Respir Investig. 2022 Mar 16:S2212-5345(22)00019-3. doi: 10.1016/j.resinv.2022.02.003. Online ahead of print.

ABSTRACT

BACKGROUND: Primary ciliary dyskinesia (PCD) is diagnosed through multiple methods, including transmission electron microscopy (TEM), a high-speed video microscopy analysis (HSVA), immunofluorescence (IF), and genetic testing. A primary cell culture has been recommended to avoid the misdiagnosis of secondary ciliary dyskinesia derived from infection or inflammation and improve diagnostic accuracy. However, primary cells fail to differentiate into ciliated cells through repeated passages. The conditional reprogramming culture (CRC) method, a combination of a Rho-kinase inhibitor and fibroblast feeder cells, has been applied to cystic fibrosis. The goal of this study was to evaluate the value of CRC in diagnosing PCD in Japanese patients.

METHODS: Eleven patients clinically suspected of having PCD were included. Airway epithelial cells were obtained from an endobronchial forceps biopsy and cultured at the air-liquid interface (ALI) combined with CRC. Ciliary movement, ultrastructure, and mutated ciliary protein evaluation were performed using HSVA, TEM, and IF, respectively. Genetic testing was performed on some patients.

RESULTS: CRC yielded dense and well-differentiated ciliated cells with a high success rate (∼90%). In patients with PCD, the ciliary ultrastructure phenotype (outer dynein arm defects or normal ultrastructure) and IF findings (absence of the mutated ciliary protein) were confirmed after CRC. In DNAH11-mutant cases with normal ultrastructure by TEM, the HSVA revealed stiff and hyperfrequent ciliary beating with low bending capacity in CRC-expanded cells, thereby supporting the diagnosis.

CONCLUSIONS: CRC could be a potential tool for improving diagnostic accuracy and contributing to future clinical and basic research in PCD.

PMID:35305968 | DOI:10.1016/j.resinv.2022.02.003

ISME J. 2022 Mar 19. doi: 10.1038/s41396-022-01218-7. Online ahead of print.

ABSTRACT

The airways of people with cystic fibrosis (CF) often harbour diverse polymicrobial communities. These airway infections can be impossible to resolve through antibiotic intervention, even though isolates of the individual species present are susceptible to the treatment when tested in vitro. In this work, we investigate how polymicrobial cultures comprised of key CF-associated pathogens respond to challenge with species-specific antimicrobial agents; colistin (targets Pseudomonas aeruginosa), fusidic acid (targets Staphylococcus aureus), and fluconazole (targets Candida albicans). We found that growth in a polymicrobial environment protects the target microorganism (sometimes by several orders of magnitude) from the effect(s) of the antimicrobial agent. This decreased antimicrobial efficacy was found to have both non-heritable (physiological) and heritable (genetic) components. Whole-genome sequencing of the colistin-resistant P. aeruginosa isolates revealed single nucleotide polymorphisms and indels in genes encoding lipopolysaccharide (LPS) biosynthesis and/or pilus biogenesis, indicating that a previously undescribed colistin resistance mechanism was in operation. This was subsequently confirmed through further genetic analyses. Our findings indicate that the polymicrobial nature of the CF airways is likely to have a significant impact on the clinical response to antimicrobial therapy.

PMID:35304578 | DOI:10.1038/s41396-022-01218-7

Sci Rep. 2022 Mar 17;12(1):4595. doi: 10.1038/s41598-022-08661-8.

ABSTRACT

Most cases of cystic fibrosis (CF) are caused by class 2 mutations in the cystic fibrosis transmembrane regulator (CFTR). These proteins preserve some channel function but are retained in the endoplasmic reticulum (ER). Partial rescue of the most common CFTR class 2 mutant, F508del-CFTR, has been achieved through the development of pharmacological chaperones (Tezacaftor and Elexacaftor) that bind CFTR directly. However, it is not clear whether these drugs will rescue all class 2 CFTR mutants to a medically relevant level. We have previously shown that the nonsteroidal anti-inflammatory drug (NSAID) ibuprofen can correct F508del-CFTR trafficking. Here, we utilized RNAi and pharmacological inhibitors to determine the mechanism of action of the NSAID glafenine. Using cellular thermal stability assays (CETSAs), we show that it is a proteostasis modulator. Using medicinal chemistry, we identified a derivative with a fourfold increase in CFTR corrector potency. Furthermore, we show that these novel arachidonic acid pathway inhibitors can rescue difficult-to-correct class 2 mutants, such as G85E-CFTR > 13%, that of non-CF cells in well-differentiated HBE cells. Thus, the results suggest that targeting the arachidonic acid pathway may be a profitable way of developing correctors of certain previously hard-to-correct class 2 CFTR mutations.

