Biochemistry (Mosc). 2025 Jan;90(Suppl 1):S214-S232. doi: 10.1134/S0006297924603496.

ABSTRACT

Mycobacterium abscessus is a non-tuberculosis fast-growing mycobacterium that has recently become a serious concern due to its rapidly increasing prevalence worldwide, mainly in individuals with a high susceptibility to pulmonary infections, for example, patients with cystic fibrosis, bronchiectasis, chronic obstructive pulmonary disease, and previous tuberculosis infection. According to present estimations, at least 20% of patients with cystic fibrosis are infected with M. abscessus. This bacterium is extremely resistant to most drugs, leading to a severe and difficult-to-treat infection. That is why M. abscessus, previously classified as a low-virulent opportunistic pathogen, is now reconsidered as a true pathogenic bacterium. There are no effective drugs for successful M. abscessus infection therapy, as well as no vaccines to prevent its spread. This review focuses on the molecular mechanisms ensuring M. abscessus resistance to immune response and its ability to survive in the aggressive intracellular environment of human immune cells, and describes virulence factors that can serve as potential targets for the development of innovative therapeutic approaches to combat the spread of infections caused by M. abscessus.

PMID:40164160 | DOI:10.1134/S0006297924603496

PLoS One. 2025 Mar 31;20(3):e0319710. doi: 10.1371/journal.pone.0319710. eCollection 2025.

ABSTRACT

Mycobacterium abscessus (MABS) is an emerging pathogen causing severe infections, particularly in cystic fibrosis (CF) patients. A prospective multicentre study included CF patients from four hospitals in Madrid between January 2022 and January 2024. Respiratory samples were collected, and MABS isolates were analysed to determine their antibiotic resistance profiles, growth dynamics, infection kinetics, intracellular behaviour, and pathogenicity. Intracellular bacterial growth and macrophage viability were evaluated through THP-1 cell infection experiments, with and without amikacin. Phenotypic susceptibility testing and genotypic susceptibility testing were also conducted. Among 148 patients, 28 MABS isolates were detected from 16 patients (10.8%), and the first isolate from each patient was analysed. Isolation was more prevalent in younger individuals (median age 24.4 vs. 28.4 years, p = 0.049), and most isolates (81.25%) were identified as M. abscessus subsp. abscessus (MABSa). MABS isolates exhibited high resistance rates (>85%) to doxycycline, tobramycin, ciprofloxacin, moxifloxacin (75%) and cotrimoxazole (56.3%). Amikacin resistance (18.8%) was higher than expected, and inducible (10/16 isolates) or acquired (1/16 isolate) macrolide resistance was found in 68.8% of strains. Phenotypic and genotypic testing results were fully concordant. Tigecycline demonstrated strong in vitro activity, and resistance to imipenem, linezolid, and cefoxitin remained low. Rough strains displayed lower optical density values in later growth stages, probably due to their increased aggregation. In THP-1 cell infection experiments, rough strains showed higher intracellular bacterial loads with statistically significant differences observed at 2 hours (both with and without amikacin) and at 72 hours (with amikacin) post infection. Notably, rough strains also exhibited a higher internalisation index and greater impact on THP-1 cell viability, especially in the absence of amikacin.

PMID:40163512 | DOI:10.1371/journal.pone.0319710

Ther Adv Respir Dis. 2025 Jan-Dec;19:17534666251323194. doi: 10.1177/17534666251323194. Epub 2025 Mar 31.

ABSTRACT

Over the past decade, major clinical advances have been made in the healthcare and therapeutic development for cystic fibrosis (CF), a lethal genetic disease caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. CFTR modulators represent innovative treatments that directly target the primary defects in the mutated CFTR protein and have demonstrated significant clinical benefits for many people with CF (pwCF) who are eligible for these treatments. In particular, the triple combination therapy composed of elexacaftor, tezacaftor, and ivacaftor (ETI) has changed the CF therapeutic landscape by significantly improving lung function, quality of life, and predicted survival rates. Here, we provided a comprehensive summary of the impact of ETI on clinical outcomes and the need for further research on long-term efficacy, side effects, pregnancy, possible drug-drug interactions, and extra-pulmonary manifestations. Moreover, a significant number of pwCF are unresponsive to these drugs or cannot afford their high costs. We, therefore, discussed health inequity issues and alternative therapeutic strategies under development aiming to obtain effective therapies for all pwCF.

