Am J Physiol Lung Cell Mol Physiol. 2023 Feb 21. doi: 10.1152/ajplung.00285.2022. Online ahead of print.

ABSTRACT

The coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2 coronavirus, is devastatingly impacting human health. A prominent component of COVID-19 is the infection and destruction of the ciliated respiratory cells, which perpetuates dissemination and disrupts protective mucociliary transport (MCT) function, an innate defense of the respiratory tract. Thus, drugs that augment MCT could improve barrier function of the airway epithelium, reduce viral replication and, ultimately, COVID-19 outcomes. We tested five agents known to increase MCT through distinct mechanisms for activity against SARS-CoV-2 infection using a model of human respiratory epithelial cells terminally differentiated in an air/liquid interphase. Three of the five mucoactive compounds tested showed significant inhibitory activity against SARS-CoV-2 replication. An archetype mucoactive agent, ARINA-1, blocked viral replication and therefore epithelial cell injury, thus, it was further studied using biochemical, genetic and biophysical methods to ascertain mechanism of action via improvement of MCT. ARINA-1 antiviral activity was dependent on enhancing the MCT cellular response, since terminal differentiation, intact ciliary expression and motion was required for ARINA-1-mediated anti-SARS-CoV2 protection. Ultimately, we showed that improvement of cilia movement was caused by ARINA-1-mediated regulation of the redox state of the intracellular environment, which benefited MCT. Our study indicates that Intact MCT reduces SARS-CoV-2 infection, and its pharmacologic activation may be effective as an anti-COVID-19 treatment.

PMID:36809189 | DOI:10.1152/ajplung.00285.2022

Pediatr Pulmonol. 2023 Feb 17. doi: 10.1002/ppul.26355. Online ahead of print.

ABSTRACT

BACKGROUND: As more people with cystic fibrosis (CF) consider their reproductive futures, the impact of parenthood on CF must be better understood. In the context of chronic disease, deciding if, when, and how to become a parent is complex. Little research has investigated how parents with CF balance their role as parents with its associated health impacts and demands of CF.

METHODS: PhotoVoice is a research methodology that utilizes photography to generate discussion about community issues. We recruited parents with CF with at least 1 child <10 years old and divided them into 3 cohorts. Each cohort met 5 times. Cohorts developed photography prompts, took photographs between sessions, and reflected on the photos at subsequent meetings. At the final meeting, participants selected 2-3 pictures, wrote captions, and as a group organized the photographs into thematic groups. Secondary thematic analysis identified metathemes.

RESULTS: Participants (n=18) generated a total of 202 photographs. Each cohort identified 3-4 themes (n=10) which secondary analysis grouped into three metathemes: 1) It is important for parents with CF to pay attention to the joyful aspects of parenting and to cultivate positive experiences; 2) Parenting with CF requires balancing your own needs with those of your child, and creativity and flexibility can be key; 3) Parenting with CF consists of competing priorities and expectations often with no clear "correct" choice.

CONCLUSIONS: Parents with CF identified unique challenges to their existence as both parents and patients as well as ways in which parenting has enhanced their lives. This article is protected by copyright. All rights reserved.

PMID:36808716 | DOI:10.1002/ppul.26355

Pediatr Pulmonol. 2023 Feb 20. doi: 10.1002/ppul.26362. Online ahead of print.

ABSTRACT

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators have shown beneficial effects on both forced expiratory volume in one second (FEV1 ) and frequency of pulmonary exacerbations in people with cystic fibrosis (CF). These positive outcomes may be related to changes in bacterial colonization within the lungs. Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is the first triple therapy CFTR modulator approved for use in people with CF six years and older. This study aimed to determine the impact of ELX/TEZ/IVA on the isolation of Pseudomonas aeruginosa (Pa), methicillin-resistant and methicillin-susceptible Staphylococcus aureus (MRSA and MSSA, respectively) in respiratory cultures.