PMID:35302062 | DOI:10.1038/s41598-022-08661-8

Eur Respir J. 2022 Mar 17:2101918. doi: 10.1183/13993003.01918-2021. Online ahead of print.

ABSTRACT

Primary ciliary dyskinesia (PCD) presents with symptoms early in life and the disease course may be progressive, but longitudinal data on lung function are scarce. This multinational cohort study describes lung function trajectories in children, adolescents, and young adults with PCD. We analysed data from 486 patients with repeated lung function measurements obtained between the age of 6 and 24 years from the international PCD Cohort (iPCD) and calculated z-scores for forced expiratory volume in the first second (FEV1), forced vital capacity (FVC), and FEV1/FVC ratio using the Global Lung Function Initiative 2012 references. We described baseline lung function and change of lung function over time and described their associations with possible determinants in mixed-effects linear regression models. Overall, FEV1, FVC, and FEV1/FVC z-scores declined over time (average crude annual FEV1 decline was -0.07 z-scores) but not at the same rate for all patients. FEV1 z-scores improved over time in 21% of patients, remained stable in 40% and declined in 39%. Low BMI was associated with poor baseline lung function and with further decline. Results differed by country and ultrastructural defect, but we found no evidence of differences by sex, calendar year of diagnosis, age at diagnosis, diagnostic certainty, or laterality defect. Our study shows that on average lung function in PCD declines throughout the entire period of lung growth, from childhood to young adult age, even among patients treated in specialised centres. It is essential to develop strategies to reverse this tendency and improve prognosis.

PMID:35301251 | DOI:10.1183/13993003.01918-2021

J Cyst Fibros. 2022 Mar 14:S1569-1993(22)00050-9. doi: 10.1016/j.jcf.2022.03.001. Online ahead of print.

ABSTRACT

BACKGROUND: The purpose of these analyses was to determine whether overall costs were reduced in cystic fibrosis (CF) patients experiencing pulmonary exacerbation (PEx) who received shorter versus longer durations of treatment.

METHODS: Among people with CF experiencing PEx, we calculated 30-day inpatient, outpatient, emergency room, and medication costs and summed these to derive total costs in 2020 USD. Using the Kaplan-Meier sample average (KMSA) method, we calculated adjusted costs and differences in costs within two pairs of randomized groups: early robust responders (ERR) randomized to receive treatment for 10 days (ERR-10 days) or 14 days (ERR-14 days), and non-early robust responders (NERR) randomized to receive treatment for 14 days (NERR-14 days) or 21 days (NERR-21 days).

RESULTS: Patients in the shorter treatment duration groups had shorter lengths of stay per hospitalization (mean ± standard deviation (SD) for ERR-10 days: 7.9 ± 3.0 days per hospitalization compared to 10.1 ± 4.2 days in ERR-14 days; for NERR-14 days: 8.7 ± 4.9 days per hospitalization compared to 9.6 ± 6.5 days in NERR-21 days). We found statistically significantly lower adjusted mean costs (95% confidence interval) among those who were randomized to receive shorter treatment durations (ERR-10 days: $60,800 ($59,150 - $62,430) vs $74,420 ($72,610 - $76,450) in ERR-14 days; NERR-14 days: $66,690 ($65,960-$67,400) versus $74,830 ($73,980-$75,650) in NERR-21 days).

CONCLUSIONS: Tied with earlier evidence that shorter treatment duration was not associated with worse clinical outcomes, our analyses indicate that treating with shorter antimicrobial durations can reduce costs without diminishing clinical outcomes.

PMID:35300932 | DOI:10.1016/j.jcf.2022.03.001

J Cyst Fibros. 2022 Mar 14:S1569-1993(22)00051-0. doi: 10.1016/j.jcf.2022.03.002. Online ahead of print.

