Sci Rep. 2023 Aug 30;13(1):14208. doi: 10.1038/s41598-023-41333-9.

ABSTRACT

Pseudomonas aeruginosa is a common pathogen in cystic fibrosis (CF) patients and a major contributor to progressive lung damage. P. aeruginosa elastase (LasB), a key virulence factor, has been identified as a potential target for anti-virulence therapy. Here, we sought to differentiate the P. aeruginosa isolates from early versus established stages of infection in CF patients and to determine if LasB was associated with either stage. The lasB gene was amplified from 255 P. aeruginosa clinical isolates from 70 CF patients from the Toulouse region (France). Nine LasB variants were identified and 69% of the isolates produced detectable levels of LasB activity. Hierarchical clustering using experimental and clinical data distinguished two classes of isolates, designated as 'Early' and 'Established' infection. Multivariate analysis revealed that the isolates from the Early infection class show higher LasB activity, fast growth, tobramycin susceptibility, non-mucoid, pigmented colonies and wild-type lasR genotype. These traits were associated with younger patients with polymicrobial infections and high pFEV1. Our findings show a correlation between elevated LasB activity in P. aeruginosa isolates and early-stage infection in CF patients. Hence, it is this patient group, prior to the onset of chronic disease, that may benefit most from novel therapies targeting LasB.

PMID:37648735 | DOI:10.1038/s41598-023-41333-9

Respirology. 2023 Aug 30. doi: 10.1111/resp.14587. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: The importance of extracellular traps (ETs) in chronic respiratory conditions is increasingly recognized but their role in paediatric bronchiectasis is poorly understood. The specialized techniques currently required to study ETs preclude routine clinical use. A simple and cost-effective ETs detection method is needed to support diagnostic applications. We aimed to determine whether ETs could be detected using light microscopy-based assessment of Romanowsky-stained bronchoalveolar lavage (BAL) slides from children with bronchiectasis, and whether the ETs cellular origin could be determined.

METHODS: Archived Romanowsky-stained BAL slides from a cross-sectional study of children with bronchiectasis were examined for ETs using light microscopy. The cellular origin of individual ETs was determined based on morphology and physical contact with surrounding cell(s).

RESULTS: ETs were observed in 78.7% (70/89) of BAL slides with neutrophil (NETs), macrophage (METs), eosinophil (EETs) and lymphocyte (LETs) ETs observed in 32.6%, 51.7%, 4.5% and 9%, respectively. ETs of indeterminate cellular origin were present in 59.6% of slides. Identifiable and indeterminate ETs were co-detected in 43.8% of slides.

CONCLUSION: BAL from children with bronchiectasis commonly contains multiple ET types that are detectable using Romanowsky-stained slides. While specialist techniques remain necessary to determining the cellular origin of all ETs, screening of Romanowsky-stained slides presents a cost-effective method that is well-suited to diagnostic settings. Our findings support further research to determine whether ETs can be used to define respiratory endotypes and to understand whether ETs-specific therapies may be required to resolve airway inflammation among children with bronchiectasis.

PMID:37648649 | DOI:10.1111/resp.14587

J Cyst Fibros. 2023 Aug 28:S1569-1993(23)00874-3. doi: 10.1016/j.jcf.2023.08.004. Online ahead of print.

ABSTRACT

BACKGROUND: Treatment advancements have improved life expectancy and nutritional status of people with cystic fibrosis (CF). Alongside reductions in malnutrition, incidences of overweight, obesity and risk factors for diet-related chronic diseases have increased in recent years. This study aimed to synthesise the available literature on diet quality, macronutrient and micronutrient intakes compared to the recommended guidelines in adults with CF, an essential step in deducing the optimal dietary pattern and intakes for CF adults.

METHODS: A systematic search of five electronic databases from inception until April 2023 was conducted using keywords related to CF, diet quality and nutrient intakes.