METHODS: A retrospective chart review of the electronic medical record at the University of Iowa was completed for individuals 12 years and older taking ELX/TEZ/IVA for at least 12 months. The primary outcome was determined by assessing bacterial cultures pre- and post-initiation of ELX/TEZ/IVA. Baseline demographic and clinical characteristics were summarized using mean and standard deviation for continuous outcomes and count and percentage for categorical outcomes. Culture positivity for Pa, MSSA, and MRSA was compared among enrolled subjects between pre- and post-triple combination therapy periods using an exact McNemar's test.

RESULTS: One hundred twenty-four subjects prescribed ELX/TEZ/IVA for at least 12 months met the requirements for inclusion within our analysis. Culture positivity for Pa, MSSA, and MRSA was approximately 54%, 33%, and 31%, respectively, for the pre-ELX/TEZ/IVA period. Prevalence decreased to approximately 30%, 32%, and 24% [-24.2% (P<0.0001), -0.7% (P=1.00), and -6.5% (P=0.0963) respectively] post-ELX/TEZ/IVA. The source of bacterial culture was predominantly sputum (70.2%) in the pre-ELX/TEZ/IVA group, whereas a throat source (66.1%) was more common post-ELX/TEZ/IVA.

CONCLUSIONS: ELX/TEZ/IVA treatment has an appreciable impact on the detection of common bacterial pathogens in CF respiratory cultures. While previous studies have found a similar effect with single and double CFTR modulator therapies, this is the first single-center study to show the impact of triple therapy, ELX/TEZ/IVA, on bacterial isolation from airway secretions. This article is protected by copyright. All rights reserved.

PMID:36807558 | DOI:10.1002/ppul.26362

Diagn Microbiol Infect Dis. 2023 Jan 26;105(4):115904. doi: 10.1016/j.diagmicrobio.2023.115904. Online ahead of print.

ABSTRACT

This study evaluated the in vitro activity of Ceftolozane/tazobactam (C/T) vs 10 comparator agents against Pseudomonas aeruginosa isolates obtained from clinical respiratory samples from pediatric patients with cystic fibrosis at three hospitals during 2015 to 2020. Antimicrobial susceptibility testing was performed using microbroth dilution technique with custom prepared Sensititre® MIC plates. MICs were determined via Sensititre Vizion® system and results were interpreted using current CLSI and EUCAST (2022) breakpoint criteria. C/T was the most potent agent as compared with other antipseudomonal drugs against 291 isolates with MIC50 = 1 μg/mL and MIC90 = 2 μg/mL with percent susceptibility as 95.2%. C/T remained active against majority of ß-lactam non-susceptible isolates; percent susceptibility ranging from 61.2% to 80% including 65.9% ceftazidime non-susceptible isolates. C/T had high activity against P. aeruginosa from 3 geographically diverse pediatric medical centers. Study results suggest that C/T may be used as a potential therapeutic option for treating pediatric patients with CF.

PMID:36806840 | DOI:10.1016/j.diagmicrobio.2023.115904

Orphanet J Rare Dis. 2023 Feb 18;18(1):31. doi: 10.1186/s13023-023-02640-6.

ABSTRACT

BACKGROUND: The objective of the study was to elaborate a conceptual framework related to the domains of patient experience along the cystic fibrosis (CF) journey from the patients and parents of children with CF to inform the design of a patient-reported experience questionnaire.

METHOD: A collaborative research group including patients and parents with clinicians and academic researchers was set up. They identified the situations along the CF care pathway from diagnosis to paediatric care, transition to adult care and adult follow-up, transfer to transplant centres and follow-up after transplantation. Participants were recruited by CF centres in metropolitan France and overseas departments. Semi-structured interviews were conducted, transcribed verbatim and subjected to an inductive analysis conducted in duos of researchers/co-researchers using NVivo®. The conceptual framework was discussed with the research group and presented to the CF centres during two video conferences. The protocol obtained a favourable opinion from the Ethics Evaluation Committee of INSERM (IRB00003888-no. 20-700).

