Biochem Soc Trans. 2023 May 4:BST20221468. doi: 10.1042/BST20221468. Online ahead of print.

ABSTRACT

The cystic fibrosis transmembrane conductance regulator (CFTR) is a cAMP-regulated anion channel, which is expressed on the apical plasma membrane (PM) of epithelial cells. Mutations in the CFTR gene cause cystic fibrosis (CF), one of the most common genetic diseases among Caucasians. Most CF-associated mutations result in misfolded CFTR proteins that are degraded by the endoplasmic reticulum quality control (ERQC) mechanism. However, the mutant CFTR reaching the PM through therapeutic agents is still ubiquitinated and degraded by the peripheral protein quality control (PeriQC) mechanism, resulting in reduced therapeutic efficacy. Moreover, certain CFTR mutants that can reach the PM under physiological conditions are degraded by PeriQC. Thus, it may be beneficial to counteract the selective ubiquitination in PeriQC to enhance therapeutic outcomes for CF. Recently, the molecular mechanisms of CFTR PeriQC have been revealed, and several ubiquitination mechanisms, including both chaperone-dependent and -independent pathways, have been identified. In this review, we will discuss the latest findings related to CFTR PeriQC and propose potential novel therapeutic strategies for CF.

PMID:37140364 | DOI:10.1042/BST20221468

J Pediatr Pharmacol Ther. 2023;28(2):172-176. doi: 10.5863/1551-6776-28.2.172. Epub 2023 Apr 26.

ABSTRACT

Lung damage caused by non-tuberculous mycobacteria (NTM) infections can be devastating to individuals that are predisposed to chronic respiratory colonization. Cystic fibrosis patients are at increased risk for diminished lung function and increased mortality from NTM pulmonary infections. Treatment regimens are often intense and prolonged. The case described in this report is of a 16-year-old male with cystic fibrosis infected with Mycobacterium abscessus who showed evidence of severe nodular pulmonary disease on chest computerized tomography. His intensive treatment phase was complicated by neutropenia and drug resistance, leading to the use of omadacycline. Because of rapid improvement clinically and on computed tomography, he was successfully treated with a modified, less intense continuation phase that included azithromycin, omadacycline, and inhaled amikacin. The patient also was switched from tezacaftor/ivacaftor to elexacaftor/tezacaftor/ivacaftor during the course of NTM treatment.

PMID:37139248 | PMC:PMC10150898 | DOI:10.5863/1551-6776-28.2.172

Am J Clin Nutr. 2023 May;117(5):1048. doi: 10.1016/j.ajcnut.2023.03.003.

NO ABSTRACT

PMID:37137610 | DOI:10.1016/j.ajcnut.2023.03.003

Eur Respir Rev. 2023 May 3;32(168):220256. doi: 10.1183/16000617.0256-2022. Print 2023 Jun 30.

ABSTRACT

Clinical management of cystic fibrosis (CF) has been greatly improved by the development of small molecule modulators of the CF transmembrane conductance regulator (CFTR). These drugs help to address some of the basic genetic defects of CFTR; however, no suitable CFTR modulators exist for 10% of people with CF (PWCF). An alternative, mutation-agnostic therapeutic approach is therefore still required. In CF airways, elevated levels of the proprotein convertase furin contribute to the dysregulation of key processes that drive disease pathogenesis. Furin plays a critical role in the proteolytic activation of the epithelial sodium channel; hyperactivity of which causes airways dehydration and loss of effective mucociliary clearance. Furin is also responsible for the processing of transforming growth factor-β, which is increased in bronchoalveolar lavage fluid from PWCF and is associated with neutrophilic inflammation and reduced pulmonary function. Pathogenic substrates of furin include Pseudomonas exotoxin A, a major toxic product associated with Pseudomonas aeruginosa infection and the spike glycoprotein of severe acute respiratory syndrome coronavirus 2, the causative pathogen for coronavirus disease 2019. In this review we discuss the importance of furin substrates in the progression of CF airways disease and highlight selective furin inhibition as a therapeutic strategy to provide clinical benefit to all PWCF.

PMID:37137509 | DOI:10.1183/16000617.0256-2022

J Cyst Fibros. 2023 May 1:S1569-1993(23)00123-6. doi: 10.1016/j.jcf.2023.04.015. Online ahead of print.

ABSTRACT

BACKGROUND: The daily treatment regimen for an individual with cystic fibrosis (CF) can take more than 2 h to complete, and chronic treatment adherence rates are low. Developing partnerships between CF clinical researchers and the CF community is essential in developing acceptable, feasible, and effective strategies to improve self-management and adherence.

