Biomolecules. 2023 Sep 8;13(9):1366. doi: 10.3390/biom13091366.

ABSTRACT

Low molecular weight alginate oligosaccharides have been shown to exhibit anti-microbial activity against a range of multi-drug resistant bacteria, including Pseudomonas aeruginosa. Previous studies suggested that the disruption of calcium (Ca2+)-DNA binding within bacterial biofilms and dysregulation of quorum sensing (QS) were key factors in these observed effects. To further investigate the contribution of Ca2+ binding, G-block (OligoG) and M-block alginate oligosaccharides (OligoM) with comparable average size DPn 19 but contrasting Ca2+ binding properties were prepared. Fourier-transform infrared spectroscopy demonstrated prolonged binding of alginate oligosaccharides to the pseudomonal cell membrane even after hydrodynamic shear treatment. Molecular dynamics simulations and isothermal titration calorimetry revealed that OligoG exhibited stronger interactions with bacterial LPS than OligoM, although this difference was not mirrored by differential reductions in bacterial growth. While confocal laser scanning microscopy showed that both agents demonstrated similar dose-dependent reductions in biofilm formation, OligoG exhibited a stronger QS inhibitory effect and increased potentiation of the antibiotic azithromycin in minimum inhibitory concentration and biofilm assays. This study demonstrates that the anti-microbial effects of alginate oligosaccharides are not purely influenced by Ca2+-dependent processes but also by electrostatic interactions that are common to both G-block and M-block structures.

PMID:37759766 | DOI:10.3390/biom13091366

J Cyst Fibros. 2023 Sep 26:S1569-1993(23)00909-8. doi: 10.1016/j.jcf.2023.09.005. Online ahead of print.

ABSTRACT

BACKGROUND: Improvement in exocrine pancreatic function in persons with CF (pwCF) on cystic fibrosis transmembrane conductance regulator (CFTR) modulators has been documented in clinical trials using fecal pancreatic elastase-1 (FE-1). Our group endeavored to evaluate real-world data on FE-1 in children on CFTR modulator therapy at three pediatric cystic fibrosis (CF) centers.

METHODS: Pediatric pwCF were offered FE-1 testing if they were on pancreatic enzyme replacement therapy (PERT) and on CFTR modulator therapy according to their center's guideline. FE-1 data were collected retrospectively. The primary outcome was absolute change in FE-1.

RESULTS: 70 pwCF were included for analysis. 53 had baseline and post-modulator FE-1 values. There was a significant increase in FE-1 from median 25 mcg/g (IQR 25-60) at baseline to 57 mcg/g (IQR 20-228) post-modulator (p<0.001 by Wilcoxon matched pairs), with an absolute change in FE-1 of median 28 mcg/g (IQR -5-161) and mean 93.5 ± 146.8 mcg/g. Age was negatively correlated with change in FE-1 (Spearman r=-0.48, p<0.001). 15 pwCF (21%) had post-modulator FE-1 values ≥200 mcg/g, consistent with pancreatic sufficiency (PS). The PS group was significant for younger age at initiation of first CFTR modulator and a higher baseline FE-1.

CONCLUSIONS: Most pwCF experienced an increase in FE-1 while receiving CFTR modulator treatment and a small percentage demonstrated values reflective of PS. These data suggest that PS may be attained in those that initiated modulator therapy at a younger age or had a higher baseline FE-1. FE-1 testing is suggested for children on any CFTR modulator therapy.

PMID:37758535 | DOI:10.1016/j.jcf.2023.09.005

Radiologia (Engl Ed). 2023 Sep-Oct;65(5):392-401. doi: 10.1016/j.rxeng.2023.09.001. Epub 2023 Sep 15.

ABSTRACT

OBJECTIVE: To describe the epidemiology and CT findings for nontuberculous mycobacterial lung infections and outcomes depending on the treatment.

MATERIAL AND METHODS: We retrospectively studied 131 consecutive patients with positive cultures for nontuberculous mycobacteria between 2005 and 2016. We selected those who met the criteria for nontuberculous mycobacterial lung infection. We analysed the epidemiologic data; clinical, microbiological, and radiological findings; treatment; and outcome according to treatment.