RESULTS: The analysis led to a conceptual framework composed of domains of the CF journey, each divided into several items. 1. CF care: Management of care by the CF centre team; in-hospital care; quality of care in the community; therapeutic education and self-management support; at-home care; new therapies and research; procreation; 2. Transplant care: management of transplant and CF care; coordination with other specialties; education and self-management support; at-home care; procreation; new therapies and research; 3. Turning points along the journey: diagnosis of CF, transition to adult care, transfer to transplantation; 4. Social life with CF: housing, employment and education, social relations, social welfare and family finances. The number of patients included and the diversity of situations made it possible to achieve a sufficient richness and saturation of codes by domain to develop patient experience questionnaires.

CONCLUSION: This conceptual framework, resulting from the participants' experience, will inform the design of a patient-reported experience tool, whose construct will be tested during the next phase of the ExPaParM project to assess its fidelity, intelligibility, and ability to report patient experience of the CF journey.

PMID:36805739 | DOI:10.1186/s13023-023-02640-6

J Allergy Clin Immunol Pract. 2023 Feb 15:S2213-2198(23)00175-7. doi: 10.1016/j.jaip.2023.01.049. Online ahead of print.

ABSTRACT

Food allergy is a chronic disease that affects individuals of all ages, and is a significant public health problem globally. This narrative overview examines clinical management strategies for IgE-mediated food allergy in children around the world, to understand variations in practice. Information was drawn from clinical practice guidelines, recent research, the websites of professional and governmental bodies with expertise in food allergy, and clinical experts from a broad cross-section of geographical regions. The structure and delivery of clinical services, allergen avoidance and food labelling, and resources to support the management of allergic reactions in the community are discussed in detail. Adoption of emerging food immunotherapies is also explored. Wide variations in clinical management of food allergy were apparent across the different countries. Common themes were continuing issues with access to specialist care, and recognition of the need to balance risk reduction with dietary and social restrictions to avoid unnecessary detrimental impacts on the quality of life of food allergy sufferers. Findings highlight the need for standardized presentation of practice and priorities, and may assist clinicians and researchers when engaging with government and funding agencies to address gaps.

PMID:36805346 | DOI:10.1016/j.jaip.2023.01.049

Respir Med. 2023 Feb 16:107167. doi: 10.1016/j.rmed.2023.107167. Online ahead of print.

ABSTRACT

Demographic and socioeconomic factors are recognized to contribute to disparities in healthcare outcomes. Originally, bronchiectasis was described in a population of predominantly White ethnic group of patients in which racial disparity could not be identified. The U.S. Bronchiectasis Research Registry (BRR), a centralized database of adult patients with bronchiectasis and/or NTM from 18 clinical institutions across the U.S., was created to support the research of this condition. The aim of this study is to describe the racial and ethnic distribution of patients enrolled in the BRR and evaluate factors associated with healthcare disparities within manifestations of and/or the care delivered to this population. At the time of this study, 3600 patients with bronchiectasis and/or NTM were enrolled in the BRR. Of those, 3510 participants were included in these analyses. The population was predominantly non-HispanicWhite (n = 3143, 89.5%), followed by Hispanic or Latino (n = 149, 4.3%), Asian (n = 130, 3.7%) and non-Hispanic Black (n = 88, 2.5%) participants. Testing for cystic fibrosis, immunoglobulin deficiency, and mycobacteria was not different between races, but non-Hispanic Black patients were tested less frequently for alpha-1 antitrypsin (A1AT) deficiency compared to other groups (P = 0.01). The four groups did not differ in the proportion of Pseudomonas aeruginosa or Hemophilus influenzae. There was no statistically significant difference in use of high-frequency chest wall oscillation, pulmonary rehabilitation services, or suppressive macrolide treatment across the groups (P > 0.05). There is a disproportionately high percentage of non-Hispainc White patients compared to non-Hispanic Black patients and Hispanic or Latino patients in the BRR. However, we found an overall similarity of care of BRR patients, regardless of racial and ethnic group.