PMID:40163448 | DOI:10.1177/17534666251323194

Microbiol Spectr. 2025 Mar 31:e0214924. doi: 10.1128/spectrum.02149-24. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that can cause sinus infections and pneumonia in cystic fibrosis (CF) patients. Bacteriophage therapy is being investigated as a treatment for antibiotic-resistant P. aeruginosa infections. Although virulent bacteriophages have shown promise in treating P. aeruginosa infections, the development of bacteriophage-insensitive mutants (BIMs) in the presence of bacteriophages has been described. The aim of this study was to examine the genetic changes associated with the BIM phenotype. Biofilms of three genetically distinct P. aeruginosa strains, including PAO1 (ATCC 15692), and two clinical respiratory isolates (one CF and one non-CF) were grown for 7 days and treated with either a cocktail of four bacteriophages or a vehicle control for 7 consecutive days. BIMs isolated from the biofilms were detected by streak assays, and resistance to the phage cocktail was confirmed using spot test assays. Comparison of whole genome sequencing between the recovered BIMs and their respective vehicle control-treated phage-sensitive isolates revealed structural variants in two strains, and several small variants in all three strains. These variations involved a TonB-dependent outer membrane receptor in one strain, and mutations in lipopolysaccharide synthesis genes in two strains. Prophage deletion and induction were also noted in two strains, as well as mutations in several genes associated with virulence factors. Mutations in genes involved in susceptibility to conventional antibiotics were also identified in BIMs, with both decreased and increased antibiotic sensitivity to various antibiotics being observed. These findings may have implications for future applications of lytic phage therapy.IMPORTANCELytic bacteriophages are viruses that infect and kill bacteria and can be used to treat difficult-to-treat bacterial infections, including biofilm-associated infections and multidrug-resistant bacteria. Pseudomonas aeruginosa is a bacterium that can cause life-threatening infections. Lytic bacteriophage therapy has been trialed in the treatment of P. aeruginosa infections; however, sometimes bacteria develop resistance to the bacteriophages. This study sheds light on the genetic mechanisms of such resistance, and how this might be harnessed to restore the sensitivity of multidrug-resistant P. aeruginosa to conventional antibiotics.

PMID:40162801 | DOI:10.1128/spectrum.02149-24

bioRxiv [Preprint]. 2025 Mar 12:2025.03.12.642861. doi: 10.1101/2025.03.12.642861.

ABSTRACT

Pseudomonas aeruginosa and Staphylococcus aureus are primary bacterial pathogens isolated from the airways of cystic fibrosis patients. P. aeruginosa produces secondary metabolites that negatively impact the fitness of S. aureus, allowing P. aeruginosa to become the most prominent bacterium when the species are co-cultured. Some of these metabolites inhibit S. aureus respiration. SrrAB is a staphylococcal two-component regulatory system (TCRS) that responds to alterations in respiratory status and helps S. aureus transition between fermentative and respiratory metabolisms. We used P. aeruginosa mutant strains and chemical genetics to demonstrate that P. aeruginosa secondary metabolites, HQNO in particular, inhibit S. aureus respiration, resulting in modified SrrAB stimulation. Metabolomic analyses found that the ratio of NAD + to NADH increased upon prolonged culture with HQNO. Consistent with this, the activity of the Rex transcriptional regulator, which senses and responds to alterations in the NAD + / NADH ratio, had altered activity upon HQNO treatment. The presence of SrrAB increased fitness when cultured with HQNO and increased survival when challenged with P. aeruginosa. S. aureus strains with a decreased ability to maintain redox homeostasis via fermentation had decreased fitness when challenged with HQNO and decreased survival when challenged with P. aeruginosa . These findings led to a model wherein P. aeruginosa secreted HQNO inhibits S. aureus respiration, stimulating SrrAB, which promotes fitness and survival by increasing carbon flux through fermentative pathways to maintain redox homeostasis.

IMPORTANCE: Cystic fibrosis (CF) is a hereditary respiratory disease that predisposes patients to bacterial infections, primarily caused by Staphylococcus aureus and Pseudomonas aeruginosa . P. aeruginosa excreted secondary metabolites decrease S. aureus fitness during co-infection, ultimately eliminating it. The genetic mechanisms that S. aureus uses to detect and respond to these metabolites are unknown. The S. aureus SrrAB two-component regulatory system senses flux through respiratory pathways and increases transcription of genes utilized for adaption to low-respiration environments. This study demonstrates that SrrAB responds to the P. aeruginosa -produced respiratory toxin HQNO and responds by increasing fermentation increasing competition. This study describes interactions between these two bacterial pathogens, which could be exploited to decrease pathogen burden in individuals living with cystic fibrosis.