RESULTS: Twenty-one studies were included comprising 18 cross-sectional, one cohort and two case control studies, reporting data from 724 adults with CF. Energy and / or macronutrient intake data was reported across 17 cohorts, eight studies provided micronutrients data, and diet quality was determined for four CF cohorts by using a diet quality score, and / or categorising food intake into servings per day for food groups and comparing findings to national dietary guidelines. Although energy intake recommendations were met, and most micronutrient requirements were achieved through supplementation, total energy intake from fat was above recommendations and diet quality was poor.

CONCLUSION: This is the first systematic review comprehensively evaluating literature on dietary intakes of adults with CF. Energy-dense, nutrient-poor foods contribute to intakes which pose risk in developing diet-related chronic diseases. Revision of dietary guidelines and practice change in CF nutritional therapy is warranted to optimise nutrition and health outcomes.

PMID:37648586 | DOI:10.1016/j.jcf.2023.08.004

Rev Paul Pediatr. 2023 Aug 25;42:e2022198. doi: 10.1590/1984-0462/2024/42/2022198. eCollection 2023.

ABSTRACT

OBJECTIVE: To evaluate the impact of COVID-19 social distancing recommendations on nutritional status, pulmonary function, and morbidity in patients with cystic fibrosis (CF).

METHODS: A retrospective cohort study including patients older than six years with a diagnosis of CF was performed. Demographic and clinical data, anthropometric measurements, pulmonary function, days of antibiotic use, and length of hospital stay were recorded. Variables were recorded at three time points relative to the baseline for implementation of social distancing measures: T-1 (14 months before implementation), T0 (baseline), and T1 (14 months after implementation). Delta (Δ) was calculated for each period: Δ1 (pre-pandemic T0-T-1) and Δ2 (pandemic T1-T0).

RESULTS: The study included 25 patients, with a mean age of 11.7±4.3 years. The mean forced expiratory volume in the first second (FEV1) was 85.6±23.6%, and body mass index (BMI) was 17.5±3.0 kg/m2. When comparing the two periods (Δ1 and Δ2), there was a significant increase in the FEV1/forced vital capacity (FVC) ratio (p=0.013) and in the forced expiratory flow between 25 and 75% of vital capacity (FEF25-75%) (p=0.037) in the pandemic period. There was also a significant reduction (p=0.005) in the use of antibiotics in the pandemic period compared with the pre-pandemic period. The Δ1 and Δ2 values did not differ significantly for BMI, FEV1, or length of hospital stay.

CONCLUSIONS: COVID-19 social distancing recommendations had a positive impact (decrease) on morbidity (use of antibiotics) and small airway obstruction (FEF25-75%) in patients with CF.

PMID:37646749 | DOI:10.1590/1984-0462/2024/42/2022198

Rev Paul Pediatr. 2023 Aug 25;42:e2022161. doi: 10.1590/1984-0462/2024/42/2022161. eCollection 2023.

ABSTRACT

OBJECTIVE: To evaluate quality indicators of the Neonatal Screening Referral Service of the state of Mato Grosso (NSRS-MT) from 2005 to 2019.

METHODS: Cross-sectional, retrospective, exploratory, descriptive, and observational study from 2005 to 2019. The following parameters were analyzed: age of newborns at the first collection, time between sample collection and arrival at the laboratory, time between the arrival and release of results and time between requesting the second sample and arrival at the NSRS. The population coverage of the program and the incidence of each clinical situation screened were also analyzed.

RESULTS: NSRS-MT coverage was analyzed and recorded as 76%. The incidence was analyzed for congenital hypothyroidism (CH) 1:1867, phenylketonuria (PKU) 1:33,311, sickle cell disease (SCD) 1:2004, cystic fibrosis (CF) 1:12,663, congenital adrenal hyperplasia (CAH) 1:15,843, and biotinidase deficiency (DB) 1:25,349. The median age (days) at the first consultation was: 44 for HC, 22 for PKU, 60 for DF, 52 for FC, 79 for HAC and 79 for DB. The mean time between exam collection and delivery to the NSRS was 8.4 days; between the arrival and release of results, 9 days; and for the return of recalls, 59 days.