RESULTS: We included 34 patients (mean age, 55 y; 67.6% men); 50% were immunodepressed (58.8% of these were HIV+), 20.6% had COPD, 5.9% had known tumors, 5.9% had cystic fibrosis, and 29.4% had no comorbidities. We found that 20.6% had a history of tuberculosis and 20.6% were also infected with other microorganisms. Mycobacterium avium complex was the most frequently isolated germ (52.9%); 7 (20.6%) were also infected with other organisms. The most common CT findings were nodules (64.7%), tree-in-bud pattern (61.8%), centrilobular nodules (44.1 %), consolidations (41.2%), bronchiectasis (35.3%), and cavities (32.4%). We compared findings between men and women and between immunodepressed and immunocompetent patients. Treatment was antituberculosis drugs in 67.6% of patients (72% of whom showed improvement) and conventional antibiotics in 20.6% (all of whom showed radiologic improvement).

CONCLUSION: The diagnosis of nontuberculous mycobacterial lung infections is complex. The clinical and radiologic findings are nonspecific and a significant percentage of pateints can have other, concomitant infections.

PMID:37758330 | DOI:10.1016/j.rxeng.2023.09.001

J Appl Lab Med. 2023 Sep 27:jfad067. doi: 10.1093/jalm/jfad067. Online ahead of print.

ABSTRACT

BACKGROUND: Guidelines for sweat chloride testing endorse a minimum sweat rate for reporting results. Bilateral sweat collection is recommended, but if both sites fail to meet the minimum rate (quantity not sufficient, QNS), the test should be repeated. In this study, we examine the correlation between sweat rate and sweat chloride concentration ([Cl-]), assess the accuracy of specimens collected at suboptimal rates, and investigate the use of pooled bilateral specimens for chloride measurement.

METHODS: Pearson correlation was employed to analyze the relationship between sweat rate and chloride concentration, [Cl-], in 674 macroduct collections. Weighted kappa was evaluated to determine cystic fibrosis (CF) diagnostic classification concordance for 18 tests with paired arms above vs below the minimum sweat rate. Deming regression was applied to compare [Cl-] from pooled bilateral specimens vs neat specimens in 27 collections with residual volume available after clinical testing.

RESULTS: Pearson correlation of sweat rate vs [Cl-] was minimal (r = -0.0735) across specimens with varying rates and [Cl-]. There was substantial agreement in CF diagnostic classification between arms for bilateral collections with discordant sweat rates. Regression analysis of [Cl-] in pooled vs nonpooled specimens revealed a slope of 0.984 and an intercept of 0.796.

CONCLUSIONS: Negligible correlation of sweat rate and [Cl-] suggests the minimum sweat rate for macroduct collectors may be overly stringent. Reporting of [Cl-] in specimens with ≥10 µL (rate ≥0.3 µL/min) may reduce QNS rates without compromising diagnostic accuracy. Preliminary data suggests pooling of bilateral collections may be a feasible option to achieve the required volume for testing.

PMID:37757465 | DOI:10.1093/jalm/jfad067

Am J Respir Crit Care Med. 2023 Sep 27. doi: 10.1164/rccm.202309-1603ED. Online ahead of print.

NO ABSTRACT

PMID:37756479 | DOI:10.1164/rccm.202309-1603ED

Am J Respir Crit Care Med. 2023 Sep 27. doi: 10.1164/rccm.202309-1646ED. Online ahead of print.

NO ABSTRACT

PMID:37756441 | DOI:10.1164/rccm.202309-1646ED

Tissue Eng Part C Methods. 2023 Sep 27. doi: 10.1089/ten.TEC.2023.0074. Online ahead of print.

ABSTRACT

The nasal cavity is covered with respiratory epithelia, including ciliated cells that eliminate foreign substances trapped in the mucus. In hereditary diseases such as primary ciliary dyskinesia and cystic fibrosis, respiratory epithelial functions are irreversibly impaired; however, no radical treatment has been established yet. Thus, we considered that the transplantation of normal airway epithelia into the nasal epithelia is one of the strategies that could lead to radical treatment in the future. In our previous study, human induced pluripotent stem cell-derived airway epithelia (hiPSC-AE) on the vitrigel membrane were transplanted into the scraped area of the nasal septal mucosa of nude rats. Although human-derived ciliated cells, club cells, and basal cells were observed, they were located in the cysts within the submucosal granulation tissue but not in the nasal mucosal epithelia and the transplanted cells may not contribute to the function of the nasal mucosa with this condition. Therefore, to achieve more functional transplantation, we prepared the graft differently in this study by wrapping the collagen sponge in hiPSC-AE on the vitrigel membrane. As a result, we found the transplanted cells surviving in the nasal mucosal epithelia. These results suggest that hiPSC-AE transplanted into the nasal cavity could be viable in the nasal mucosa. In addition, our method leads to the establishment of nasal mucosa-humanized rats which are used for the development of the drugs and therapeutic methods for hereditary diseases of nasal respiratory epithelia.