PMID:40161799 | PMC:PMC11952440 | DOI:10.1101/2025.03.12.642861

bioRxiv [Preprint]. 2025 Mar 13:2025.03.11.642711. doi: 10.1101/2025.03.11.642711.

ABSTRACT

Drug delivery platforms, complex lipid nanoparticles (LNPs) and extracellular vesicles (EVs) have both faced a number of key challenges ranging from organ specificity to loading capacity and stability. A key challenge in EV biology as well as LNP design remains vesicle to cell interaction and the creation of a polar permeability pathway necessary for cargo exchange. Membrane to membrane recognition and intercalation are tantamount to delivery and integral to function of both EVs and LNPs, both complex and single component. We reasoned that the overlapping advantages of both nanoparticles centered on compositional lipids. EVs are encapsulations using biological membrane lipids and expressed proteins and have a larger carrier capacity. LNPs are composed of synthetic lipids differing in charge and amount mimicking those present in biological membranes and include a synthetic lipid of choice that carries a charge, designed to enhance biological membrane disruption and subsequent cargo off-loading. Our goal was to design hybrid EVs (HEVs) that combined both elements. We manufactured positively charged liposomes (Lip) carrying mRNA coding for fluorescent proteins to load isolated EVs in order to create a combinatorial delivery platform. Using knowledge from LNP-based mRNA vaccine delivery, we have formulated and characterized HEVs. Future therapeutic strategies could involve isolating EVs from patients, hybridizing them with synthetic lipids loaded with desired payloads, and reintroducing them to the patient. This approach is particularly relevant for enhancing the function of pulmonary innate immunity in diseases like cystic fibrosis, chronic granulomatous disease, and pulmonary fibrosis. By conducting both in-vitro and in-vivo assays, we demonstrate that HEVs exhibit comparable transfection efficacy to LNPs composed of complex synthetic lipids, while significantly reducing cytotoxicity. This highlights their potential as safer and more efficient delivery vehicles.

PMID:40161690 | PMC:PMC11952422 | DOI:10.1101/2025.03.11.642711

Respiration. 2025 Mar 28:1-10. doi: 10.1159/000545552. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR gene. A minority of people with CF carry two heterozygous CFTR mutations other than the common Phe508del, complicating diagnosis and treatment.

CASE PRESENTATION: We report the case of a 25-year-old South American male diagnosed with CF respiratory disease, characterized by a history of recurrent infections, pulmonary Mycobacterium abscessus infection, airway disease on high-resolution CT, and an elevated sweat chloride level (74 mmol/L). Exome sequencing identified a unique combination of CFTR mutations: a pathogenic frameshift variant (c.2052dup) and a variant of unknown clinical significance (c.710A>C). Notably, there were no signs of pancreatic insufficiency. Rectal mucosal organoid cultures demonstrated residual CFTR function with responsiveness to ivacaftor and the combination of elexacaftor, tezacaftor, and ivacaftor.

CONCLUSION: This case highlights a unique combination of heterozygous CFTR variants in a person with late-onset CF respiratory disease, which may be amenable to CFTR modulation therapy.

PMID:40159410 | DOI:10.1159/000545552

Nucleic Acids Res. 2025 Mar 20;53(6):gkaf216. doi: 10.1093/nar/gkaf216.

ABSTRACT

Premature termination codon (PTC) diseases account for ∼12% of all human disease mutations. Although there are no FDA approved treatments for increasing PTC readthrough, one readthrough inducing drug, ataluren, has conditional approval for treatment of Duchenne muscular dystrophy elsewhere. Ataluren displays low toxicity in clinical trials for treatment of PTC diseases, but its therapeutic effects are inconsistent. The messenger RNA (mRNA) sequence context of a PTC is a major determinant of PTC readthrough efficiency. We have shown that ataluren stimulates readthrough exclusively by competitively inhibiting release factor complex (RFC) catalysis of translation termination. Here, using an in vitro reconstituted system, we demonstrate that PTC identity and the immediately adjacent mRNA sequence contexts modulate RFC activity in terminating peptide elongation. Such modulation largely determines the effectiveness of ataluren in stimulating readthrough, whether added alone or in combination with either the aminoglycoside G418 or an anticodon edited aa-tRNA, which stimulate readthrough by mechanisms orthogonal to that of ataluren. Our results suggest a potential rationale for the variability of ataluren effectiveness in stimulating readthrough. We hypothesize that patients harboring a PTC mutation within a sequence context promoting strong interaction with RFC will be resistant to ataluren, but that ataluren treatment will be more effective for patient sequences conferring weaker interaction with RFC.

