Am J Respir Crit Care Med. 2024 May 7. doi: 10.1164/rccm.202402-0466RL. Online ahead of print.

NO ABSTRACT

PMID:38712994 | DOI:10.1164/rccm.202402-0466RL

Expert Opin Drug Discov. 2024 May 7:1-4. doi: 10.1080/17460441.2024.2350567. Online ahead of print.

NO ABSTRACT

PMID:38712907 | DOI:10.1080/17460441.2024.2350567

Pediatr Pulmonol. 2024 May 7. doi: 10.1002/ppul.27027. Online ahead of print.

ABSTRACT

OBJECTIVES: To analyze the evolution of clinical and anthropometric characteristics of children and adolescents with cystic fibrosis (CF) over 24 months, including the period of the COVID-19 pandemic.

METHODS: A longitudinal study with data collection from May 2018 to November 2020 in physical and electronic records from a pediatric reference center, including individuals with CF aged up to 18 years.

RESULTS: The sample encompassed 72 individuals. Weight (p < 0.01), height (p < 0.01), and body mass index (BMI) (p = 0.043) were higher in 2020 than in 2018. There were no significant changes in BMI-Z (p = 0.977) and in percentiles of weight (p = 0.540), height (p = 0.458), and BMI percentile (p = 0.454) between both periods. Pancreatic insufficiency was observed in 91.7% of patients in 2020, and there were twice as many confirmed cases of diabetes compared to 2018. There was a 9.7% increase in individuals colonized by the oxacillin-sensitive Staphylococcus aureus (OSSA) (p = 0.039) and an 11.1% reduction in non-colonized individuals (p = 0.008).

CONCLUSION: Although there was an increase in weight, height, and BMI from 2018 to 2020, there were no significant changes in BMI-Z and in percentiles of weight, height, and BMI percentile, suggesting that the anthropometric aspects of nutritional status did not change in this period of 2 years. Moreover, there was an increase in the prevalence of individuals colonized by OSSA and a reduction in the prevalence of individuals non-colonized with any bacteria.

PMID:38712790 | DOI:10.1002/ppul.27027

Pediatr Pulmonol. 2024 May 7. doi: 10.1002/ppul.27047. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) related diabetes affects up to half of all adults with CF and is associated with higher morbidity and mortality. Our aim is to codevelop an ideal model of care that integrates diabetes technology and better meets the needs of adults living with the condition to improve attendance, engagement, service satisfaction, and clinical outcomes.

METHODS: Using qualitative research methods, we evaluated disease perceptions, barriers, and enablers to optimal CF-related diabetes management and service delivery. Integration of continuous glucose monitoring (CGM) was also explored. An initial broad purposive consumer survey was followed by focus groups with end-users. Grounded theory approach was utilized with major problem areas identified then explored, coded, and grouped into requisites for an "ideal model of care" for adults living with CF-related diabetes.

RESULTS: Two key themes emerged (i) an ideal model of care consisted of a dual-specialty service co-led by endocrinology and CF physicians and supported by diabetes educator and CF dietitian with a goal to provide consistent and personalized diabetes management and (ii) CGM was acceptable for use in adults with CF-related diabetes with many perceived benefits and should be integrated into the model of care. Barriers to optimizing glycemic control included diet, finger-prick testing, reduced access to CGM, and pulmonary exacerbations. End-user feedback on CGM was overwhelmingly positive with regard to operability. CGM was also identified as a tool that could be used to engage, educate, and empower adults living with CF-related diabetes and facilitate constructive and personalized clinical decision-making by healthcare providers.

CONCLUSION: For adults living with CF, a diagnosis of diabetes is associated with increased treatment burden. Our findings suggest an "ideal model of care" for CF-related diabetes would be co-led by endocrinology services integrated within a pre-existing CF service, incorporating CGM.

PMID:38712766 | DOI:10.1002/ppul.27047

Contemp Clin Trials Commun. 2024 Apr 26;39:101301. doi: 10.1016/j.conctc.2024.101301. eCollection 2024 Jun.