ABSTRACT

BACKGROUND: Many individuals with cystic fibrosis (CF) have chronic rhinosinusitis resulting in nasal obstruction, sinus infections, and repeated surgeries. Elexacaftor-tezacaftor-ivacaftor is a highly effective modulator therapy approved for individuals aged 6 years or older with CF who have at least one F508del allele or other responsive mutation. The current study tests the hypothesis that ELX/TEZ/IVA improves sinonasal disease in CF.

METHODS: The study was a pre/post, observational cohort study conducted at two sites. Participants underwent a study visit prior to starting ELX/TEZ/IVA and a second visit at a median of 9 months on therapy. Each visit included sinus CT scan, rigid nasal endoscopy, and sweat chloride measurement. Symptoms were measured with the 22 item Sinonasal Outcome Test at scheduled intervals during the study. Regression models were used to test for improvement in symptoms, endoscopy, and CT scales.

RESULTS: The study enrolled 34 individuals, with a median age of 27 years (range 12-60). Symptoms improved within 7 days of therapy and plateaued by day 28. Endoscopic crusting resolved and nasal polyposis improved, with a decrease in size or resolution of polyps. Sinus opacification and mucosal thickening improved on CT radiographs with treatment.

CONCLUSIONS: Sinonasal symptoms improved rapidly and durably for at least 180 days on ELX/TEZ/IVA therapy. Objective measures of disease including endoscopic and CT findings improved with ELX/TEZ/IVA.

PMID:35300931 | DOI:10.1016/j.jcf.2022.03.002

J Pharmacol Sci. 2022 Apr;148(4):369-376. doi: 10.1016/j.jphs.2022.02.003. Epub 2022 Feb 20.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) plays crucial role in renal cyst expansion via increase in fluid accumulation. Inhibition of CFTR has been proposed to retard cyst development and enlargement in polycystic kidney disease (PKD). Pinostrobin, a bioactive natural flavonoid, possesses several pharmacological effects. The present study investigated pharmacological effects of pinostrobin on CFTR-mediated Cl- secretion and renal cyst expansion in in vitro and in vivo models. Pinostrobin (10 and 50 μM) reduced number of MDCK cell-derived cyst colonies and inhibited cyst expansion via inhibition of cell proliferation and CFTR-mediated Cl- secretion. The inhibitory effect of pinostrobin was not due to the decrease in cell viability and activity of Na+-K+-ATPase. We also investigated the natural analogue pinocembrin as well as the synthetic analogue pinostrobin oxime. Both pinocembrin and pinostrobin oxime did not reduce CFTR-mediated Cl- secretion. In PKD rats, oral administration of pinostrobin (40 mg/kg/day) exhibited a decreasing in cystic area compared to vehicle-treated rats. Pinostrobin treatment inhibited renal expression of CFTR protein in PKD rats. Our findings highlighted the potential therapeutic application of pinostrobin in PKD.

PMID:35300812 | DOI:10.1016/j.jphs.2022.02.003

Stem Cells Transl Med. 2022 Mar 17;11(2):178-188. doi: 10.1093/stcltm/szab016.

ABSTRACT

Over the last decades, several studies demonstrated the possibility of lung regeneration through transplantation of various lung progenitor populations. Recently, we showed in mice that fetal or adult lung progenitors could potentially provide donor cells for transplantation, provided that the lung stem cell niche in the recipient is vacated of endogenous lung progenitors by adequate conditioning. Accordingly, marked lung regeneration could be attained following i.v. infusion of a single cell suspension of lung cells into recipient mice conditioned with naphthalene (NA) and 6Gy total body irradiation (TBI). As clinical translation of this approach requires the use of allogenic donors, we more recently developed a novel transplantation modality based on co-infusion of hematopoietic and lung progenitors from the same donor. Thus, by virtue of hematopoietic chimerism, which leads to immune tolerance toward donor antigens, the lung progenitors can be successfully engrafted without any need for post-transplant immune suppression. In the present study, we demonstrate that it is possible to replace NA in the conditioning regimen with Cyclophosphamide (CY), approved for the treatment of many diseases and that a lower dose of 2 GY TBI can successfully enable engraftment of donor-derived hematopoietic and lung progenitors when CY is administered in 2 doses after the stem cell infusion. Taken together, our results suggest a feasible and relatively safe protocol that could potentially be translated to clinical transplantation of lung progenitors across major MHC barriers in patients with terminal lung diseases.