CONCLUSIONS: Regarding the coverage of the target population and collection at the ideal age, the NSRS-MT presents values below the national average. However, regarding the mean age at the time of the first consultation, the state's performance is better than the national.

PMID:37646746 | DOI:10.1590/1984-0462/2024/42/2022161

Pediatr Pulmonol. 2023 Aug 30. doi: 10.1002/ppul.26655. Online ahead of print.

ABSTRACT

BACKGROUND: Effective work of breathing and bronchial hygiene requires synergy of inspiratory and expiratory muscles. Inspiratory muscle training (IMT) is a part of pulmonary rehabilitation in chronic obstructive pulmonary disease (COPD). There is some evidence of its efficacy in cystic fibrosis (CF) and, recently, in long COVID-19. We are not aware of studies on IMT in primary ciliary dyskinesia (PCD). Our aim was to assess the effect of IMT on respiratory muscle strength and pulmonary function in PCD and CF patients.

METHODS: A single center pilot study. Spirometry, lung clearance index (LCI), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were measured at baseline (visit 1), after a month of IMT with ®POWERbreathe (visit 2), and at follow-up (visit 3).

RESULTS: The cohort included 27 patients (19 PCD, 8 CF); mean age 18.4 ± 9.8 years. After a month of IMT, there was a significant increase in MIP and MIP% (6.19-7.44, p = .015; and 81.85%-100.41%, p = .046, respectively), which was sustained at visit 3. Compliance ≥90% led to higher improvement in MIP. In sub-group analysis, improvement in MIP and MIP% remained significant for PCD patients (p = .026 and p = .049, respectively). No significant changes were found in spirometry, MEP or LCI.

CONCLUSIONS: IMT was well-tolerated and led to improved inspiratory muscle strength in PCD patients. The clinical implication of improved MIP should be further investigated. Larger, long-term studies are needed to evaluate long-term effects of IMT on pulmonary function, respiratory muscle strength, pulmonary exacerbations, and quality of life.

PMID:37646121 | DOI:10.1002/ppul.26655

Pediatr Pulmonol. 2023 Aug 30. doi: 10.1002/ppul.26666. Online ahead of print.

NO ABSTRACT

PMID:37646113 | DOI:10.1002/ppul.26666

bioRxiv. 2023 Aug 14:2023.08.14.553173. doi: 10.1101/2023.08.14.553173. Preprint.

ABSTRACT

People with muco-obstructive pulmonary diseases such as cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD) often have acute or chronic respiratory infections that are difficult to treat due in part to the accumulation of hyperconcentrated mucus within the airway. Mucus accumulation and obstruction promote chronic inflammation and infection and reduce therapeutic efficacy. Bacterial aggregates in the form of biofilms exhibit increased resistance to mechanical stressors from the immune response (e.g., phagocytosis) and chemical treatments including antibiotics. Herein, combination treatments designed to disrupt the mechanical properties of biofilms and potentiate antibiotic efficacy are investigated against mucus-grown Pseudomonas aeruginosa biofilms and optimized to 1) alter biofilm viscoelastic properties, 2) increase mucociliary transport rates, and 3) reduce bacterial viability. A disulfide bond reducing agent (tris(2-carboxyethyl)phosphine, TCEP), a surfactant (NP40), a biopolymer (hyaluronic acid, HA), a DNA degradation enzyme (DNase), and an antibiotic (tobramycin) are tested in various combinations to maximize biofilm disruption. The viscoelastic properties of biofilms are quantified with particle tracking microrheology and transport rates are quantified in a mucociliary transport device comprised of fully differentiated primary human bronchial epithelial cells. The combination of the NP40 with hyaluronic acid and tobramycin was the most effective at increasing mucociliary transport rates, decreasing the viscoelastic properties of mucus, and reducing bacterial viability. Multimechanistic targeting of biofilm infections may ultimately result in improved clinical outcomes, and the results of this study may be translated into future in vivo infection models.