ABSTRACT

Cystic fibrosis (CF) is a multisystem, genetic disease with a significantly reduced life expectancy. Despite substantial progress in therapies in the last 10-15 years, there is still no cure. There are dozens of drugs in the development pipeline and multiple clinical trials are being conducted across the globe. The UK Cystic Fibrosis Trust's (CFT) Clinical Trials Accelerator Platform (CTAP) is a national initiative bringing together 25 UK based CF centres to support the CF community in accessing and participating in CF clinical trials. CTAP enables more CF centres to run a broader portfolio of trials and increases the range of CF studies available for UK patients. There are four large specialist CF centres based in London, all within a small geographical region as well as two smaller centres which deliver CF care. At the launch of CTAP, these centres formed a sub-network in a consortium-style collaboration. The purpose of the network was to ensure equity of access to trials for patients across the UK's capital, and to share experience and knowledge. Four years into the programme we have reviewed our practices through working group meetings and an online survey. We sought to identify strengths and areas for improvement. We share our findings here, as we believe they are relevant to others delivering research in regions outside of London and in other chronic diseases.

PMID:38711836 | PMC:PMC11070816 | DOI:10.1016/j.conctc.2024.101301

Microbiol Spectr. 2024 May 6:e0034624. doi: 10.1128/spectrum.00346-24. Online ahead of print.

ABSTRACT

Across the Burkholderia genus O-linked protein glycosylation is highly conserved. While the inhibition of glycosylation has been shown to be detrimental for virulence in Burkholderia cepacia complex species, such as Burkholderia cenocepacia, little is known about how specific glycosylation sites impact protein functionality. Within this study, we sought to improve our understanding of the breadth, dynamics, and requirement for glycosylation across the B. cenocepacia O-glycoproteome. Assessing the B. cenocepacia glycoproteome across different culture media using complementary glycoproteomic approaches, we increase the known glycoproteome to 141 glycoproteins. Leveraging this repertoire of glycoproteins, we quantitively assessed the glycoproteome of B. cenocepacia using Data-Independent Acquisition (DIA) revealing the B. cenocepacia glycoproteome is largely stable across conditions with most glycoproteins constitutively expressed. Examination of how the absence of glycosylation impacts the glycoproteome reveals that the protein abundance of only five glycoproteins (BCAL1086, BCAL2974, BCAL0525, BCAM0505, and BCAL0127) are altered by the loss of glycosylation. Assessing ΔfliF (ΔBCAL0525), ΔmotB (ΔBCAL0127), and ΔBCAM0505 strains, we demonstrate the loss of FliF, and to a lesser extent MotB, mirror the proteomic effects observed in the absence of glycosylation in ΔpglL. While both MotB and FliF are essential for motility, we find loss of glycosylation sites in MotB or FliF does not impact motility supporting these sites are dispensable for function. Combined this work broadens our understanding of the B. cenocepacia glycoproteome supporting that the loss of glycoproteins in the absence of glycosylation is not an indicator of the requirement for glycosylation for protein function.

IMPORTANCE: Burkholderia cenocepacia is an opportunistic pathogen of concern within the Cystic Fibrosis community. Despite a greater appreciation of the unique physiology of B. cenocepacia gained over the last 20 years a complete understanding of the proteome and especially the O-glycoproteome, is lacking. In this study, we utilize systems biology approaches to expand the known B. cenocepacia glycoproteome as well as track the dynamics of glycoproteins across growth phases, culturing media and in response to the loss of glycosylation. We show that the glycoproteome of B. cenocepacia is largely stable across conditions and that the loss of glycosylation only impacts five glycoproteins including the motility associated proteins FliF and MotB. Examination of MotB and FliF shows, while these proteins are essential for motility, glycosylation is dispensable. Combined this work supports that B. cenocepacia glycosylation can be dispensable for protein function and may influence protein properties beyond stability.

PMID:38709084 | DOI:10.1128/spectrum.00346-24

J Vis Exp. 2024 Apr 19;(206). doi: 10.3791/66785.

ABSTRACT

Most in vitro models lack the capacity to fully probe bacterial phenotypes emerging from the complex interactions observed in real-life environments. This is particularly true in the context of hard-to-treat, chronic, and polymicrobial biofilm-based infections detected in the airways of individuals living with cystic fibrosis (CF), a multiorgan genetic disease. While multiple microbiome studies have defined the microbial compositions detected in the airway of people with CF (pwCF), no in vitro models thus far have fully integrated critical CF-relevant lung features. Therefore, a significant knowledge gap exists in the capacity to investigate the mechanisms driving the pathogenesis of mixed species CF lung infections. Here, we describe a recently developed four-species microbial community model, including Pseudomonas aeruginosa, Staphylococcus aureus, Streptococcus sanguinis, and Prevotella melaninogenica grown in CF-like conditions. Through the utilization of this system, clinically relevant phenotypes such as antimicrobial recalcitrance of several pathogens were observed and explored at the molecular level. The usefulness of this in vitro model resides in its standardized workflow that can facilitate the study of interspecies interactions in the context of chronic CF lung infections.