PMID:35298657 | DOI:10.1093/stcltm/szab016

BMJ Open Respir Res. 2022 Mar;9(1):e001165. doi: 10.1136/bmjresp-2021-001165.

ABSTRACT

Machine learning (ML) holds great potential for predicting clinical outcomes in heterogeneous chronic respiratory diseases (CRD) affecting children, where timely individualised treatments offer opportunities for health optimisation. This paper identifies rate-limiting steps in ML prediction model development that impair clinical translation and discusses regulatory, clinical and ethical considerations for ML implementation. A scoping review of ML prediction models in paediatric CRDs was undertaken using the PRISMA extension scoping review guidelines. From 1209 results, 25 articles published between 2013 and 2021 were evaluated for features of a good clinical prediction model using the Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis (TRIPOD) guidelines.Most of the studies were in asthma (80%), with few in cystic fibrosis (12%), bronchiolitis (4%) and childhood wheeze (4%). There were inconsistencies in model reporting and studies were limited by a lack of validation, and absence of equations or code for replication. Clinician involvement during ML model development is essential and diversity, equity and inclusion should be assessed at each step of the ML pipeline to ensure algorithms do not promote or amplify health disparities among marginalised groups. As ML prediction studies become more frequent, it is important that models are rigorously developed using published guidelines and take account of regulatory frameworks which depend on model complexity, patient safety, accountability and liability.

PMID:35297371 | DOI:10.1136/bmjresp-2021-001165

Exp Clin Transplant. 2022 Mar 15. doi: 10.6002/ect.2021.0468. Online ahead of print.

ABSTRACT

The triple-combination cystic fibrosis transmembrane conductance regulator modulator elexacaftor/- tezacaftor/ivacaftor is known to improve lung function and have extrapulmonary benefits in people with cystic fibrosis. However, there is limited evidence for its use in patients with cystic fibrosis after lung transplant, where the donor lung expresses normal levels of the cystic fibrosis transmembrane conductance regulator. We describe the use of elexacaftor/tezacaftor/ivacaftor as a bridge to potential lung retransplant in a 37-year-old man with cystic fibrosis and chronic lung allograft dysfunction. Although forced expiratory volume in 1 second did not improve, the patient had decreased sputum volume, no pulmonary exacerbations of cystic fibrosis, and no longer required continuous antibiotic therapy. Pancreatic function, revised Cystic Fibrosis Questionnaire scores, sinus symptoms, weight, and corticosteroid dependence significantly improved. There were no reported side effects attributable to elexacaftor/tezacaftor/ivacaftor. However, the patient exhibited declined renal function, which had been initially attributed to lability in cyclosporin levels but which were corrected after lithotripsy for renal calculi. Triple-combination modulators of the cystic fibrosis transmembrane conductance regulator may offer benefits to carefully selected individuals awaiting retransplant, balanced against the risk of worsened immunosuppressant level control.

PMID:35297329 | DOI:10.6002/ect.2021.0468

Am J Med. 2022 Mar 13:S0002-9343(22)00185-1. doi: 10.1016/j.amjmed.2022.02.026. Online ahead of print.

NO ABSTRACT

PMID:35296405 | DOI:10.1016/j.amjmed.2022.02.026

ERJ Open Res. 2022 Mar 14;8(1):00440-2021. doi: 10.1183/23120541.00440-2021. eCollection 2022 Jan.

ABSTRACT

BACKGROUND: Volumetric capnography (VCap) is a simpler alternative to multiple-breath washout (MBW) to detect ventilation inhomogeneity in patients with cystic fibrosis (CF). However, its diagnostic performance is influenced by breathing dynamics. We introduce two novel VCap indices, the capnographic inhomogeneity indices (CIIs), that may overcome this limitation and explore their diagnostic characteristics in a cohort of CF patients.

METHODS: We analysed 320 N2-MBW trials from 50 CF patients and 65 controls (age 4-18 years) and calculated classical VCap indices, such as slope III (SIII) and the capnographic index (KPIv). We introduced novel CIIs based on a theoretical lung model and assessed their diagnostic performance compared to classical VCap indices and the lung clearance index (LCI).