PMID:40156864 | DOI:10.1093/nar/gkaf216

Laryngoscope. 2025 Mar 29. doi: 10.1002/lary.32155. Online ahead of print.

ABSTRACT

OBJECTIVES: Olfactory dysfunction (OD) is common among people with cystic fibrosis (PwCF) and chronic rhinosinusitis (CRS). OD is associated with impaired quality of life (QOL) and dietary alterations in certain non-CF populations. This study explored relationships between OD, QOL, and modulator use in PwCF.

METHODS: This is a cross-sectional analysis of an ongoing multicenter, prospective study (2019-2023) investigating PwCF with comorbid CRS. Participants completed the 40-Question Smell Identification Test (SIT-40), 22-question SinoNasal Outcome Test-(SNOT-22), Questionnaire of Olfactory Disorders (QOD-NS), and Cystic Fibrosis Questionnaire-Revised (CFQ-R). Clinical and sinus CT data were collected. After stratification by SIT-40 score, data was analyzed by chi-square, Kruskal-Wallis, Spearman correlation, and logistic regression to identify factors associated with OD.

RESULTS: Of 59 participants, those with anosmia (n = 12) had worse eating-related QOL (CFQ-R eating) compared to individuals with normosmia (n = 16) and hyposmia (n = 31). Participants with anosmia had worse sinus CT scores than those with hyposmia. Although PwCF treated with highly effective modulator therapy (HEMT; n = 30) had better CT scores vs. non-HEMT individuals (n = 23), rates of OD in both groups were comparable. Higher SNOT-22 total scores were associated with increased odds of hyposmia or anosmia. In an eating-related QOD-NS subscore, those with worse CFQ-R eating had 2.38 times higher odds of having OD. Each point decrease in CFQ-R eating domain score was associated with 10% increased odds of OD.

CONCLUSION: In PwCF, OD was associated with increased CRS severity, impaired olfactory QOL, and decreased CFQ-R eating. There were no differences in SIT-40 or QOD-NS scores based on HEMT status.

TRIAL REGISTRATION: NCT04469439.

PMID:40156369 | DOI:10.1002/lary.32155

Int J Tuberc Lung Dis. 2025 Mar 31;29(4):153-158. doi: 10.5588/ijtld.24.0544.

ABSTRACT

<sec><title>BACKGROUND</title>Post-infectious bronchiolitis obliterans (PIBO) is a complication of severe childhood respiratory infection resulting in small airway injury, bronchiectasis, and prolonged respiratory consequences. Risk factors for PIBO and PIBO-associated bronchiectasis are unclear.</sec><sec><title>METHODS</title>This retrospective study identified all children with PIBO at a South African tertiary hospital between 1 January 2016 and 31 December 2022. The clinical characteristics, chest CT findings, and details of prior hospitalisation for respiratory infection were collected, and the characteristics of those with and without bronchiectasis were compared.</sec><sec><title>RESULTS</title>A total of 59 children were included (median age at primary lung insult: 10 months, IQR 6-17; median age at PIBO diagnosis: 16 months, IQR 11-28). Twenty-three had comorbidities, most frequently premature birth (30.5%) and HIV infection (6.8%). The most common pathogen was adenovirus (n = 41; 69.5%). At initial lung insult, 19 (32.2%) required mechanical ventilation. Mosaic attenuation on the chest CT was present in all. Thirty-three (55.9%) had bronchiectasis. The clinical characteristics, ventilation, causative pathogen, and comorbidity were similar in those with and without bronchiectasis.</sec><sec><title>CONCLUSION</title>Bronchiectasis occurs frequently in paediatric PIBO and is present within months of initial respiratory insult with no identified risk factors. Premature birth is common and may contribute to PIBO development.</sec>.

PMID:40155792 | DOI:10.5588/ijtld.24.0544

Biomedicines. 2025 Mar 13;13(3):707. doi: 10.3390/biomedicines13030707.