PMID:38709077 | DOI:10.3791/66785

J Antimicrob Chemother. 2024 May 6:dkae126. doi: 10.1093/jac/dkae126. Online ahead of print.

ABSTRACT

OBJECTIVES: Despite the introduction of cystic fibrosis transmembrane conductance regulator (CFTR) modulators, Pseudomonas aeruginosa is still a major pathogen in people with cystic fibrosis (pwCF). We determine the activity of cefiderocol and comparators in a collection of 154 P. aeruginosa isolates recovered from pwCF during three multicentre studies performed in 17 Spanish hospitals in 2013, 2017 and 2021.

METHODS: ISO broth microdilution was performed and MICs were interpreted with CLSI and EUCAST criteria. Mutation frequency and WGS were also performed.

RESULTS: Overall, 21.4% were MDR, 20.8% XDR and 1.3% pandrug-resistant (PDR). Up to 17% of the isolates showed a hypermutator phenotype. Cefiderocol demonstrated excellent activity; only 13 isolates (8.4%) were cefiderocol resistant by EUCAST (none using CLSI). A high proportion of the isolates resistant to ceftolozane/tazobactam (71.4%), meropenem/vaborbactam (70.0%), imipenem/relebactam (68.0%) and ceftazidime/avibactam (55.6%) were susceptible to cefiderocol. Nine out of 13 cefiderocol-resistant isolates were hypermutators (P < 0.001). Eighty-three STs were detected, with ST98 being the most frequent. Only one isolate belonging to the ST175 high-risk clone carried blaVIM-2. Exclusive mutations affecting genes involved in membrane permeability, AmpC overexpression (L320P-AmpC) and efflux pump up-regulation were found in cefiderocol-resistant isolates (MIC = 4-8 mg/L). Cefiderocol resistance could also be associated with mutations in genes related to iron uptake (tonB-dependent receptors and pyochelin/pyoverdine biosynthesis).

CONCLUSIONS: Our results position cefiderocol as a therapeutic option in pwCF infected with P. aeruginosa resistant to most recent β-lactam/β-lactamase inhibitor combinations.

PMID:38708553 | DOI:10.1093/jac/dkae126

Int J Nanomedicine. 2024 Apr 29;19:3861-3890. doi: 10.2147/IJN.S445955. eCollection 2024.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is associated with pulmonary Pseudomonas aeruginosa infections persistent to antibiotics.

METHODS: To eradicate pseudomonal biofilms, solid lipid nanoparticles (SLNs) loaded with quorum-sensing-inhibitor (QSI, disrupting bacterial crosstalk), coated with chitosan (CS, improving internalization) and immobilized with alginate lyase (AL, destroying alginate biofilms) were developed.

RESULTS: SLNs (140-205 nm) showed prolonged release of QSI with no sign of acute toxicity to A549 and Calu-3 cells. The CS coating improved uptake, whereas immobilized-AL ensured >1.5-fold higher uptake and doubled SLN diffusion across the artificial biofilm sputum model. Respirable microparticles comprising SLNs in carbohydrate matrix elicited aerodynamic diameters MMAD (3.54, 2.48 µm) and fine-particle-fraction FPF (65, 48%) for anionic and cationic SLNs, respectively. The antimicrobial and/or antibiofilm activity of SLNs was explored in Pseudomonas aeruginosa reference mucoid/nonmucoid strains as well as clinical isolates. The full growth inhibition of planktonic bacteria was dependent on SLN type, concentration, growth medium, and strain. OD measurements and live/dead staining proved that anionic SLNs efficiently ceased biofilm formation and eradicated established biofilms, whereas cationic SLNs unexpectedly promoted biofilm progression. AL immobilization increased biofilm vulnerability; instead, CS coating increased biofilm formation confirmed by 3D-time lapse confocal imaging. Incubation of SLNs with mature biofilms of P. aeruginosa isolates increased biofilm density by an average of 1.5-fold. CLSM further confirmed the binding and uptake of the labeled SLNs in P. aeruginosa biofilms. Considerable uptake of CS-coated SLNs in non-mucoid strains could be observed presumably due to interaction of chitosan with LPS glycolipids in the outer cell membrane of P. aeruginosa.