METHODS: The Success with Therapies Research Consortium (STRC) was formed as a multi-center US collaborative to conduct rigorous research studies of adherence to CF treatments. A multidisciplinary team of researchers from 15 sites, collaborating with members of the CF community, is charged with developing, implementing, and disseminating real-world, patient-centered interventions for people living with CF.

RESULTS: Since 2014, the STRC has conducted 8 studies. The CF community, people with CF (pwCF), and caregivers have come to serve in multiple valuable capacities on the STRC, including as members of the Steering Committee and Co-Principal Investigators. Additionally, while people with CF are irreplaceable participants in STRC studies, their influence, and that of their families and healthcare professionals, extends beyond the traditional research participant role.

CONCLUSIONS: Engaging broadly with the CF community is the optimal model for developing interventions to support those living with CF in sustaining daily care. Input and direct involvement from people with CF, their families, and their caregivers has enabled the STRC to advance its mission through innovative clinical research approaches.

PMID:37137747 | DOI:10.1016/j.jcf.2023.04.015

J Cyst Fibros. 2023 May 1:S1569-1993(23)00121-2. doi: 10.1016/j.jcf.2023.04.017. Online ahead of print.

ABSTRACT

BACKGROUND: Changes in upper airway microbiota may impact early disease manifestations in infants with cystic fibrosis (CF). To investigate early airway microbiota, the microbiota present in the oropharynx of CF infants over the first year of life was assessed along with the relationships between microbiota and growth, antibiotic use and other clinical variables.

METHODS: Oropharyngeal (OP) swabs were collected longitudinally between 1 and 12 months of age from infants diagnosed with CF by newborn screen and enrolled in the Baby Observational and Nutrition Study (BONUS). DNA extraction was performed after enzymatic digestion of OP swabs. Total bacterial load was determined by qPCR and community composition assessed using 16S rRNA gene analysis (V1/V2 region). Changes in diversity with age were evaluated using mixed models with cubic B-splines. Associations between clinical variables and bacterial taxa were determined using a canonical correlation analysis.

RESULTS: 1,052 OP swabs collected from 205 infants with CF were analyzed. Most infants (77%) received at least one course of antibiotics during the study and 131 OP swabs were collected while the infant was prescribed an antibiotic. Alpha diversity increased with age and was only marginally impacted by antibiotic use. Community composition was most highly correlated with age and was only moderately correlated with antibiotic exposure, feeding method and weight z-scores. Relative abundance of Streptococcus decreased while Neisseria and other taxa increased over the first year.

CONCLUSIONS: Age was more influential on the oropharyngeal microbiota of infants with CF than clinical variables including antibiotics in the first year of life.

PMID:37137746 | DOI:10.1016/j.jcf.2023.04.017

Pediatr Pulmonol. 2023 May 3. doi: 10.1002/ppul.26442. Online ahead of print.

ABSTRACT

INTRODUCTION: No data are available on the values and role of lung clearance index (LCI) in cystic fibrosis (CF) Screen Positive Inconclusive Diagnosis (CFSPID) progressed to CF diagnosis (CFSPID > CF). This study aimed to assess the value of the LCI in correctly predicting the progression of CFSPID to CF.

METHODS: This is a prospective study carried out at the CF Regional Center of Florence, Italy from September 1, 2019. We compared LCI values in children with CF diagnosed for positive newborn screening (NBS), CFSPID or CFSPID > CF for pathological sweat chloride (SC). The Exhalyzer-D (EcoMedics AG, Duernten, Switzerland, software version 3.3.1) was used to conduct the LCI tests, every 6 months on stable children.

RESULTS: Forty-two cooperating children were enrolled (mean age at LCI tests: 5.4 years, range: 2.7-8.7): 26 (62%) had CF, 8 (19%) were CFSPID > CF for positive SC, while 8 (19%) kept the CFSPID label at last LCI test. The mean LCI value for patients with CF (7.39; 5.98-10.24) was statistically higher compared to both the mean LCI in the CFSPID > CF (6.62; 5.69-7.58) and in CFSPID (6.56; 5.64-7.21).

CONCLUSIONS: Most of asymptomatic CFSPID or progressed to CF have normal LCI. Further data on the longitudinal course of LCI during follow up of CFSPID and on larger cohorts is needed.

PMID:37133232 | DOI:10.1002/ppul.26442

Pediatr Pulmonol. 2023 May 3. doi: 10.1002/ppul.26445. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) has seen a multitude of therapeutic advances targeting its downstream effects. This has led to a steady increase in survival over the past few decades. The recent development of disease-modifying drugs targeting the underlying CFTR mutation has revolutionized treatment for CF. Despite these advances, individuals with CF who are racial and ethnic minorities, from low socioeconomic status, or female sex have worse clinical outcomes. The inequitable access to CFTR modulators from cost and/or genetic eligibility has the potential to further worsen the existing health disparities seen within the CF community.