ABSTRACT

Backgroung/objectives: Diffuse large B-cell lymphoma (DLBCL) is the most frequent subtype of malignant lymphoma and is a heterogeneous disease with various gene and chromosomal abnormalities. The development of novel therapeutic treatments has improved DLBCL prognosis, but patients with early relapse or refractory disease have a poor outcome (with a mortality of around 40%). Metabolic reprogramming is a hallmark of cancer cells. Fatty acid (FA) metabolism is frequently altered in cancer cells and recently emerged as a critical survival path for cancer cell survival. Methods: We first performed the metabolic characterization of an extended panel of DLBCL cell lines, including lipid droplet content. Then, we investigated the effect of drugs targeting FA metabolism on DLBCL cell survival. Further, we studied how the combination of drugs targeting FA and either mitochondrial metabolism or mTOR pathway impacts on DLBCL cell death. Results: Here, we reveal, using a large panel of DLBCL cell lines characterized by their metabolic status, that targeting of FA metabolism induces massive DLBCL cell death regardless of their OxPhos or BCR/glycolytic subtype. Further, FA drives resistance of DLBCL cell death induced by mitochondrial stress upon treatment with either metformin or L-asparaginase, two FDA-approved antimetabolic drugs. Interestingly, combining inhibition of FA metabolism with that of the mTOR oncogenic pathway strongly potentiates DLBCL cell death. Conclusion: Altogether, our data highlight the central role played by FA metabolism in DLBCL cell survival, independently of their metabolic subtype, and provide the framework for the use of drugs targeting this metabolic vulnerability to overcome resistance in DLBCL patients.

PMID:40149683 | PMC:PMC11940118 | DOI:10.3390/biomedicines13030707

J Biol Chem. 2025 Mar 26:108460. doi: 10.1016/j.jbc.2025.108460. Online ahead of print.

ABSTRACT

Activation of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl‒ channel requires PKA phosphorylation at the regulatory (R) domain to relieve inhibition of ATP-dependent channel activity. This study aimed to identify the primary inhibitory site that prevents channel activation. CFTR mutants with deletion of residues 760-783 (ΔR760-783) elicited constitutive macroscopic and single-channel Cl‒ currents in the presence of ATP before PKA phosphorylation, suggesting that protein segment R760-783 in the R domain blocks CFTR activation. With the background of ΔR760-835, further deletion of R708-759 led to fully active channels in the presence of ATP, but absence of PKA, suggesting that R708-759 prevents the activation of ΔR760-835-CFTR. R760-783 peptides were unstructured in buffered solutions in circular dichroism spectroscopy and the N771P mutation that interrupts the α-helix formation induced no apparent constitutive current before PKA phosphorylation. These data suggest that interpeptide interactions by α-helices likely contribute trivially to the blocking effect of R760-783. CFTR mutants with small deletions or alanine replacements containing any one of residues R766 and S768 in a PKA consensus sequence and M773 and T774 generated PKA-independent CFTR Cl‒ currents. Similarly, introducing the mutations Q767C or T774C into a control CFTR construct produced constitutive CFTR Cl‒ currents by positively charged MTSET modification of target cysteines. Moreover, PKA-independent single-channel activity was evidently observed in R766K-, S768K- and T774K-CFTR mutants. Therefore, the four residues R766, S768, M773 and T774 may form an inhibitory module that precludes CFTR activation through side-chain interactions. This inhibitory mechanism might be emulated by other PKA-dependent proteins.

PMID:40154618 | DOI:10.1016/j.jbc.2025.108460

Am J Respir Crit Care Med. 2025 Mar 28. doi: 10.1164/rccm.202409-1792OC. Online ahead of print.

ABSTRACT

RATIONALE: Mycobacteroides abscessus infections affect immunocompromised patients and those with underlying pulmonary disease. Conventional imaging cannot distinguish M. abscessus infections from underlying pulmonary disease or sterile inflammation, requiring invasive procedures for definitive diagnosis.

OBJECTIVE: We evaluated 11C-para-aminobenzoic acid (11C-PABA), a chemically identical radioanalog of PABA, to detect and localize infections due to M. abscessus.

METHODS: In vitro uptake assays were performed to test the metabolism and accumulation of PABA into M. abscessus reference and clinical isolates. Dynamic 11C-PABA positron emission tomography (PET) was performed in a mouse model of M. abscessus pulmonary infection and in a patient with microbiologically-confirmed M. abscessus pulmonary infection (NCT05611905).