AUTHOR SUMMARY: One of the major challenges associated with chronic respiratory infections in cystic fibrosis and chronic obstructive pulmonary disease is difficult to treat biofilms that form in hyperconcentrated mucus. Biofilms are mechanically robust due to an exterior polymeric matrix that protects from the immune response and antibiotics. Antibiotics like tobramycin alone have little impact on the biofilm matrix, but disruption of viscous mucus and the biofilm architecture has previously been shown to improve antibiotic efficacy. Combination treatments must be used to break up mucus and biofilms and simultaneously kill bacteria. The most promising combination in this study includes the surfactant NP40, the biopolymer hyaluronic acid, and the antibiotic tobramycin which together decreased biofilm viscosity, reduced bacterial load, and increased mucociliary transport rates. The results from this study may be translated to an infected animal study for eventual clinical trials.

PMID:37645913 | PMC:PMC10461968 | DOI:10.1101/2023.08.14.553173

medRxiv. 2023 Aug 16:2023.08.11.23293949. doi: 10.1101/2023.08.11.23293949. Preprint.

ABSTRACT

The intestinal microbiome influences growth and disease progression in children with cystic fibrosis (CF). Elexacaftor-tezacaftor-ivacaftor (ELX/TEZ/IVA), the newest pharmaceutical modulator for CF, restores function of the pathogenic mutated CFTR channel. We performed a single-center longitudinal analysis of the effect of ELX/TEZ/IVA on the intestinal microbiome, intestinal inflammation, and clinical parameters in children with CF. Following ELX/TEZ/IVA, children with CF had significant improvements in BMI, ppFEV 1 and required fewer antibiotics for respiratory infections. Intestinal microbiome diversity increased following ELX/TEZ/IVA coupled with a decrease in the intestinal carriage of Staphylococcus aureus , the predominant respiratory pathogen in children with CF. There was a reduced abundance of microbiome-encoded antibiotic-resistance genes. Microbial pathways for aerobic respiration were reduced after ELX/TEZ/IVA. The abundance of microbial acid tolerance genes was reduced, indicating microbial adaptation to increased CFTR function. In all, this study represents the first comprehensive analysis of the intestinal microbiome in children with CF receiving ELX/TEZ/IVA.

PMID:37645804 | PMC:PMC10462202 | DOI:10.1101/2023.08.11.23293949

Orphanet J Rare Dis. 2023 Aug 29;18(1):246. doi: 10.1186/s13023-023-02807-1.

ABSTRACT

BACKGROUND: One of the most prevalent cancers in the world is lung cancer, with adenocarcinoma (LUAD) making up a significant portion of cases. According to the National Cancer Institute (NCI), there are new cases and fatality rates per 100,000 individuals as follows: New instances of lung and bronchial cancer occur annually at a rate of 50.0 per 100,000 persons. The yearly death rate for men and women is 35.0 per 100,000. DNA methylation is one of the earliest discovered and widely studied epigenetic regulatory mechanisms, and its abnormality is closely related to the occurrence and development of cancer. However, the prognostic value of DNA methylation and LUAD needs to be further explored to improve the survival prediction of LUAD patients.

METHODS: The transcriptome data and clinical data of LUAD were downloaded from TCGA and GEO databases, and the Illumina Human Methylation450 array (450k array) data were downloaded from the TCGA database. Firstly, the intersection of the expressed genes of the two databases is corrected, the differential analysis is performed, and the methylation data is evaluated by the MethylMix package to obtain differentially methylated genes. Independent prognostic genes were screened out using univariate and multivariate Cox regression analysis, and a methylation prognostic model was developed using univariate Cox analysis and validated with the GSE30219 dataset in the GEO database. Survival analysis between methylation high-risk and low-risk groups was performed and a methylation-based gene prognostic model was constructed. Finally, the prediction of potential drugs associated with the LUAD gene signature using Drug Sensitivity Genomics in Cancer (GDSC).