PMID:37133222 | DOI:10.1002/ppul.26445

Pediatr Pulmonol. 2023 May 3. doi: 10.1002/ppul.26446. Online ahead of print.

ABSTRACT

The respiratory tract antimicrobial defense system is a multilayered defense mechanism that relies upon mucociliary clearance and components of both the innate and adaptive immune systems to protect the lungs from inhaled or aspirated microorganisms. One of these potential pathogens, nontypeable Haemophilus influenzae (NTHi), adopts several, multifaceted redundant strategies to successfully colonize the lower airways and establish a persistent infection. NTHi can impair mucociliary clearance, express multiple multifunctional adhesins for various cell types within the respiratory tract and evade host defenses by surviving within and between cells, forming biofilms, increasing antigenic drift, secreting proteases and antioxidants, and by host-pathogen cross-talk, impair macrophage and neutrophil function. NTHi is recognized as an important pathogen in several chronic lower respiratory disorders, such as protracted bacterial bronchitis, bronchiectasis, cystic fibrosis, and primary ciliary dyskinesia. The persistence of NTHi in human airways, including its capacity to form biofilms, results in chronic infection and inflammation, which can ultimately injure airway wall structures. The complex nature of the molecular pathogenetic mechanisms employed by NTHi is incompletely understood but improved understanding of its pathobiology will be important for developing effective therapies and vaccines, especially given the marked genetic heterogeneity of NTHi and its possession of phase-variable genes. Currently, no vaccine candidates are ready for large phase III clinical trials.

PMID:37133207 | DOI:10.1002/ppul.26446

Pediatr Pulmonol. 2023 May 3. doi: 10.1002/ppul.26443. Online ahead of print.

NO ABSTRACT

PMID:37133203 | DOI:10.1002/ppul.26443

Pediatr Pulmonol. 2023 May 3. doi: 10.1002/ppul.26430. Online ahead of print.

NO ABSTRACT

PMID:37133200 | DOI:10.1002/ppul.26430

Pediatr Pulmonol. 2023 May 3. doi: 10.1002/ppul.26444. Online ahead of print.

ABSTRACT

The continued inclusion of race in spirometry reference equations is a topic of intense debate for adult lung function, but less discussion has focused on implications for children. Obtaining accurate estimates of children's lung function is an important component of the diagnosis of childhood respiratory illnesses, including asthma, cystic fibrosis, and interstitial lung disease. Given the higher burden among racial/ethnic minorities for many respiratory illnesses, it is critical to avoid racial bias in interpreting lung function. We recommend against the continued use of race-specific reference equations for a number of reasons. The original reference populations used to develop the equations were comprised of children with restricted racial diversity, relatively small sample sizes, and likely included some unhealthy children. Moreover, there is no scientific justification for innate racial differences in lung function, as there is no clear physiological or genetic explanation for the disparities. Alternatively, many environmental factors harm lung development, including allergens from pests, asbestos, lead, prenatal smoking, and air pollution, as well as preterm birth and childhood respiratory illnesses, which are all more common among minority racial groups. Race-neutral equations may provide a temporary solution, but still rely on the racial diversity of the reference populations used to build them. Ultimately researchers must uncover the underlying factors truly driving racial differences in lung function.

PMID:37132943 | DOI:10.1002/ppul.26444

Oman Med J. 2023 Mar 31;38(2):e490. doi: 10.5001/omj.2023.10. eCollection 2023 Mar.

ABSTRACT

Based on experience with other viral respiratory illnesses, patients with cystic fibrosis were believed to have worse prognosis when infected with COVID-19. We report a case of a 14-year-old female with cystic fibrosis who developed COVID-19 with short-term evolution and made a good recovery with no known major long-term sequelae.