CONCLUSION: The biofilm-destructive potential of QSI/SLNs/AL inhalation is promising for site-specific biofilm-targeted interventional CF therapy. Nevertheless, the intrinsic/extrinsic fundamentals of nanocarrier-biofilm interactions require further investigation.

PMID:38708178 | PMC:PMC11068056 | DOI:10.2147/IJN.S445955

ISME Commun. 2024 Mar 28;4(1):ycae043. doi: 10.1093/ismeco/ycae043. eCollection 2024 Jan.

ABSTRACT

While several environmental factors contribute to the evolutionary diversification of the pathogenic bacterium Pseudomonas aeruginosa during cystic fibrosis lung infections, relatively little is known about the impact of the surrounding microbiota. By using in vitro experimental evolution, we show that the presence of Stenotrophomonas maltophilia, Staphylococcus aureus, or them both, prevent the evolution of loss of virulence, which repeatedly occurs in the absence of these species due to mutations in regulators of the Pseudomonas Quinolone Signal quorum sensing system, vqsM and pqsR. Moreover, the strength of the effect of co-occurring species is attenuated through changes in the physical environment by the addition of mucin, resulting in selection for phenotypes resembling those evolved in the absence of the co-occurring species. Together, our findings show that variation in mucosal environment and the surrounding polymicrobial environment can determine the evolutionary trajectory of P. aeruginosa, partly explaining its diversification and pathoadaptation from acute to chronic phenotype during cystic fibrosis lung infections.

PMID:38707844 | PMC:PMC11067959 | DOI:10.1093/ismeco/ycae043

Heliyon. 2024 Apr 24;10(9):e30034. doi: 10.1016/j.heliyon.2024.e30034. eCollection 2024 May 15.

ABSTRACT

BACKGROUND: Metabolic complications post-lung transplant are poorly understood and little is known about how these complications differ between patients with or without cystic fibrosis (pwCF and pwoCF). This study compared post-lung transplant outcomes between pwCF and pwoCF relating to survival and incidence of diabetes, dyslipidaemia, hypertension, and renal impairment.

METHODS: A retrospective (2004-2017) case-control study involving 90 pwCF and 90 pwoCF (age, sex and year of transplant matched) was conducted. Demographic variables, pre/post-transplant metabolic diseases, blood investigations and medications were extracted. Descriptive statistics were used to describe the cohort. Mann-Whitney U and Chi-squared tests were used to analyse morbidity and mortality data. Regression analyses were used to identity independent variables that impacted clinical outcomes. Kaplan Meier analysis with log-rank testing was used to compare survival.

RESULTS: PwCF were younger, had lower BMIs, and were less likely to have pre-transplant extracorporeal membrane oxygenation (ECMO) use. A total of 37 pwCF and 41 pwoCF died (p = 0.65) during the period of observation with no differences in survival. Adjusting for covariates of age, sex and BMI via multiple logistic regression, CF status was associated with a dramatic increased risk of new-onset diabetes post-transplant (adjusted odds ratio 28.7; 95 % CI, 28.76 to 108.7). No other differences in adjusted risk were found.

CONCLUSIONS: As pwCF had a greater adjusted risk of developing new post-transplant diabetes and experienced metabolic complications at similar rates as pwoCF, the findings highlight the need for rigorous monitoring of pwCF for possible metabolic complications post-transplant.

PMID:38707432 | PMC:PMC11066389 | DOI:10.1016/j.heliyon.2024.e30034

Thorac Res Pract. 2024 May 3. doi: 10.5152/ThoracResPract.2024.23112. Online ahead of print.

ABSTRACT

OBJECTIVE: With the significant increase in the life expectancy of cystic fibrosis (CF) patients, many individuals now reach adulthood and develop specific coping strategies to maintain their physical and mental well-being. This study aims to evaluate coping styles and their relationship with mental health and Health-Related Quality of Life (H-RQoL) in adult CF patients.

MATERIALS AND METHODS: Thirty adult CF patients completed the Hospital Anxiety and Depression Scale to assess anxiety and depression, the Cystic Fibrosis Questionnaire-Revised to evaluate quality of life, and the Brief Coping Orientation to Problems Experienced questionnaire to assess coping strategies.