RESULTS: In this study, a total of 555 samples from the TCGA database and 307 samples from GSE30219 were included, and a total of 24 differential methylation driver genes were identified. Univariate and multivariate Cox regression analyzes were used to screen out independent prognostic genes, involving 2 genes: CFTR, PKIA. Survival analysis was different between the methylation high-risk group and the low-risk group, the CFTR high methylation group and the low methylation group were poor, and the opposite was true for PKIA.

CONCLUSIONS: Our study revealed that the methylation status of CFTR and PKIA can serve as potential prognostic biomarkers and therapeutic targets in lung cancer.

PMID:37644544 | DOI:10.1186/s13023-023-02807-1

BMJ Case Rep. 2023 Aug 29;16(8):e253542. doi: 10.1136/bcr-2022-253542.

ABSTRACT

With increasing survival in patients with cystic fibrosis (CF), complications such as gastrointestinal (GI) malignancies are becoming more apparent, especially in transplanted patients. In patients with CF, these malignancies are most commonly found in the small bowel, colon, biliary tract and pancreas. We describe a patient with esophageal squamous cell cancer at the site of trachea-esophageal fistula repair in the setting of long-standing CF. Many factors such as low expression of CF transmembrane conductance regulator gene, inflammation and resulting metaplasia, bacterial dysbiosis, dysregulation of Wnt/β-catenin signalling, immune cell infiltration, disruption of intestinal stem cell homeostasis and intestinal barrier integrity have all been implicated in the causation of GI malignancy in patients with CF. Based on shared decision-making in high-risk transplanted individuals, esophagogastroduodenoscopy can be considered alongside colon cancer screening which is currently recommended starting at age 30-35 years.

PMID:37643818 | DOI:10.1136/bcr-2022-253542

Nat Microbiol. 2023 Sep;8(9):1717-1731. doi: 10.1038/s41564-023-01451-6. Epub 2023 Aug 24.

ABSTRACT

Mycobacteriophages show promise as therapeutic agents for non-tuberculous mycobacterium infections. However, little is known about phage recognition of Mycobacterium cell surfaces or mechanisms of phage resistance. We show here that trehalose polyphleates (TPPs)-high-molecular-weight, surface-exposed glycolipids found in some mycobacterial species-are required for infection of Mycobacterium abscessus and Mycobacterium smegmatis by clinically useful phages BPs and Muddy. TPP loss leads to defects in adsorption and infection and confers resistance. Transposon mutagenesis shows that TPP disruption is the primary mechanism for phage resistance. Spontaneous phage resistance occurs through TPP loss by mutation, and some M. abscessus clinical isolates are naturally phage-insensitive due to TPP synthesis gene mutations. Both BPs and Muddy become TPP-independent through single amino acid substitutions in their tail spike proteins, and M. abscessus mutants resistant to TPP-independent phages reveal additional resistance mechanisms. Clinical use of BPs and Muddy TPP-independent mutants should preempt phage resistance caused by TPP loss.

PMID:37644325 | DOI:10.1038/s41564-023-01451-6

Nucleic Acid Ther. 2023 Aug 29. doi: 10.1089/nat.2023.0015. Online ahead of print.