PMID:37756360 | DOI:10.1089/ten.TEC.2023.0074

Int J Neonatal Screen. 2023 Sep 21;9(3):52. doi: 10.3390/ijns9030052.

ABSTRACT

The collection of dried blood spots (DBS) facilitates newborn screening for a variety of rare, but very serious conditions in healthcare systems around the world. Sub-punches of varying sizes (1.5-6 mm) can be taken from DBS specimens to use as inputs for a range of biochemical assays. Advances in DNA sequencing workflows allow whole-genome sequencing (WGS) libraries to be generated directly from inputs such as peripheral blood, saliva, and DBS. We compared WGS metrics obtained from libraries generated directly from DBS to those generated from DNA extracted from peripheral blood, the standard input for this type of assay. We explored the flexibility of DBS as an input for WGS by altering the punch number and size as inputs to the assay. We showed that WGS libraries can be successfully generated from a variety of DBS inputs, including a single 3 mm or 6 mm diameter punch, with equivalent data quality observed across a number of key metrics of importance in the detection of gene variants. We observed no difference in the performance of DBS and peripheral-blood-extracted DNA in the detection of likely pathogenic gene variants in samples taken from individuals with cystic fibrosis or phenylketonuria. WGS can be performed directly from DBS and is a powerful method for the rapid discovery of clinically relevant, disease-causing gene variants.

PMID:37754778 | DOI:10.3390/ijns9030052

Int J Neonatal Screen. 2023 Aug 23;9(3):47. doi: 10.3390/ijns9030047.

ABSTRACT

The aim of this study is to evaluate the strategy of the cystic fibrosis newborn screening (CFNBS) programme in Hungary based on the results of the first year of screening. A combined immunoreactive trypsinogen (IRT) and pancreatitis-associated protein (PAP) CFNBS protocol (IRT/IRT×PAP/IRT) was applied with an IRT-dependent safety net (SN). Out of 88,400 newborns, 256 were tested screen-positive. Fourteen cystic fibrosis (CF) and two cystic fibrosis-positive inconclusive diagnosis (CFSPID) cases were confirmed from the screen-positive cases, and two false-negative cases were diagnosed later. Based on the obtained results, a sensitivity of 88% and a positive predictive value (PPV) of 5.9% were calculated. Following the recognition of false-negative cases, the calculation method of the age-dependent cut-off was changed. In purely biochemical CFNBS protocols, a small protocol change, even after a short period, can have a significant positive impact on the performance. CFNBS should be monitored continuously in order to fine-tune the screening strategy and define the best local practices.

PMID:37754773 | DOI:10.3390/ijns9030047

Cochrane Database Syst Rev. 2023 Sep 27;9:CD015236. doi: 10.1002/14651858.CD015236.pub2.

ABSTRACT

BACKGROUND: Cystic fibrosis (CF) is a multisystem disease; the importance of growth and nutritional status is well established given their implications for lung function and overall survivability. Furthermore, it has been established that intestinal microbial imbalance and inflammation are present in people with CF. Oral prebiotics are commercially available substrates that are selectively utilised by host intestinal micro-organisms and may improve both intestinal and overall health.

OBJECTIVES: To evaluate the benefits and harms of prebiotics for improving health outcomes in children and adults with CF.

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 the reference lists of relevant articles and reviews. Date of last search: 19 October 2022. We also searched PubMed and online trials registries. Date of last search: 13 January 2023.

SELECTION CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs assessing the efficacy of prebiotics in children and adults with CF. We planned to only include the first treatment period from cross-over RCTs, regardless of washout period.

DATA COLLECTION AND ANALYSIS: We did not identify any relevant trials.

MAIN RESULTS: We did not identify any relevant trials for inclusion in this review.