MAIN RESULTS: 11C-PABA was intracellularly metabolized by M. abscessus to 11C-7,8-dihydropteroate. Additionally, and the reference and all thirteen randomly chosen clinical isolates, including three resistant to trimethoprim-sulfamethoxazole, rapidly accumulated PABA. No PABA accumulation was noted by heat-inactivated bacteria or mammalian cells. Dynamic 11C-PABA PET in a mouse model of M. abscessus pulmonary infection rapidly distinguished infection from sterile inflammation and also accurately monitored response to antibiotic treatment. Finally, dynamic 11C-PABA PET in a 33-year-old female with cystic fibrosis and microbiologically confirmed M. abscessus pulmonary infection was safe and demonstrated significantly higher and sustained PET uptake in the affected lesions.

CONCLUSIONS: 11C-PABA PET is an innovative, clinically-translatable, noninvasive, bacteria-specific diagnostic to differentiate M. abscessus infections from underlying pulmonary disease in patients. This tool could also help in monitoring treatment responses and enable precision medicine approaches for patients with complicated infections. This article is open access and distributed under the terms of the Creative Commons Attribution Non-Commercial No Derivatives License 4.0 (http://creativecommons.org/licenses/by-nc-nd/4.0/).

PMID:40153540 | DOI:10.1164/rccm.202409-1792OC

J Proteome Res. 2025 Mar 28. doi: 10.1021/acs.jproteome.4c00827. Online ahead of print.

ABSTRACT

Intercellular communication is important for host immunity in response to bacterial infections. Nontuberculous mycobacterium (NTM), such as Mycobacterium abscessus (M. ab), is a group of environmental bacteria that can cause severe lung infections in individuals with pre-existing lung conditions, including cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD). There is limited knowledge understanding the interaction between airway epithelial cells and immune cells during NTM infections. In this study, we characterized microvesicles (MVs) released from uninfected and M. ab-infected human bronchial epithelial cells and investigated the effect of these MVs on the activation and polarization of THP-1-derived macrophages in cell culture. Our results indicate that MVs released by M. ab-infected human bronchial epithelial cells stimulated the activation of M2-polarized macrophages in cell culture when compared to MVs released by uninfected cells. Additionally, the proteomic analysis for isolated MVs showed that the proteins involved in the cell adhesion pathway were enriched in MVs from M. ab-infected human bronchial epithelial cells compared to MVs from uninfected cells. Among those, the cell surface protein, intercellular adhesion molecule 1 (ICAM-1), regulated the uptake of MVs released by M. ab-infected human bronchial epithelial cells by recipient macrophages in cell culture. In conclusion, our data suggest that in response to M. ab infection, human airway epithelial cells release MVs to modulate the activation of macrophages, which are key cells for mycobacterial intracellular survival in the host.

PMID:40153482 | DOI:10.1021/acs.jproteome.4c00827

Lung. 2025 Mar 28;203(1):55. doi: 10.1007/s00408-025-00806-6.

ABSTRACT

PURPOSE: Cystic fibrosis (CF) is a genetic disease caused by mutations in the CFTR gene, leading to multisystemic complications, particularly in the lungs. CFTR dysfunction results in altered ion transport, chronic inflammation, and progressive lung damage. The triple therapy elexacaftor/tezacaftor/ivacaftor (ETI) has demonstrated significant improvements in pulmonary function and quality of life. This study aimed to evaluate the anti-inflammatory effects of ETI by analysing systemic cytokine profiles over 12 months.

METHODS: A prospective study included 32 CF patients ≥ 18 years with at least one delF508 mutation, undergoing ETI therapy. Clinical stability was ensured prior to therapy initiation. Demographic data, BMI (Body Mass Index), FEV1% (Forced expiratory Volume in the first second), VR/TLC (residual volume/total lung capacity) and sweat chloride concentrations were recorded at baseline, 6 months and 12 months. Inflammatory markers, including fibrinogen, C-reactive protein (CRP), and a panel of 8 cytokines, were measured using multiplex bead-based immunoassays and electrochemiluminescence. Longitudinal changes were analysed using mixed-effects models and statistical tests, with significance set at p < 0.05.