RESULTS: Twelve individuals (40%) met the diagnostic criteria for being at risk of experiencing anxiety and/or depression. Anxiety risk group exhibited lower life quality scores in the domains of vitality, emotional functioning, and role limitations (P = .027, P = .001, and P = .001, respectively). Patients reporting depressive symptoms had lower scores in emotional functioning and role limitations domains of quality of life (P = .005 and P = .018, respectively). Multivariate analysis indicated that depression and anxiety scores were significant predictors of emotional quality of life. In terms of coping strategies, "acceptance" was the most commonly preferred, while "substance use" was the least preferred strategy among all participants. Patients at risk of anxiety and/or depression often chose "avoidance" as their coping strategy.

CONCLUSION: Anxiety and depressive symptoms are prevalent and associated with poorer H-RQoL in adult CF patients. These patients preferred to employ giving up strategy when dealing with the disease. Therefore, it is essential to screen adult CF patients for mental health risks and to work on improving their coping strategies.

PMID:38705998 | DOI:10.5152/ThoracResPract.2024.23112

Braz J Microbiol. 2024 May 6. doi: 10.1007/s42770-024-01334-w. Online ahead of print.

ABSTRACT

Alginate is a major extra polymeric substance in the biofilm formed by mucoid Pseudomonas aeruginosa. It is the main proven perpetrator of lung infections in patients suffering from cystic fibrosis. Alginate lyases are very important in the treatment of cystic fibrosis. This study evaluated the role of standalone and in conjugation, effect of alginate lyase of SG4 + isolated from Paenibacillus lautus in enhancing in vitro bactericidal activity of gentamicin and amikacin on mucoid P. aeruginosa. Using Response Surface Methodology (RSM) alginate lyase SG4 + production was optimized in shake flask and there 8.49-fold enhancement in enzyme production. In fermenter, maximum growth (10.15 mg/ml) and alginate lyase (1.46 International Units) production, 1.71-fold was increased using Central Composite Design (CCD). Further, fermentation time was reduced from 48 to 20 h. To the best of our knowledge this is the first report in which CCD was used for fermenter studies to optimize alginate lyase production. The Km and Vmax of purified enzyme were found to be 2.7 mg/ml and 0.84 mol/ml-min, respectively. The half-life (t 1/2) of purified alginate lyase SG4 + at 37 °C was 180 min. Alginate lyase SG4 + in combination with gentamicin and amikacin eradiated 48.4- 52.3% and 58- 64.6%, alginate biofilm formed by P. aeruginosa strains, respectively. The study proves that alginate lyase SG4 + has excellent exopolysaccharide disintegrating ability and may be useful in development of potent therapeutic agent to treat P. aeruginosa biofilms.

PMID:38705960 | DOI:10.1007/s42770-024-01334-w

Transplant Proc. 2024 May 4:S0041-1345(24)00190-8. doi: 10.1016/j.transproceed.2024.03.016. Online ahead of print.

ABSTRACT

INTRODUCTION: Lung transplantation is well-established treatment for patients with advanced lung dysfunction in cystic fibrosis (CF). Pregnancy in CF lung transplant recipients is feasible, although it still remains challenging for even professionals and demands a multidisciplinary approach.

CASE REPORT: We report the case of pregnancy in a 22-year-old woman after lung transplantation (LTx) due to end-stage respiratory failure in the course of CF. The interval from transplant to conception was 2.5 years. In 2019, orthotopic LTx was performed and a 3-drug immunosuppressive scheme was used-tacrolimus, mycophenolate mofetil, and prednisolone. There were no complications in the postoperative course. In April 2022, the patient was confirmed pregnant. All fetotoxic or teratogenic drugs were discontinued. Throughout the whole pregnancy, the patient was regularly monitored in the transplant and obstetrics centers. Due to the vaginal bleeding and irregular contractions at the 33 weeks of pregnancy, the course of steroids was administered. At 38 weeks and 5 days of gestation, she presented premature rupture of membranes. The caesarean section was performed because of breech presentation of the fetus. A live, term daughter was born and according to the screening test she does not have CF. Currently, 12 months after the delivery, the mother's lung function is good.

CONCLUSIONS: Getting pregnant and having a safe pregnancy after LTx is possible, but it requires a specialized and individual approach. The patient should be well informed about possible complications and risks including graft failure. The patient's attitude and her cooperation with doctors play a major role.