RESULTS: Both CIIs were significantly higher in CF patients compared with controls (mean±sd CII1 5.9±1.4% versus 5.1±1.0%, p=0.002; CII2 7.7±1.8% versus 6.8±1.4%, p=0.002) and presented strong correlation with LCI (CII1 r2=0.47 and CII2 r2=0.44 in CF patients). Classical VCap indices showed inferior discriminative ability (SIII 2.3±1.0%/L versus 1.9±0.7%/L, p=0.013; KPIv 3.9±1.3% versus 3.5±1.2%, p=0.071), while the correlation with LCI was weak (SIII r2=0.03; KPIv r2=0.08 in CF patients). CIIs showed lower intra-subject inter-trial variability, calculated as coefficient of variation for three and relative difference for two trials, than classical VCap indices, but higher than LCI (CII1 11.1±8.2% and CII2 11.0±8.0% versus SIII 16.3±13.5%; KPIv 15.9±12.8%; LCI 5.9%±4.2%).

CONCLUSION: CIIs detect ventilation inhomogeneity better than classical VCap indices and correlate well with LCI. However, further studies on their diagnostic performance and clinical utility are required.

PMID:35295235 | PMC:PMC8918935 | DOI:10.1183/23120541.00440-2021

Am J Respir Cell Mol Biol. 2022 Mar 16. doi: 10.1165/rcmb.2022-0065ED. Online ahead of print.

NO ABSTRACT

PMID:35294854 | DOI:10.1165/rcmb.2022-0065ED

mBio. 2022 Feb 22;13(1):e0016122. doi: 10.1128/mbio.00161-22. Epub 2022 Feb 22.

ABSTRACT

In the opportunistic pathogenic bacterium Pseudomonas aeruginosa acyl-homoserine lactone quorum sensing (QS) can activate expression of dozens to hundreds of genes depending on the strain under investigation. Many QS-activated genes code for extracellular products. P. aeruginosa has become a model for studies of cell-cell communication and coordination of cooperative activities, which result from production of extracellular products. We hypothesized that strain variation in the size of the QS regulon might reflect the environmental history of an isolate. We tested the hypothesis by performing long-term growth experiments with the well-studied strain PAO1, which has a relatively large QS regulon, under conditions where only limited QS-controlled functions are required. We grew P. aeruginosa for about 1000 generations in a condition where expression of QS-activated genes was required, and emergence of QS mutants was constrained and compared the QS regulons of populations after 35 generations to those after about 1000 generations in two independent lineages by using quorum quenching and RNA-seq technology. In one lineage the number of QS-activated genes identified was reduced by over 60% and in the other by about 30% in 1000-generation populations compared to 35-generation populations. Our results provide insight about the variations in the number of QS-activated genes reported for different P. aeruginosa environmental and clinical isolates and, about how environmental conditions might influence social evolution. IMPORTANCE Pseudomonas aeruginosa uses quorum sensing (QS) to activate expression of dozens of genes (the QS regulon). Because there is strain-to-strain variation in the size and content of the QS regulon, we asked how the regulon might evolve during long-term P. aeruginosa growth when cells require some but not all the functions activated by QS. We demonstrate that the P. aeruginosa QS-regulon can undergo a reductive adaptation in response to continuous QS-dependent growth. Our results provide insights into why there is strain-to-strain variability in the size and content of the P. aeruginosa QS regulon.

PMID:35294222 | DOI:10.1128/mbio.00161-22

Pediatr Pulmonol. 2022 Mar 15. doi: 10.1002/ppul.25891. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary exacerbations (PE) tend to complicate the course of cystic fibrosis and worsen the disease prognosis. One of the diagnostic criteria for an exacerbation is the FEV1 decline. Not all children, however, are able to perform spirometry. Therefore, the aim of this study was to evaluate alternative lung function tests in the diagnosis of PE.

METHODS: We assessed retrospectively the results of impulse oscillometry (IOS) and lung clearance index in multiple breath washout (MBW) during 259 visits in 47 CF paediatric patients. The differences in the results were compared between patients diagnosed with PE (ΔPE) and those in stable condition (ΔS).

