotic accumulation model which incorporated these phenomena better fit observed periphery sequestration data compared to previous models.

PMID:37956290 | DOI:10.1073/pnas.2312995120

Curr Microbiol. 2023 Nov 13;81(1):6. doi: 10.1007/s00284-023-03524-5.

ABSTRACT

Stenotrophomonas maltophilia is a Gram-negative opportunistic pathogen that can cause many infections, such as chronic pulmonary infections in patients with cystic fibrosis and infections in immunocompromised patients with hematology-oncology diseases. Because of its remarkable and increasing antimicrobial resistance, the treatment of S. maltophilia infections is quite challenging. Meanwhile, the prevalence of S. maltophilia infections is increasing in recent decades. S. maltophilia is usually considered to be of low virulence but has numerous virulence factors involved in the pathogenesis of infections caused by S. maltophilia. By revealing its pathogenesis associated with virulence factors and molecular mechanisms of antimicrobial resistance, many existing or potential therapeutic strategies have been developed. However, because of the limited treatment options, new strategies are urgently needed. Here, we review the recent progresses in research on S. maltophilia which may help to develop more effective treatments against this increasing threat.

PMID:37955756 | DOI:10.1007/s00284-023-03524-5

Cureus. 2023 Oct 11;15(10):e46866. doi: 10.7759/cureus.46866. eCollection 2023 Oct.

ABSTRACT

Muco-obstructive lung disease is a new classification under the diseases of respiratory tract. A lot of discussion is still going on regarding this new group of diseases. It is characterised by obstruction of the respiratory tract with a thick mucin layer. Usually in normal individuals, the mucus is swept out of the respiratory system while coughing in the form of sputum or phlegm, but if the consistency of the mucus is thick, or the amount is heavy or there is a certain defect in the ciliary function of the respiratory tract, the mucus is not cleared and it gets accumulated in the lungs alveoli, therefore blocking it. The mucus trapped in the distal airways cannot be cleared by coughing therefore forming a layer in the alveoli and bronchioles. Long-standing condition causes inflammation and infection. This new group of diseases specifically includes chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), primary ciliary dyskinesia (PCD) and non-cystic fibrosis bronchiectasis (NCFB). Asthma, although an obstructive disease of the lung, is not particularly included under muco-obstructive lung disease. The major symptoms with which these diseases present are sputum production, chronic cough and acute exacerbations of the condition. The mucus adheres to the lung parenchyma causing airway obstruction and hyperinflation. In this article, we will see how muco-obstructive lung diseases affect the normal physiology of the respiratory system and how is it different from other obstructive and restrictive lung diseases. We will individually look into all the four conditions that come under the category of muco-obstructive lung diseases.

PMID:37954759 | PMC:PMC10637992 | DOI:10.7759/cureus.46866

Front Microbiol. 2023 Oct 26;14:1256785. doi: 10.3389/fmicb.2023.1256785. eCollection 2023.

ABSTRACT

The Gram-negative opportunistic pathogen Pseudomonas aeruginosa possesses hierarchical quorum sensing (QS) systems. The intricate QS network of P. aeruginosa synchronizes a suite of virulence factors, contributing to the mortality and morbidity linked to the pathogenicity of this bacterium. Previous studies have revealed that variations in the lasR gene are frequently observed in chronic isolates of cystic fibrosis (CF). Specifically, LasRQ45stop was identified as a common variant among CF, lasR mutants during statistical analysis of the clinical lasR mutants in the database. In this study, we introduced LasRQ45stop into the chromosome of P. aeruginosa PAO1 through allelic replacement. The social traits of PAO1 LasRQ45stop were found to be equivalent to those of PAO1 LasR-null isolates. By co-evolving with the wild-type in caseinate broth, elastase-phenotypic-variability variants were derived from the LasRQ45stop subpopulation. Upon further examination of four LasRQ45stop sublines, we determined that the variation of T2SS-peptidase xcpA and mexT genes plays a pivotal role in the divergence of various phenotypes, including public goods elastase secretion and other pathogenicity traits. Furthermore, XcpA mutants demonstrated a fitness advantage compared to parent strains during co-evolution. Numerous phenotypic variations were associated with subline-specific genetic alterations. Collectively, these findings suggest that even within the same parental subline, there is ongoing microevolution of individual mutational trajectory diversity during adaptation.

PMID:37954251 | PMC:PMC10637944 | DOI:10.3389/fmicb.2023.1256785

Ann Otol Rhinol Laryngol. 2023 Nov 12:34894231211626. doi: 10.1177/00034894231211626. Online ahead of print.

ABSTRACT

BACKGROUND: Many people with cystic fibrosis (PwCF) have chronic rhinosinusitis (CRS). CRS requires additional management beyond that of pulmonary disease and leads to increased utilization of healthcare resources. Elexacaftor/tezacaftor/ivacaftor (ETI) is a highly effective modulator therapy that has been shown to improve CRS in PwCF. However, the impact of ETI on rhinologic healthcare utilization is understudied.

OBJECTIVE: To compare rates of rhinologic healthcare utilization and procedures among PwCF prior to and after initiating ETI therapy.

METHODS: A single-center, cohort study investigating adult PwCF was performed in January 2023. Demographics, clinical characteristics, and data related to CF treatment were retrospectively abstracted. Characteristics of the cohort were compared over 2 periods: the 12-months prior to ETI initiation and the 12-months after ETI initiation. Post-ETI data were linearly extrapolated if a subject had not yet completed the full 12 months of ETI. Paired t-testing, Wilcoxon signed rank testing, and regression analysis were performed.

RESULTS: Of 126 PwCF, 98 (77.8%) were on ETI therapy and 35 (27.7%) were both on ETI and concurrently followed by the rhinology service (ETI-ENT). Rhinology clinic visits (P = .007) and frequency of obtaining nasal cultures (P = .046) decreased for the ETI-ENT cohort after initiating ETI treatment. There were no significant changes in the number of endoscopic sinus surgeries (P = .452) performed. Beyond ETI use, regression analysis did not identify any factors associated with changes in utilization.

CONCLUSION: Aspects of rhinology healthcare utilization by PwCF decreased after initiation of ETI therapy. Additional studies are needed to determine rhinologic healthcare requirements for PwCF who remain on ETI for the long-term and to evaluate larger cohorts of PwCF on ETI.

PMID:37953524 | DOI:10.1177/00034894231211626