PMID:38705735 | DOI:10.1016/j.transproceed.2024.03.016

J Cyst Fibros. 2024 May 2:S1569-1993(24)00059-6. doi: 10.1016/j.jcf.2024.04.015. Online ahead of print.

ABSTRACT

BACKGROUND: Excessive inflammation and recurrent airway infections characterize people with cystic fibrosis (pwCF), a disease with highly heterogeneous clinical outcomes. How the overall immune response is affected in pwCF, its relationships with the lung microbiome, and the source of clinical heterogeneity have not been fully elucidated.

METHODS: Peripheral blood and sputum samples were collected from 28 pwCF and an age-matched control group. Systemic immune cell subsets and surface markers were quantified using multiparameter flow cytometry. Lung microbiome composition was reconstructed using metatranscriptomics on sputum samples, and microbial taxa were correlated to circulating immune cells and surface markers expression.

RESULTS: In pwCF, we found a specific systemic immune profile characterized by widespread hyperactivation and altered frequencies of several subsets. These included substantial changes in B-cell subsets, enrichment of CD35+/CD49d+ neutrophils, and reduction in dendritic cells. Activation markers and checkpoint molecule expression levels differed from healthy subjects. CTLA-4 expression was increased in Tregs and, together with impaired B-cell subsets, correlated with patients' lung function. Concentrations and frequencies of key immune cells and marker expression correlated with the relative abundance of commensal and pathogenic bacteria in the lungs.

CONCLUSION: The CF-specific immune signature, involving hyperactivation, immune dysregulation with alteration in Treg homeostasis, and impaired B-cell function, is a potential source of lung function heterogeneity. The activity of specific microbes contributes to disrupting the balance of the immune response. Our data provide a unique foundation for identifying novel markers and immunomodulatory targets to develop the future of cystic fibrosis treatment and management.

PMID:38702223 | DOI:10.1016/j.jcf.2024.04.015

BMJ Open Respir Res. 2024 May 3;11(1):e002049. doi: 10.1136/bmjresp-2023-002049.

ABSTRACT

The major cause of mortality in people with cystic fibrosis (pwCF) is progressive lung disease characterised by acute and chronic infections, the accumulation of mucus, airway inflammation, structural damage and pulmonary exacerbations. The prevalence of Pseudomonas aeruginosa rises rapidly in the teenage years, and this organism is the most common cause of chronic lung infection in adults with cystic fibrosis (CF). It is associated with an accelerated decline in lung function and premature death. New P. aeruginosa infections are treated with antibiotics to eradicate the organism, while chronic infections require long-term inhaled antibiotic therapy. The prevalence of P. aeruginosa infections has decreased in CF registries since the introduction of CF transmembrane conductance regulator modulators (CFTRm), but clinical observations suggest that chronic P. aeruginosa infections usually persist in patients receiving CFTRm. This indicates that pwCF may still need inhaled antibiotics in the CFTRm era to maintain long-term control of P. aeruginosa infections. Here, we provide an overview of the changing perceptions of P. aeruginosa infection management, including considerations on detection and treatment, the therapy burden associated with inhaled antibiotics and the potential effects of CFTRm on the lung microbiome. We conclude that updated guidance is required on the diagnosis and management of P. aeruginosa infection. In particular, we highlight a need for prospective studies to evaluate the consequences of stopping inhaled antibiotic therapy in pwCF who have chronic P. aeruginosa infection and are receiving CFTRm. This will help inform new guidelines on the use of antibiotics alongside CFTRm.

PMID:38702073 | DOI:10.1136/bmjresp-2023-002049

Balkan Med J. 2024 May 3;41(3):206-212. doi: 10.4274/balkanmedj.galenos.2024.2023-12-57.

ABSTRACT

BACKGROUND: Bronchiectasis is a chronic lung disease characterized by permanent bronchial wall dilatation. Although it has been known as an orphan disease, it has recently gained attention because of registry-based studies and drug research.

AIMS: We aimed to use a multicenter database to analyze and compare data regarding the etiology, associated comorbidities, microbiological characteristics, and preventive strategies of bronchiectasis in Türkiye to those of other countries.

STUDY DESIGN: A multicenter prospective cohort study.

METHODS: The multicenter, prospective cohort study was conducted between March 2019 and January 2022 using the Turkish Adult Bronchiectasis Database, in which 25 centers in Türkiye participated. Patients aged > 18 years who presented with respiratory symptoms such as cough, sputum, and dyspnea and were diagnosed with non-cystic fibrosis bronchiectasis using computed tomography were included in the study. Demographic information, etiologies, comorbidities, pulmonary functions, and microbiological, radiological, and clinical data were collected from the patients.