ABSTRACT

Recent advances in the therapeutic potential of RNA-related treatments, specifically for antisense oligonucleotide (ASO)-based drugs, have led to increased numbers of ASO regulatory approvals. In this study, we focus on SPL84, an inhaled ASO-based drug, developed for the treatment of the pulmonary disease cystic fibrosis (CF). Pulmonary drug delivery is challenging, due to a variety of biological, physical, chemical, and structural barriers, especially when targeting the cell nucleus. The distribution of SPL84 throughout the lungs, penetration into the epithelial cells and nucleus, and structural stability are critical parameters that will impact drug efficacy in a clinical setting. In this study, we demonstrate broad distribution, as well as cell and nucleus penetration of SPL84 in mouse and monkey lungs. In vivo and in vitro studies confirmed the stability of our inhaled drug in CF patient-derived mucus and in lung lysosomal extracts. The mobility of SPL84 through hyperconcentrated mucus was also demonstrated. Our results, supported by a promising preclinical pharmacological effect of full restoration of cystic fibrosis transmembrane conductance regulator channel activity, emphasize the high potential of SPL84 as an effective drug for the treatment of CF patients. In addition, successfully tackling the lung distribution of SPL84 offers immense opportunities for further development of SpliSense's inhaled ASO-based drugs for unmet needs in pulmonary diseases.

PMID:37643307 | DOI:10.1089/nat.2023.0015

Am J Physiol Lung Cell Mol Physiol. 2023 Aug 29. doi: 10.1152/ajplung.00065.2023. Online ahead of print.

ABSTRACT

The clinical definition of "difficult asthma" has expanded recently to include an ever-growing subset of patients with symptoms that cannot be controlled by conventional means, forcing the medical community to develop innovative therapeutics. Beneficial effects of coffee for asthmatics, primarily the effect of methylxanthine components, have long been described. Methylxanthines, including theophylline and caffeine, inhibit phosphodiesterases and downstream cAMP signaling to prevent mast cell degranulation while promoting immunomodulation.1,11 Caffeine is also a bitter taste receptor agonist, binding to TAS2R before releasing calcium to hyperpolarize airway smooth muscle membranes, inducing bronchodilation.10, 38 Theophylline is conventionally used to treat asthma, whereas, according to the literature, the dosage required for orally administered caffeine has yielded modest improvement. We sought to determine whether aerosolization of ultrafine caffeine particles (2.5 - 4 μm) directly to the lungs of susceptible A/J mice challenged with methacholine would improve pulmonary function via forced oscillation technique. Additionally, we assessed whether nebulization of caffeine leads to changes in lung pathophysiology and bronchoalveolar lavage cell profiles. We found that mice that received aerosolized caffeine had statistically significant decreases in maximum airway resistance (6.3 vs. 3.9 cmH2O.s/mL at 62.5 mg/mL caffeine; CI = -4.3, -0.4; P = 0.02), as well as significant delays in the time required to reach maximum resistance compared with controls (64.7 vs. 172.1 sec at 62.5 mg/mL caffeine, CI = 96.0, 118.9; P < 0.0001). Nebulized caffeine yielded a consistent effect on airway hyperresponsiveness at a range of doses without evidence of significant pathology relative to vehicle control.

PMID:37643013 | DOI:10.1152/ajplung.00065.2023

J Clin Invest. 2023 Aug 29:e163591. doi: 10.1172/JCI163591. Online ahead of print.

ABSTRACT

The gastrointestinal tract relies on the production, maturation, and transit of mucin to protect against pathogens and to lubricate the epithelial lining. Although the molecular and cellular mechanisms that regulate mucin production and movement are beginning to be understood, the upstream epithelial signals that contribute to mucin regulation remain unclear. Here, we report that the inflammatory cytokine tumor necrosis factor (TNF), generated by the epithelium, contributes to mucin homeostasis by regulating both cell differentiation and cystic fibrosis transmembrane conductance regulator (CFTR) activity. We used genetic mouse models and non-inflamed samples from Inflammatory Bowel Disease (IBD) patients undergoing anti-TNF therapy to assess the effect of in vivo perturbation of TNF. We found that inhibition of epithelial TNF promotes the differentiation of secretory progenitor cells into mucus-producing goblet cells. Furthermore, TNF treatment and CFTR inhibition in intestinal organoids demonstrated that TNF promotes ion transport and luminal flow via CFTR. The absence of TNF led to slower gut transit times, which we propose results from increased mucus accumulation coupled with decreased luminal fluid pumping. These findings point to a TNF-CFTR signaling axis in the adult intestine and identify epithelial-derived TNF as an upstream regulator of mucin homeostasis.