AUTHORS' CONCLUSIONS: This review did not find any evidence for the use of prebiotics in people with CF. Until such evidence is available, it is reasonable for clinicians to follow any local guidelines and to discuss the use of dietary prebiotics with their patients. Large and robust RCTs assessing the dietary prebiotics of inulin or galacto-oligosaccharides or fructo-oligosaccharides, or any combination of these, are needed. Such studies should be of at least 12 months in duration and assess outcomes such as growth and nutrition, gastrointestinal symptoms, pulmonary exacerbations, lung function, inflammatory biomarkers, hospitalisations, intestinal microbial profiling, and faecal short-chain fatty acids. Trials should include both children and adults and aim to be adequately powered to allow for subgroup analysis by age.

PMID:37753791 | DOI:10.1002/14651858.CD015236.pub2

Acta Med Port. 2023 Sep 23. doi: 10.20344/amp.20106. Online ahead of print.

ABSTRACT

Cystic fibrosis is the most common lethal genetic disease in the white population, affecting approximately 80 000 people worldwide. It is an autosomal recessive, monogenic, and multisystemic disease, with over 2000 mutations described in the CFTR protein gene. The dysfunction of this protein leads to a decrease in the secretion of chlorine and bicarbonate, sodium hyperabsorption, and consequent water absorption, resulting in the thickening of secretions and accumulation of pathogens. These changes culminate in inflammation, chronic pulmonary infection, and recurrent exacerbations, with lung disease being the main cause of morbidity and mortality. In the early stages of the disease, Staphylococcus aureus is generally the agent responsible for chronic infection. Over time, Pseudomonas aeruginosa becomes more prevalent, being the most frequent bacteria in adults. However, in up to 70% of patients, colonization is polymicrobial, with frequent isolation of S. aureus and P. aeruginosa, associated with Haemophilus influenzae or Streptococcus pneumoniae, as well as isolation of other bacterial agents, viruses, or fungi. In recent years, drugs modulating CFTR have been developed which have shown a positive effect on lung function, body mass index, exacerbation rate, chlorine concentration, and quality of life. Currently, four drugs are approved that act by improving the function or increasing the amount of protein produced and consequently the ion transport. [...].

PMID:37753663 | DOI:10.20344/amp.20106

Clin Pract Pediatr Psychol. 2023 Sep;11(3):262-273. doi: 10.1037/cpp0000486.

ABSTRACT

OBJECTIVE: To map the range of multidisciplinary palliative care interventions that are available to adolescents and young adults (AYAs) with serious illness.

METHODS: Scoping review methodology as outlined by Arksey and O'Malley.

RESULTS: Twenty-two articles describing nine specific AYA-focused, multidisciplinary palliative care interventions were included in this review. Interventions focused on supporting advance care planning (ACP), facilitating treatment decision making, managing pain, and promoting resilience, psychosocial well-being, and quality of life. Interventions were delivered face-to-face and via different eHealth platforms and were targeted to AYAs with cancer, HIV/AIDS, and cystic fibrosis in both inpatient and outpatient settings.

CONCLUSIONS: Few evidence-based multidisciplinary palliative care interventions have documented benefit for AYAs with serious illness. The limited work that has been done demonstrates that AYAs are open to engaging in palliative care interventions and suggests that individual members of the multidisciplinary team can implement these different interventions to support enhanced patient outcomes.

PMID:37753528 | PMC:PMC10519447 | DOI:10.1037/cpp0000486

ERJ Open Res. 2023 Sep 25;9(5):00282-2023. doi: 10.1183/23120541.00282-2023. eCollection 2023 Sep.

ABSTRACT

BACKGROUND: Computed tomography (CT) is increasingly used for assessing skeletal muscle characteristics. In cystic fibrosis (CF) and chronic obstructive pulmonary disease (COPD), reduced limb muscle mass predicts poor clinical outcomes. However, the degree to which quantity or quality of respiratory and nonrespiratory muscles is affected by these diseases remains controversial.

METHODS: Thoracic CT images of 29 CF, 21 COPD and 20 normal spirometry control subjects were analysed to measure indices of muscle quantity (volume or cross-sectional area) and quality (radiodensity) in respiratory (diaphragm, abdominal) and nonrespiratory (pectoralis, lumbar paraspinal) muscles. Multivariable linear regression assessed relationships of CT measurements with body mass index (BMI), forced expiratory volume in 1 s (FEV1) % pred, inflammation and infection biomarkers, nutritional status and CF genotype.