RESULTS: Among the whole group of patients, we found significant differences between the changes during exacerbation (ΔPEs) and stable condition (ΔSs) values for LCI, Sacin , R5Hz, R5-20Hz, X10Hz, AX and Fres. The predictive values of Fres and X10Hz in IOS (AUCROC 0.71 both parameters) were higher than those of LCI (AUCROC 0.67). There was no difference in the predictive values (AUCROC ) of Δ LCI and IOS parameters in the subgroups of patients stratified based on FEV1 z-score cut-off value of -1.64. In both groups of patients, predictive values of LCI were slightly lower than of IOS parameters (AUC 0.66 for LCI vs 0.69 for both ΔX10Hz z-score and Δ Fres z-score in patients with FEV1 z-score ≥ -1.64 and AUC 0.69 for LCI vs 0.69 for both ΔX10Hz z-score and Δ Fres z-score).

CONCLUSIONS: Both IOS and MBW measurements are useful in the assessment of pediatric CF patients with pulmonary exacerbation. LCI has a similar predictive value to IOS in children with CF independently of their FEV1 value. This article is protected by copyright. All rights reserved.

PMID:35293155 | DOI:10.1002/ppul.25891

Clin Pharmacol Ther. 2022 Mar 16. doi: 10.1002/cpt.2585. Online ahead of print.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator (CFTR) modulating therapies including elexacaftor, tezacaftor, and ivacaftor (ETI) are primarily eliminated through cytochrome P450 (CYP) 3A-mediated metabolism. This creates a therapeutic challenge to the treatment of COVID-19 with nirmatrelvir-ritonavir in people with cystic fibrosis (CF) due to the potential for significant drug-drug interactions (DDI). However, CF population is more at risk of serious illness following COVID-19 infection and hence it is important to manage the DDI risk and provide treatment options. CYP3A-mediated DDI of ETI was evaluated using a physiologically based pharmacokinetic (PBPK) modeling approach. Modeling was performed incorporating physiological information and drug dependent parameters of ETI to predict the effect of ritonavir (the CYP3A inhibiting component of the combination) on pharmacokinetics of ETI. The ETI models were verified using independent clinical pharmacokinetic and DDI data of ETI with a range of CYP3A modulators. When ritonavir was administered on day 1 through 5, the predicted AUC ratio of ivacaftor (the most sensitive CYP3A substrate) on day 6 was 9.31, indicating that its metabolism was strongly inhibited. Based on the predicted DDI, the dose of ETI should be reduced when co-administered with nirmatrelvir-ritonavir to elexacaftor 200mg-tezacaftor 100mg-ivacaftor 150mg on days 1 and 5, with delayed resumption of full dose ETI on day 9, considering the residual inhibitory effect of ritonavir as a mechanism-based inhibitor. The simulation predicts a regimen of ETI administered concomitantly with nirmatrelvir/ritonavir in people with CF that will likely decrease the impact of the drug interaction.

PMID:35292968 | DOI:10.1002/cpt.2585

Cell Mol Life Sci. 2022 Mar 16;79(4):192. doi: 10.1007/s00018-022-04215-3.

ABSTRACT

The advent of Trikafta (Kaftrio in Europe) (a triple-combination therapy based on two correctors-elexacaftor/tezacaftor-and the potentiator ivacaftor) has represented a revolution for the treatment of patients with cystic fibrosis (CF) carrying the most common misfolding mutation, F508del-CFTR. This therapy has proved to be of great efficacy in people homozygous for F508del-CFTR and is also useful in individuals with a single F508del allele. Nevertheless, the efficacy of this therapy needs to be improved, especially in light of the extent of its use in patients with rare class II CFTR mutations. Using CFBE41o- cells expressing F508del-CFTR, we provide mechanistic evidence that targeting the E1 ubiquitin-activating enzyme (UBA1) by TAK-243, a small molecule in clinical trials for other diseases, boosts the rescue of F508del-CFTR induced by CFTR correctors. Moreover, TAK-243 significantly increases the F508del-CFTR short-circuit current induced by elexacaftor/tezacaftor/ivacaftor in differentiated human primary airway epithelial cells, a gold standard for the pre-clinical evaluation of patients' responsiveness to pharmacological treatments. This new combinatory approach also leads to an improvement in CFTR conductance on cells expressing other rare CF-causing mutations, including N1303K, for which Trikafta is not approved. These findings show that Trikafta therapy can be improved by the addition of a drug targeting the misfolding detection machinery at the beginning of the ubiquitination cascade and may pave the way for an extension of Trikafta to low/non-responding rare misfolded CFTR mutants.

PMID:35292885 | DOI:10.1007/s00018-022-04215-3

Open Life Sci. 2022 Feb 28;17(1):107-120. doi: 10.1515/biol-2022-0014. eCollection 2022.