PMID:37643009 | DOI:10.1172/JCI163591

J Exp Med. 2023 Oct 2;220(10):e20230104. doi: 10.1084/jem.20230104. Epub 2023 Aug 29.

ABSTRACT

Human airway and corneal epithelial cells, which are critically altered during chronic infections mediated by Pseudomonas aeruginosa, specifically express the inflammasome sensor NLRP1. Here, together with a companion study, we report that the NLRP1 inflammasome detects exotoxin A (EXOA), a ribotoxin released by P. aeruginosa type 2 secretion system (T2SS), during chronic infection. Mechanistically, EXOA-driven eukaryotic elongation factor 2 (EEF2) ribosylation and covalent inactivation promote ribotoxic stress and subsequent NLRP1 inflammasome activation, a process shared with other EEF2-inactivating toxins, diphtheria toxin and cholix toxin. Biochemically, irreversible EEF2 inactivation triggers ribosome stress-associated kinases ZAKα- and P38-dependent NLRP1 phosphorylation and subsequent proteasome-driven functional degradation. Finally, cystic fibrosis cells from patients exhibit exacerbated P38 activity and hypersensitivity to EXOA-induced ribotoxic stress-dependent NLRP1 inflammasome activation, a process inhibited by the use of ZAKα inhibitors. Altogether, our results show the importance of P. aeruginosa virulence factor EXOA at promoting NLRP1-dependent epithelial damage and identify ZAKα as a critical sensor of virulence-inactivated EEF2.

PMID:37642996 | DOI:10.1084/jem.20230104

Chembiochem. 2023 Aug 29:e202300346. doi: 10.1002/cbic.202300346. Online ahead of print.

ABSTRACT

Human neutrophil elastase (HNE) is an enzyme that plays key role in the body's inflammatory response. It has been linked to a number of diseases such as chronic obstructive pulmonary disease (COPD), emphysema, and cystic fibrosis. As potential treatments for these diseases, HNE inhibitors are of great interest. Metabolites derived from plants, particularly terpenoids such as β-caryophyllene found in black pepper and other plants, and geraniol present in several essential oils, are recognized as significant sources of inhibitors for HNE. Because of their ability to inhibit HNE, terpenoids are considered promising candidates for developing novel therapies to treat inflammatory conditions such as COPD and emphysema. Furthermore, nature can serve as an excellent designer, and it may offer a safer drug candidate for inhibiting HNE production and activity in the future. This review focuses on the isolation, chemical diversity, and inhibition of Human neutrophil elastase (HNE) of various terpenoids reported from natural sources up to 2022. Further it also provides a summary of HNE inhibitors and includes a through discussion was made on structure activity relationship.

PMID:37642535 | DOI:10.1002/cbic.202300346

Curr Opin Pulm Med. 2023 Aug 30. doi: 10.1097/MCP.0000000000001010. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Pulmonary exacerbations are critical events with significant negative impacts in persons with cystic fibrosis, but their diagnosis and management are highly variable. Highly effective modulator therapies have greatly improved health and reduced exacerbation events, but have also reshaped how they present. This review discusses the complexities of the diagnosis and management of pulmonary exacerbations as well as the emerging work and evidence in this area.

RECENT FINDINGS: The shifting epidemiology and our understanding of risk factors for pulmonary exacerbations are discussed. As symptoms may be more subtle in the modulator context, novel technologies including studies of remote monitoring are presented. The continued relevance of pulmonary exacerbations, the heterogeneity in their management, as well as current and forthcoming clinical trials to optimize treatment approaches are detailed.