RESULTS: During a 12-month follow-up, the neutrophils number and proinflammatory biomarkers analyzed, fibrinogen, CRP, GM-CSF, IFN- γ, IL-1 α, IL-1 β, IL-8 (CXCL8), IL-12p70, IL-17A (CTLA-8), and TNF-α, significantly decreased, while eosinophils remained stable. Mixed-effects models confirmed the significant association of inflammatory biomarkers with FEV1, BMI, sweat chloride levels, and VR/TLC highlighting the role of inflammation in the progression of CF.

CONCLUSIONS: ETI demonstrated marked anti-inflammatory effects in CF patients, reducing systemic inflammation and improving clinical parameters.

PMID:40153049 | DOI:10.1007/s00408-025-00806-6

Med Lett Drugs Ther. 2025 Mar 31;67(1725):e56. doi: 10.58347/tml.2025.1725d.

NO ABSTRACT

PMID:40152724 | DOI:10.58347/tml.2025.1725d

Cochrane Database Syst Rev. 2025 Mar 28;3:CD015313. doi: 10.1002/14651858.CD015313.pub2.

ABSTRACT

BACKGROUND: Chronic suppurative lung disease (CSLD) is an umbrella term to define the spectrum of endobronchial suppurative lung disease, including bronchiectasis and protracted bacterial bronchitis (PBB), associated with chronic wet or productive cough. Research that explores new therapeutic options in children with CSLD has been identified by clinicians and patients as one of the top research priorities. Mucolytic agents work to improve mucociliary clearance and interrupt the vicious vortex of airway infection and inflammation, hence they have potential as a therapeutic option.

OBJECTIVES: To assess the effects of mucolytics for reducing exacerbations, improving quality of life and other clinical outcomes in children with CSLD (including PBB and bronchiectasis), and to assess the risk of harm due to adverse events.

SEARCH METHODS: An Information Specialist searched the Cochrane Airways Trials Register to June 2022, and a review author searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE and Embase databases to 27 September 2024. Other review authors handsearched respiratory journals.

SELECTION CRITERIA: We included randomised controlled trials (RCTs), of both cross-over and parallel design, that compared a mucolytic with a placebo or 'no intervention' control group and included children (aged 18 years and under) with any type of CSLD (including PBB and bronchiectasis). We excluded studies with adult participants and studies in children with cystic fibrosis, empyema, pulmonary abscess or bronchopulmonary fistula.

DATA COLLECTION AND ANALYSIS: Two authors independently reviewed titles and abstracts to assess eligibility for inclusion. The authors then assessed study quality and extracted data. They assessed the quality of the study using the Cochrane risk of bias tool (RoB 2), and used GRADE to assess the certainty of evidence. Outcomes of interest to be analysed included: i) for maintenance or stable state: rate of exacerbations, ii) for exacerbation state: time to resolution of respiratory exacerbation, iii) lung function - forced expiratory volume in one second (FEV1) and forced vital capacity (FVC), iv) quality of life and v) adverse events. Only one study met the inclusion criteria, so we could not perform a meta-analysis. Data were continuous, so we reported outcomes as mean differences.

MAIN RESULTS: The sole included RCT was a cross-over study of 63 children in the total cohort, with reported data and analysis of only 52 children (26 per arm) with non-cystic fibrosis bronchiectasis. The study compared 3% hypertonic saline nebulised before chest physiotherapy with a control arm (physiotherapy alone), with each phase lasting eight weeks. Children in the hypertonic saline arm had a mean age of 9.80 (SD 2.97) years and 42.3% were male; those in the control arm had a mean age of 9.10 (SD 2.40) years and 38.4% were male. Only results of the first arm of the cross-over study were included in this review. The RCT reported a clinically important difference between the groups for our review's primary outcome: rate of respiratory exacerbations. The mean number of exacerbations per child-year was 2.50 (SD 0.64) in the intervention group and 7.80 (SD 1.05) in the control group (mean difference (MD) -5.30, 95% CI -5.77 to -4.83; 1 study, 52 participants; very low-certainty evidence). The RCT also reported that the percentage point improvement in mean % predicted FEV1 and FVC from baseline to week eight was better with hypertonic saline compared to control. Mean FEV1 improvement was 14.15% (SD 5.50) in the intervention group versus 5.04% (SD 5.55) in the control group (MD 9.11%, 95% CI 6.11 to 12.11; 1 study, 52 participants; very low-certainty evidence). While for FVC, the mean improvement was 13.77% (SD 5.73) compared with 7.54% (SD 4.90), respectively (MD 6.23%, 95% CI 3.33 to 9.13; 1 study, 52 participants; very low-certainty evidence). Quality of life measures were not used. We judged the study to have a high risk of bias due to unblinding, missing data, deviation from the intended intervention and reporting bias with measurement and selection of outcome measures. The authors reported that there were no dropouts due to adverse events. No data were available regarding quality of life. The included study assessed mucolytic use during a stable state, and we found no studies of mucolytic use during an exacerbation. We also found no studies assessing oral mucolytics, other inhaled mucolytics, use in PBB, or in settings other than hospital outpatients. We also found two ongoing studies, one using hypertonic saline and one using an oral mucolytic agent erdosteine, which will potentially be included in future updates of this review.