PMID:37132009 | PMC:PMC10148969 | DOI:10.5001/omj.2023.10

bioRxiv. 2023 Apr 20:2023.04.20.537720. doi: 10.1101/2023.04.20.537720. Preprint.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that can establish acute and chronic infections in individuals that lack fully functional innate immunity. In particular, phagocytosis by neutrophils and macrophages is a key mechanism that modulates host control and clearance of P. aeruginosa . Individuals with neutropenia or cystic fibrosis are highly susceptible to P. aeruginosa infection thus underscoring the importance of the host innate immune response. Cell-to-cell contact between host innate immune cells and the pathogen, a first step in phagocytic uptake, is facilitated by simple and complex glycan structures present at the host cell surface. We have previously shown that endogenous polyanionic N-linked glycans localized to the cell surface of phagocytes mediate binding and subsequent phagocytosis of P. aeruginosa . However, the suite of glycans that P. aeruginosa binds to on host phagocytic cells remains poorly characterized. Here we demonstrate, with the use of exogenous N-linked glycans and a glycan array, that P. aeruginosa PAO1 preferentially attaches to a subset of glycans, including a bias towards monosaccharide versus more complex glycan structures. Consistent with these findings, we were able to competitively inhibit bacterial adherence and uptake by the addition of exogenous N-linked mono- and di-saccharide glycans. We discuss of findings in the context of previous reports of P. aeruginosa glycan binding.

IMPORTANCE: P. aeruginosa binds to a variety of glycans as part of its interaction with host cells, and a number of P. aeruginosa- encoded receptors and target ligands have been described that allow this microbe to bind to such glycans. Here we extend this work by studying the glycans used by P. aeruginosa PAO1 to bind to phagocytic cells and by using a glycan array to characterize the suite of such molecules that could facilitate host cell-binding by this microbe. This study provides an increased understanding of the glycans bound by P. aeruginosa , and furthermore, provides a useful dataset for future studies of P. aeruginosa- glycan interactions.

PMID:37131708 | PMC:PMC10153242 | DOI:10.1101/2023.04.20.537720

Curr Res Microb Sci. 2023 Apr 20;4:100190. doi: 10.1016/j.crmicr.2023.100190. eCollection 2023.

ABSTRACT

Staphylococcus aureus and Pseudomonas aeruginosa are well-known opportunistic pathogens that frequently coexist in chronic wounds and cystic fibrosis. The exoproducts of P. aeruginosa have been shown to affect the growth and pathogenicity of S. aureus, but the detailed mechanisms are not well understood. In this study, we investigated the effect of extracellular vesicles from P. aeruginosa (PaEVs) on the growth of S. aureus. We found that PaEVs inhibited the S. aureus growth independently of iron chelation and showed no bactericidal activity. This growth inhibitory effect was also observed with methicillin-resistant S. aureus but not with Acinetobacter baumannii, Enterococcus faecalis, S. Typhimurium, E. coli, Listeria monocytogenes, or Candida albicans, suggesting that the growth inhibitory effect of PaEVs is highly specific for S. aureus. To better understand the detailed mechanism, the difference in protein production of S. aureus between PaEV-treated and non-treated groups was further analyzed. The results revealed that lactate dehydrogenase 2 and formate acetyltransferase enzymes in the pyruvate fermentation pathway were significantly reduced after PaEV treatment. Likewise, the expression of ldh2 gene for lactate dehydrogenase 2 and pflB gene for formate acetyltransferase in S. aureus was reduced by PaEV treatment. In addition, this inhibitory effect of PaEVs was abolished by supplementation with pyruvate or oxygen. These results suggest that PaEVs inhibit the growth of S. aureus by suppressing the pyruvate fermentation pathway. This study reported a mechanism of PaEVs in inhibiting S. aureus growth which may be important for better management of S. aureus and P. aeruginosa co-infections.

PMID:37131486 | PMC:PMC10149184 | DOI:10.1016/j.crmicr.2023.100190

Am J Physiol Lung Cell Mol Physiol. 2023 May 2. doi: 10.1152/ajplung.00338.2022. Online ahead of print.

ABSTRACT

Chronic lung disease is often accompanied by disabling extrapulmonary symptoms, notably skeletal muscle dysfunction and atrophy. Moreover, the severity of respiratory symptoms correlates with decreased muscle mass and in turn lowered physical activity and survival rates. Previous models of muscle atrophy in chronic lung disease often modeled COPD and relied on cigarette smoke exposure and LPS-stimulation, but these conditions independently affect skeletal muscle even without accompanying lung disease. Moreover, there is an emerging and pressing need to understand the extrapulmonary manifestations of long-term post-viral lung disease (PVLD) as found in Covid-19. Here, we examine the development of skeletal muscle dysfunction in the setting of chronic pulmonary disease using a mouse model of PVLD caused by infection due to the natural pathogen Sendai virus. We identify a significant decrease in myofiber size when PVLD is maximal at 49 d after infection. We find no change in the relative types of myofibers, but the greatest decrease in fiber size is localized to fast-twitch type IIB myofibers based on myosin heavy chain immunostaining. Remarkably, all biomarkers of myocyte protein synthesis and degradation (total RNA, ribosomal abundance, and ubiquitin-proteasome expression) were stable throughout the acute infectious illness and chronic post-viral disease process. Together, the results demonstrate a distinct pattern of skeletal muscle dysfunction in a mouse model of long-term PVLD. The findings thereby provide new insight into prolonged limitations in exercise capacity in patients with chronic lung disease after viral infections and perhaps other types of lung injury.