RESULTS: Of the 1,035 study participants, 518 (50%) were females. The mean age of the patients was 56.1 ± 16.1 years. The underlying etiology was detected in 565 (54.6%) patients. While postinfectious origin was the most common cause of bronchiectasis (39.5%), tuberculosis was identified in 11.3% of the patients. An additional comorbidity was detected in 688 (66.5%) patients. The most common comorbidity was cardiovascular disease, and chronic obstructive pulmonary disease (COPD) and bronchiectasis was identified in 19.5% of the patients. The most commonly detected microbiological agent was Pseudomonas aeruginosa (29.4%). Inhaled corticosteroids (ICS) were used in 70.1% of the patients, and the frequency of exacerbations in the last year was significantly higher in patients using ICS than in nonusers (p < 0.0001). Age [odds ratio (OR): 1.028; 95% confidence interval (CI): 1.005-1.051], cachexia (OR: 4.774; 95% CI: 2,054-11,097), high modified medical research council dyspnea scale score (OR: 1,952; 95% CI: 1,459-2,611), presence of chronic renal failure (OR: 4,172; 95% CI: 1,249-13,938) and use of inhaled steroids (OR: 2,587; 95% CI: 1,098-6,098) were significant risk factors for mortality. Mortality rates were higher in patients with COPD than in those with no COPD (21.7-9.1%, p = 0.016). Patients with bronchiectasis and COPD exhibited more frequent exacerbations, exacerbation-related hospitalizations, and hospitalization in the intensive care unit in the previous year than patients without COPD.

CONCLUSION: This is the first multicenter study of bronchiectasis in Türkiye. The study results will provide important data that can guide the development of health policies in Türkiye on issues such as infection control, vaccination, and the unnecessary use of antibiotics and steroids.

PMID:38700365 | DOI:10.4274/balkanmedj.galenos.2024.2023-12-57

Future Microbiol. 2024 May 3. doi: 10.2217/fmb-2023-0237. Online ahead of print.

ABSTRACT

Aim: This study aims to explore the molecular mechanisms of cystic fibrosis (CF) complicated with nontuberculous mycobacteria (NTM) infection. Materials & methods: Expression profiles of CF with NTM-infected patients were downloaded from GEO database. Intersection analysis yielded 78 genes associated with CF with NTM infection. The protein-protein interaction (PPI) network and the functions of hub genes were investigated. Results: Five hub genes (PIK3R1, IL1A, CXCR4, ACTN1, PFN1) were identified, which were primarily enriched in actin-related biological processes and pathways. Transcription factors RELA, JUN, NFKB1 and FOS that regulated hub genes modulated IL1A expression, while 21 other transcription factors regulated CXCR4 expression. Conclusion: In summary, this study may provide new insights into the mechanisms of CF with NTM infection.

PMID:38700285 | DOI:10.2217/fmb-2023-0237

Cochrane Database Syst Rev. 2024 May 3;5:CD009530. doi: 10.1002/14651858.CD009530.pub5.

ABSTRACT

BACKGROUND: Early diagnosis and treatment of lower respiratory tract infections is the mainstay of management of lung disease in cystic fibrosis (CF). When sputum samples are unavailable, diagnosis relies mainly on cultures from oropharyngeal specimens; however, there are concerns about whether this approach is sensitive enough to identify lower respiratory organisms. Bronchoscopy and related procedures such as bronchoalveolar lavage (BAL) are invasive but allow the collection of lower respiratory specimens from non-sputum producers. Cultures of bronchoscopic specimens provide a higher yield of organisms compared to those from oropharyngeal specimens. Regular use of bronchoscopy and related procedures may increase the accuracy of diagnosis of lower respiratory tract infections and improve the selection of antimicrobials, which may lead to clinical benefits. This is an update of a previous review that was first published in 2013 and was updated in 2016 and in 2018.

OBJECTIVES: To evaluate the use of bronchoscopy-guided (also known as bronchoscopy-directed) antimicrobial therapy in the management of lung infection in adults and children with cystic fibrosis.

SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched three registries of ongoing studies and the reference lists of relevant articles and reviews. The date of the most recent searches was 1 November 2023.