AUTHORS' CONCLUSIONS: This systematic review is limited to a single small study, which we judged to be at high risk of bias. It remains uncertain whether regular nebulised hypertonic saline during a stable state reduces exacerbations or improves lung function. Further multi-centre, well-designed RCTs of longer duration that investigate various mucolytics are required to answer this important clinical question.

PMID:40152354 | DOI:10.1002/14651858.CD015313.pub2

Pediatr Pulmonol. 2025 Apr;60(4):e71067. doi: 10.1002/ppul.71067.

NO ABSTRACT

PMID:40152078 | DOI:10.1002/ppul.71067

Bioengineering (Basel). 2025 Mar 3;12(3):254. doi: 10.3390/bioengineering12030254.

ABSTRACT

Pancreatitis is a prominent and severe type of inflammatory disorder that has grabbed a lot of scientific and clinical interest to prevent its onset. It should be detected early to avoid the development of serious complications, which occur due to long-term damage to the pancreas. The accurate measurement of biomarkers that are released from the pancreas during inflammation is essential for the detection and early treatment of patients with severe acute and chronic pancreatitis, but this is sub-optimally performed in clinically relevant practices, mainly due to the complexity of the procedure and the cost of the treatment. Clinically available tests for the early detection of pancreatitis are often time-consuming. The early detection of pancreatitis also relates to disorders of the exocrine pancreas, such as cystic fibrosis in the hereditary form and cystic fibrosis-like syndrome in the acquired form of pancreatitis, which are genetic disorders with symptoms that can be correlated with the overexpression of specific markers such as creatinine in biological fluids like urine. In this review, we studied how to develop a minimally invasive system using hydrogel-based biosensors, which are highly absorbent and biocompatible polymers that can respond to specific stimuli such as enzymes, pH, temperature, or the presence of biomarkers. These biosensors are helpful for real-time health monitoring and medical diagnostics since they translate biological reactions into quantifiable data. This paper also sheds light on the possible use of Ayurvedic formulations along with hydrogels as a treatment strategy. These analytical devices can be used to enhance the early detection of severe pancreatitis in real time.

PMID:40150718 | DOI:10.3390/bioengineering12030254

Children (Basel). 2025 Feb 25;12(3):277. doi: 10.3390/children12030277.

ABSTRACT

Background/Objectives: Home spirometry allows people with cystic fibrosis (CF) to monitor their lung function from home. However, there are concerns about its feasibility and validity compared to traditional clinic spirometry. The aim of this study was to evaluate the feasibility and validity of telehealth spirometry for patients with CF living in a regional setting. Methods: This retrospective study included forty-eight people with cystic fibrosis (pwCF) aged 6-33 years. Participants performed home spirometry using a portable flow sensor spirometer over a one-year period, without supervision. Spirometry readings from portable spirometers were compared with the nearest in-clinic spirometry using the intra-correlation coefficient (ICC) and Bland-Altman plots. Data were collected over a period of one year, with regular intervals of measurements. Results: In 427 of the 877 (48.6%) attempted sessions, successful spirometry at home was recorded. Although we showed good reliability between at-home and in-clinic measurements using the Bland-Altman plots and intraclass correlation co-efficient (ICC) (values ranged from 0.76 to 0.88), analysis of the 117 pairs of at-home and in-clinic spirometries showed that mean differences of forced expiratory volume in the 1st sec (FEV1) and forced vital capacity (FVC) obtained at home (both in liter and z-score) had, on average, lower values than the corresponding values at the clinic. Conclusions: Home-based telehealth spirometry is feasible among pwCF and provides advantages, especially for those from remote or secluded areas. However, lower values in FVC and FEV1 obtained through home spirometry should not be used interchangeably with clinic values.

PMID:40150559 | DOI:10.3390/children12030277