RESULTS: Diaphragm volume in CF was significantly higher than in COPD (by 154%) or controls (by 140%). Abdominal muscle area in CF was also greater than in COPD (by 130%). Nonrespiratory muscles in COPD had more low radiodensity muscle (marker of lipid content) compared to CF and controls. In CF but not COPD, higher BMI and FEV1 % pred were independently associated with higher diaphragm and/or abdominal muscle quantity indices. Serum creatinine also predicted respiratory and nonrespiratory muscle quantity in CF, whereas other biomarkers including genotype correlated poorly with muscle CT parameters.

CONCLUSIONS: Our data suggest that the CF diaphragm undergoes hypertrophic remodelling, whereas in COPD the nonrespiratory muscles show altered muscle quality consistent with greater lipid content. Thoracic CT can thus identify distinctive respiratory and nonrespiratory muscle remodelling signatures associated with different chronic lung diseases.

PMID:37753287 | PMC:PMC10518894 | DOI:10.1183/23120541.00282-2023

Am J Respir Crit Care Med. 2023 Sep 26. doi: 10.1164/rccm.202309-1669ED. Online ahead of print.

NO ABSTRACT

PMID:37751560 | DOI:10.1164/rccm.202309-1669ED

Pediatr Pulmonol. 2023 Sep 26. doi: 10.1002/ppul.26673. Online ahead of print.

NO ABSTRACT

PMID:37750598 | DOI:10.1002/ppul.26673

Lancet Respir Med. 2023 Sep 22:S2213-2600(23)00262-X. doi: 10.1016/S2213-2600(23)00262-X. Online ahead of print.

ABSTRACT

INTRODUCTION: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures.

METHODS: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025.

FINDINGS: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2-6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5-5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4-10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32-4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23-11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation.

INTERPRETATION: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification.

FUNDING: UK Research and Innovation and National Institute for Health Research.

PMID:37748493 | DOI:10.1016/S2213-2600(23)00262-X

Nat Commun. 2023 Sep 25;14(1):5976. doi: 10.1038/s41467-023-41704-w.

ABSTRACT

Chronic infection with the bacterial pathogen Pseudomonas aeruginosa often leads to coexistence of heterogeneous populations carrying diverse mutations. In particular, loss-of-function mutations affecting the quorum-sensing regulator LasR are often found in bacteria isolated from patients with lung chronic infection and cystic fibrosis. Here, we study the evolutionary dynamics of polymorphic P. aeruginosa populations using isolates longitudinally collected from patients with chronic obstructive pulmonary disease (COPD). We find that isolates deficient in production of different sharable extracellular products are sequentially selected in COPD airways, and lasR mutants appear to be selected first due to their quorum-sensing defects. Polymorphic populations including lasR mutants display survival advantages in animal models of infection and modulate immune responses. Our study sheds light on the multistage evolution of P. aeruginosa populations during their adaptation to host lungs.

PMID:37749088 | DOI:10.1038/s41467-023-41704-w

J Cyst Fibros. 2023 Sep 23:S1569-1993(23)00911-6. doi: 10.1016/j.jcf.2023.09.007. Online ahead of print.

ABSTRACT

BACKGROUND: We aimed to investigate the effect of the use of electronic home spirometry in children with cystic fibrosis (CF) on 1-year FEV1 (% predicted, pp) change.

METHODS: This is a randomised, one-year prospective study including children with CF between 6 and 18 years of age. Subjects were randomised into home spirometry group (HSG) and usual care group (UCG). Children in HSG performed two pulmonary function tests (PFT) per week. Data regarding acute pulmonary exacerbations (PEx) was obtained from patients' records. At baseline and 12th month, health related quality of life questionnaire for CF patients (CFQ-R) and lung clearance index (LCI) were performed.

RESULTS: Sixty children were recruited with a median (IQR) age of 13.3 (11.4-15.4) years. Absolute change in FEV1pp from baseline to 12th month as median (IQR) was +1% (-6.75-9.75) in HSG and -2.50% (-7.50-3.25) in UCG (p = 0.10). Sensitivity analysis including only adherent children in HSG (n = 22), yielded an increase of 5% (-3.50-12) in HSG and a decrease of 2.50% (-7.50-3.25) in UCG (p = 0.009). A total of 29 (96.7%) subjects in HSG and 23 (76.7%) in UCG had PEx (p = 0.05). Absolute change in median (IQR) LCI2.5 from baseline to the 12th month was -1.6 [-2.9-0] (p<0.001) in HSG and -1.5 [-2.8-(-0.6)] (p<0.001) in UCG (p = 0.94). There was a significant increase in the social domain of the CFQ-R in HSG (from 59.1 to 76.2, p = 0.01).