PMID:37130808 | DOI:10.1152/ajplung.00338.2022

BMJ Open Respir Res. 2023 May;10(1):e001590. doi: 10.1136/bmjresp-2022-001590.

ABSTRACT

BACKGROUND: Previous studies showed that the combination of Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) corrector and potentiator, lumacaftor-ivacaftor (LUMA-IVA) provides meaningful clinical benefits in patients with cystic fibrosis who are homozygous for the Phe508del CFTR mutation. However, little is known about the effect of LUMA-IVA on Proinflammatory Cytokines (PICs).

OBJECTIVES: To investigate the impact of LUMA-IVA CFTR modulation on circulatory and airway cytokines before and after 12 months of LUMA-IVA treatment in a real-world setting.

METHODS: We assessed both plasma and sputum PICs, as well as standard clinical outcomes including Forced Expiratory Volume in one second (FEV1) %predicted, Body Mass Index (BMI), sweat chloride and pulmonary exacerbations at baseline and prospectively for one year post commencement of LUMA-IVA in 44 patients with cystic fibrosis aged 16 years and older homozygous for the Phe508del CFTR mutation.

RESULTS: Significant reduction in plasma cytokines including interleukin (IL)-8 (p<0.05), tumour necrosis factor (TNF)-α (p<0.001), IL-1ß (p<0.001) levels were observed while plasma IL-6 showed no significant change (p=0.599) post-LUMA-IVA therapy. Significant reduction in sputum IL-6 (p<0.05), IL-8 (p<0.01), IL-1ß (p<0.001) and TNF-α (p<0.001) levels were observed after LUMA-IVA therapy. No significant change was noted in anti-inflammatory cytokine IL-10 levels in both plasma and sputum (p=0.305) and (p=0.585) respectively. Clinically significant improvements in FEV1 %predicted (mean+3.38%, p=0.002), BMI (mean+0.8 kg/m2, p<0.001), sweat chloride (mean -19 mmol/L, p<0.001), as well as reduction in intravenous antibiotics usage (mean -0.73, p<0.001) and hospitalisation (mean -0.38, p=0.002) were observed after initiation of LUMA-IVA therapy.

CONCLUSION: This real-world study demonstrates that LUMA-IVA has significant and sustained beneficial effects on both circulatory and airway inflammation. Our findings suggest that LUMA-IVA may improve inflammatory responses, which could potentially contribute to improved standard clinical outcomes.

PMID:37130650 | DOI:10.1136/bmjresp-2022-001590

Indian J Pediatr. 2023 May 2. doi: 10.1007/s12098-023-04571-3. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a chronic childhood illness with gradually improving survival and significant burden of disease during adult life. Transition of CF care from pediatric to an adult based multidisciplinary team is a complex process and careful coordination with a transition key worker is necessary for successful transition without adverse outcome. Transition is associated with a key change in CF management with shift from family-centred care to self-reliance and independence on part of the patient. Readiness and skills of self-managed care play central part in successful transition. Resource materials for transition are available online for different countries for improved readiness and smooth transition. Situation is worse in resource-limited settings as facilities of fully functional adult multidisciplinary care for CF is not readily available.

PMID:37129754 | DOI:10.1007/s12098-023-04571-3

AMIA Annu Symp Proc. 2023 Apr 29;2022:922-931. eCollection 2022.

ABSTRACT

People living with cystic fibrosis (CF) need educational resources about lung transplant prior to engaging in shared decision making with their medical providers. We conducted a usability study to elicit preferences of people living with CF about how didactic and experiential content could be used in an educational resource to learn about lung transplant. We created two prototypes with different design features that participants used in a scenario-based task and evaluated using the System Usability Scale. We interviewed participants and analyzed the data to understand their preferences for educational content and design. Study participants indicated that didactic resource articles were important to understanding their illness trajectory, while experiential patient stories supported fear reduction and knowledge discovery. When learning about lung transplant participants stated a preference to control the amount of information they receive and preferred a combination of didactic and experiential knowledge.

PMID:37128444 | PMC:PMC10148363

Arch Bronconeumol. 2023 Apr 20:S0300-2896(23)00126-6. doi: 10.1016/j.arbres.2023.04.002. Online ahead of print.

NO ABSTRACT

PMID:37127448 | DOI:10.1016/j.arbres.2023.04.002