SELECTION CRITERIA: We included randomised controlled studies involving people of any age with CF that compared the outcomes of antimicrobial therapies guided by the results of bronchoscopy (and related procedures) versus those guided by any other type of sampling (e.g. cultures from sputum, throat swab and cough swab).

DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies, assessed their risk of bias and extracted data. We contacted study investigators for further information when required. We assessed the certainty of the evidence using the GRADE criteria.

MAIN RESULTS: We included two studies in this updated review. One study enrolled 170 infants under six months of age who had been diagnosed with CF through newborn screening. Participants were followed until they were five years old, and data were available for 157 children. The study compared outcomes for pulmonary exacerbations following treatment directed by BAL versus standard treatment based on clinical features and oropharyngeal cultures. The second study enrolled 30 children with CF aged between five and 18 years and randomised participants to receive treatment based on microbiological results of BAL triggered by an increase in lung clearance index (LCI) of at least one unit above baseline or to receive standard treatment based on microbiological results of oropharyngeal samples collected when participants were symptomatic. We judged both studies to have a low risk of bias across most domains, although the risk of bias for allocation concealment and selective reporting was unclear in the smaller study. In the larger study, the statistical power to detect a significant difference in the prevalence of Pseudomonas aeruginosa was low because Pseudomonas aeruginosa isolation in BAL samples at five years of age in both groups were much lower than the expected rate that was used for the power calculation. We graded the certainty of evidence for the key outcomes as low, other than for high-resolution computed tomography scoring and cost-of-care analysis, which we graded as moderate certainty. Both studies reported similar outcomes, but meta-analysis was not possible due to different ways of measuring the outcomes and different indications for the use of BAL. Whether antimicrobial therapy is directed by the use of BAL or standard care may make little or no difference in lung function z scores after two years (n = 29) as measured by the change from baseline in LCI and forced expiratory volume in one second (FEV1) (low-certainty evidence). At five years, the larger study found little or no difference between groups in absolute FEV1 z score or forced vital capacity (FVC) (low-certainty evidence). BAL-directed therapy probably makes little or no difference to any measure of chest scores assessed by computed tomography (CT) scan at either two or five years (different measures used in the two studies; moderate-certainty evidence). BAL-directed therapy may make little or no difference in nutritional parameters or in the number of positive isolates of P aeruginosa per participant per year, but may lead to more hospitalisations per year (1 study, 157 participants; low-certainty evidence). There is probably no difference in average cost of care per participant (either for hospitalisations or total costs) at five years between BAL-directed therapy and standard care (1 study, 157 participants; moderate-certainty evidence). We found no difference in health-related quality of life between BAL-directed therapy and standard care at either two or five years, and the larger study found no difference in the number of isolates of Pseudomonas aeruginosa per child per year. The eradication rate following one or two courses of eradication treatment and the number of pulmonary exacerbations were comparable in the two groups. Mild adverse events, when reported, were generally well tolerated. The most common adverse event reported was transient worsening of cough after 29% of procedures. Significant clinical deterioration was documented during or within 24 hours of BAL in 4.8% of procedures.

AUTHORS' CONCLUSIONS: This review, limited to two well-designed randomised controlled studies, shows no evidence to support the routine use of BAL for the diagnosis and management of pulmonary infection in preschool children with CF compared to the standard practice of providing treatment based on results of oropharyngeal culture and clinical symptoms. No evidence is available for adults.

PMID:38700027 | DOI:10.1002/14651858.CD009530.pub5

Front Physiol. 2024 Apr 18;15:1385661. doi: 10.3389/fphys.2024.1385661. eCollection 2024.

ABSTRACT

Dysfunction of the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel by genetic mutations causes the inherited disease cystic fibrosis (CF). CF lung disease that involves multiple disorders of epithelial function likely results from loss of CFTR function as an anion channel conducting chloride and bicarbonate ions and its function as a cellular regulator modulating the activity of membrane and cytosol proteins. In the absence of CFTR activity, abundant mucus accumulation, bacterial infection and inflammation characterize CF airways, in which inflammation-associated tissue remodeling and damage gradually destroys the lung. Deciphering the link between CFTR dysfunction and bacterial infection in CF airways may reveal the pathogenesis of CF lung disease and guide the development of new treatments. Research efforts towards this goal, including high salt, low volume, airway surface liquid acidosis and abnormal mucus hypotheses are critically reviewed.

PMID:38699141 | PMC:PMC11063615 | DOI:10.3389/fphys.2024.1385661