CONCLUSIONS: Electronic home monitoring of children with CF by spirometry may result in improvement in lung function.

PMID:37748990 | DOI:10.1016/j.jcf.2023.09.007

JDR Clin Trans Res. 2023 Sep 25:23800844231196884. doi: 10.1177/23800844231196884. Online ahead of print.

ABSTRACT

AIMS: Brensocatib is a reversible inhibitor of dipeptidyl peptidase 1 (cathepsin C), in development to treat chronic non-cystic fibrosis bronchiectasis. The phase 2, randomized, placebo-controlled WILLOW trial (NCT03218917) was conducted to examine whether brensocatib reduced the incidence of pulmonary exacerbations. Brensocatib prolonged the time to the first exacerbation and led to fewer exacerbations than placebo. Because brensocatib potentially affects oral tissues due to its action on neutrophil-mediated inflammation, we analyzed periodontal outcomes in the trial participants.

MATERIALS AND METHODS: Patients with bronchiectasis were randomized 1:1:1 to receive once-daily oral brensocatib 10 or 25 mg or placebo. Periodontal status was monitored throughout the 24-week trial in a prespecified safety analysis. Periodontal pocket depth (PPD) at screening, week 8, and week 24 was evaluated. Gingival inflammation was evaluated by a combination of assessing bleeding upon probing and monitoring the Löe-Silness Gingival Index on 3 facial surfaces and the mid-lingual surface.

RESULTS: At week 24, mean ± SE PPD reductions were similar across treatment groups: -0.07 ± 0.007, -0.06 ± 0.007, and -0.15 ± 0.007 mm with brensocatib 10 mg, brensocatib 25 mg, and placebo, respectively. The distribution of changes in PPD and the number of patients with multiple increased PPD sites were similar across treatment groups at weeks 8 and 24. The frequencies of gingival index values were generally similar across treatment groups at each assessment. An increase in index values 0-1 and a decrease in index values 2-3 over time and at the end of the study were observed in all groups, indicating improved oral health.

CONCLUSIONS: In patients with non-cystic fibrosis bronchiectasis, brensocatib 10 or 25 mg had an acceptable safety profile after 6 months' treatment, with no changes in periodontal status noted. Improvement in oral health at end of the study may be due to regular dental care during the trial and independent of brensocatib treatment.

KNOWLEDGE TRANSFER STATEMENT: The results of this study suggest that 24 weeks of treatment with brensocatib does not affect periodontal disease progression. This information can be used by clinicians when considering treatment approaches for bronchiectasis and suggests that the use of brensocatib will not be limited by periodontal disease risks. Nevertheless, routine dental/periodontal care should be provided to patients irrespective of brensocatib treatment.

PMID:37746735 | DOI:10.1177/23800844231196884

Expert Rev Respir Med. 2023 Sep 25. doi: 10.1080/17476348.2023.2262920. Online ahead of print.

ABSTRACT

INTRODUCTION: In response to injury, epithelial cells release alarmins including thymic stromal lymphopoietin (TSLP), high mobility group-box-1 (HMGB1), interleukin (IL)-33 and -25 that can initiate innate immune responses. These alarmins are recognized as activators of T2-immune responses characteristic for asthma, but recent evidence highlighted their role in non-T2 inflammation, airway remodeling and pulmonary fibrosis making them an attractive therapeutic target for chronic respiratory diseases (CRD).

AREAS COVERED: In this review, firstly we discuss the role of TSLP, IL-33, IL-25 and HMGB1 in the pathogenesis of asthma, COPD, idiopathic pulmonary fibrosis and cystic fibrosis according to the published data. In the second part, we summarize the current evidence concerning the efficacy of the antialarmin therapies in CRD. Recent clinical trials showed that anti-TSLP and IL-33/R antibodies can improve severe asthma outcomes. Blocking the IL-33-mediated pathway decreased the exacerbation rates in COPD patients with more important benefit for former-smokers.

EXPERT OPINION: Despite progress in the understanding of the alarmins' role in the pathogenesis of CRD, all their mechanisms of action are not yet identified. Blocking IL-33 and TSLP pathways offer an interesting option to treat severe asthma and COPD but future investigations are needed to established their place in the treatment strategies.

PMID:37746733 | DOI:10.1080/17476348.2023.2262920