SUMMARY: In spite of the dramatic reductions in pulmonary exacerbations, airway infections persist, a proportion of persons with cystic fibrosis either on or off modulator therapies continue to experience exacerbation events, and long-term data is lacking. Innovative approaches and studies will be crucial to enable standardized and generalizable strategies to improve outcomes in persons with cystic fibrosis.

PMID:37642491 | DOI:10.1097/MCP.0000000000001010

Int J Organ Transplant Med. 2022;13(2):51-62.

ABSTRACT

BACKGROUND: This study aims to evaluate the entire experience in heart-lung transplantation (HLTx) in a country of the European Union with 47 million inhabitants according to the etiologies that motivated the procedure.

METHODS: A retrospective study on 1,751 consecutive transplants (HLTx: 78) was performed from 1990 to 2020 in two centers. Overall survival, adjusted for clinical profile and etiological subgroups, was compared. 7 subgroups were considered: 1) Cardiomyopathy with pulmonary hypertension (CM + PH). 2) Eisenmenger syndrome. 3) Congenital heart disease (CHD). 4) Idiopathic pulmonary arterial hypertension (IPAH). 5) Cystic fibrosis. 6) Chronic obstructive pulmonary disease (COPD)/Emphysema. 7) Diffuse interstitial lung disease (ILD).

RESULTS: Early mortality was 44% and that of the rest of the follow-up was 31%. There were differences between HTLx and HTx in survival, also comparing groups with a similar clinical profile with propensity score (p= 0.04). Median survival was low in CM + PH (18 days), ILD (29 days) and CHD (114 days), intermediate in Eisenmenger syndrome (600 days), and longer in IPAH, COPD/Emphysema and cystic fibrosis.

CONCLUSION: HLTx has a high mortality. The etiological analysis is of the utmost interest to make the most of the organs and improve survival.

PMID:37641734 | PMC:PMC10460527

Afr J Thorac Crit Care Med. 2023 Aug 3;29(2). doi: 10.7196/AJTCCM.2023.v29i2.647. eCollection 2023.

ABSTRACT

BACKGROUND: Bronchiectasis is a chronic lung disorder that affects the lives of many South Africans. Post-tuberculosis (TB) bronchiectasis is an important complication of previous pulmonary TB and a common cause of bronchiectasis in South Africa (SA). No previous statements on the management of bronchiectasis in SA have been published.

OBJECTIVES: To provide a position statement that will act as a template for the management of adult patients with bronchiectasis in SA.

METHODS: The South African Thoracic Society appointed an editorial committee to compile a position statement on the management of adult non-cystic fibrosis (CF) bronchiectasis in SA.

RESULTS: A position statement addressing the management of non-CF bronchiectasis in adults in SA was compiled. This position statement covers the epidemiology, aetiology, diagnosis, investigations and various aspects of management of adult patients with non-CF bronchiectasis in SA.

CONCLUSION: Bronchiectasis has largely been a neglected lung condition, but new research has improved the outlook for patients. Collaboration between interprofessional team members in patient management is important. In SA, more research into the epidemiology of bronchiectasis, especially post-TB bronchiectasis and HIV-associated bronchiectasis, is required.

ABSTRACT: The South African Thoracic Society mandated a multidisciplinary team of healthcare providers to compile a position statement on the management of non-cystic fibrosis bronchiectasis in South Africa (SA). International guidelines on the management of bronchiectasis were reviewed and used as a basis from which the current position statement was compiled. This is the first position statement on the management of adult non-cystic fibrosis bronchiectasis in SA. A description of the epidemiology and aetiology of bronchiectasis is provided, as well as guidance on its diagnosis and management. The position statement provides guidance on the management of bronchiectasis to healthcare providers, policymakers and regulatory authorities.

PMID:37638142 | PMC:PMC10450449 | DOI:10.7196/AJTCCM.2023.v29i2.647