ABSTRACT

This study explored the impact of pulmonary microecological changes on disease progression in non-cystic fibrosis bronchiectasis (nCFB). A careful search of the NCBI BioProject database revealed the 16S rRNA-based microbiological testing results of 441 pulmonary sputum samples from patients in the relatively stable (baseline), acute exacerbation, or recovery stage. After preliminary analysis and screening, we selected 152 samples for further analyses, including determination of the operational taxonomic unit (OTU) distribution at the phylum, class, order, family and genus levels, community structure, alpha diversity, beta diversity, microbial multivariables, correlations, and community structure after the abundances of intragroup samples were averaged. The recovery group showed significant differences in pulmonary microbiological changes (P < 0.05) compared with the other groups. There were 30 differentially abundant OTUs, with 27 and 7 at the genus and phylum levels, respectively. The Chao1 value of the recovery group was comparable to that of the baseline group, and the Shannon and Simpson values of the recovery group were the highest. Rhodococcus in Actinobacteria was positively correlated with Ochrobactrum in Firmicutes. The differences in pulmonary microecological changes at different nCFB stages may serve as a biologically predictive indicator of nCFB progression.

PMID:35291562 | PMC:PMC8886608 | DOI:10.1515/biol-2022-0014

ERJ Open Res. 2022 Mar 14;8(1):00588-2021. doi: 10.1183/23120541.00588-2021. eCollection 2022 Jan.

ABSTRACT

FEV1 % predicted decreased substantially in paediatric patients with #cysticfibrosis during the first lockdown of the ongoing #SARSCoV2 pandemic in Germany. More information on consequences of repetitive shutdowns in people with cystic fibrosis is needed. https://bit.ly/3fZwuIb.

PMID:35291421 | PMC:PMC8867750 | DOI:10.1183/23120541.00588-2021

Ann Am Thorac Soc. 2022 Mar 15. doi: 10.1513/AnnalsATS.202111-1294OC. Online ahead of print.

ABSTRACT

RATIONALE: Antibiotic selection for pulmonary exacerbation (PEx) management in children with CF is typically guided by prior respiratory culture results. While antipseudomonal antibiotics are often used in children with chronic Pseudomonas aeruginosa (Pa) airway infection, no data exist to guide antibiotic selection in children who are culture negative for Pa for ≥1 year.

OBJECTIVES: To determine among children classified as 1-, 2-, or 3-years Pa-negative if PEx treatment with at least 1 oral and/or intravenous anti-Pa antibiotic is associated with improved clinical outcomes compared to treatment with antibiotics not effective against Pa.

METHODS: Retrospective cohort study using the linked CF Foundation Patient Registry-Pediatric Health Information System (CFFPR-PHIS) database. We included children 6-21 years old hospitalized between 2008-2018 consistently culture-negative for Pa 1 year prior to a study PEx. Children were classified as 1- or 2-years Pa-negative if their last Pa-positive culture occurred in the 13-24 months or 25-36 months prior to a study PEx, respectively, with all subsequent cultures negative for Pa. Children classified as 3-years Pa-negative had no Pa-positive cultures in the 36 months prior to a study PEx. Inverse probability of treatment weighted linear or logistic regression models were used to compare clinical outcomes (pre- to post-PEx forced expiratory volume in one second, odds of returning to ≥90% of baseline lung function, and odds of having a future PEx) between anti-Pa and non-anti-Pa antibiotic strategies.

RESULTS: Among all children included in the linked dataset, 1,290 children with 2,347 PEx were eligible for analysis. Among all study PEx, 530, 326, and 1,491 PEx were classified as 1-, 2-, or 3-years Pa-negative, respectively, and anti-Pa antibiotics were administered in 79%, 67%, and 66% of all PEx classified as 1-, 2-, or 3-years Pa-negative, respectively. For all Pa-negative groups, when compared to non-anti-Pa antibiotic regimens, anti-Pa antibiotic treatment was not associated with greater improvement in any studied clinical outcomes.

CONCLUSIONS: Despite its common use, including antibiotics effective against Pa may provide no additional benefit for PEx treatment among children who are Pa-negative for at least 1 year prior. Prospective trials are warranted to directly test this hypothesis.

PMID:35289740 | DOI:10.1513/AnnalsATS.202111-1294OC