PMID:36804343 | DOI:10.1016/j.rmed.2023.107167

Chest. 2023 Feb 16:S0012-3692(23)00259-3. doi: 10.1016/j.chest.2023.02.014. Online ahead of print.

NO ABSTRACT

PMID:36803648 | DOI:10.1016/j.chest.2023.02.014

J Cyst Fibros. 2023 Feb 16:S1569-1993(23)00055-3. doi: 10.1016/j.jcf.2023.02.006. Online ahead of print.

ABSTRACT

CF registry pulmonary exacerbation (PEx) analyses have employed "before and after" spirometry recovery, where the best percent predicted forced expiratory volume in 1 s (ppFEV1) prior to PEx ("baseline") is compared to the best ppFEV1 <3 months post-PEx. This methodology lacks comparators and ascribes recovery failure to PEx. Herein, we describe 2014 CF Foundation Patient Registry PEx analyses including a comparator: recovery around nonPEx events, birthdays. 49.6% of 7357 individuals with PEx achieved baseline ppFEV1 recovery while 36.6% of 14,141 achieved baseline recovery after birthdays; individuals with both PEx and birthdays were more likely to recover baseline after PEx than after birthdays (47% versus 34%); mean ppFEV1 declines were 0.3 (SD=9.3) and 3.1 (9.3), respectively. Post-event measure number had more effect on baseline recovery than did real ppFEV1 loss in simulations, suggesting that PEx recovery analyses lacking comparators are prone to artifact and poorly describe PEx contributions to disease progression.

PMID:36803635 | DOI:10.1016/j.jcf.2023.02.006

BMC Microbiol. 2023 Feb 21;23(1):44. doi: 10.1186/s12866-023-02788-y.

ABSTRACT

BACKGROUND: Impaired respiratory and intestinal microbiome composition is linked to cystic fibrosis lung disease severity. In people with cystic fibrosis (pwCF), regular exercise is recommended to delay disease progression and preserve a stable lung function. An optimal nutritional status is vital for best clinical outcomes. Our study investigated whether regular and monitored exercise and nutritional support promotes CF microbiome health.

METHODS: A personalized nutrition and exercise program promoted nutritional intake and physical fitness in 18 pwCF for 12 months. Throughout the study, patients performed strength and endurance training monitored by a sports scientist via an internet platform. After three months, food supplementation with Lactobacillus rhamnosus LGG was introduced. Nutritional status and physical fitness were assessed before the study started, after three and nine months. Sputum and stool were collected, and microbial composition was analyzed by 16S rRNA gene sequencing.

RESULTS: Sputum and stool microbiome composition remained stable and highly specific to each patient during the study period. Disease-associated pathogens dominated sputum composition. Lung disease severity and recent antibiotic treatment had the highest impact on taxonomic composition in stool and sputum microbiome. Strikingly, the long-term antibiotic treatment burden had only a minor influence.

CONCLUSION: Despite the exercise and nutritional intervention, respiratory and intestinal microbiomes proved to be resilient. Dominant pathogens drove the composition and functionality of the microbiome. Further studies are required to understand which therapy could destabilize the dominant disease-associated microbial composition of pwCF.

PMID:36803565 | DOI:10.1186/s12866-023-02788-y

Expert Rev Respir Med. 2023 Feb 20. doi: 10.1080/17476348.2023.2179989. Online ahead of print.

ABSTRACT

INTRODUCTION: Cystic fibrosis is a life-limiting, autosomal recessive genetic disorder resulting in multi-organ disease due to CF transmembrane conductance regulator (CFTR) protein dysfunction. CF treatment previously focused on mitigation of disease signs and symptoms. The recent introduction of highly effective CFTR modulators, for which ~90% of people with CF are CFTR variant-eligible, has resulted in substantial health improvements.

AREAS COVERED: In this review, we will describe the clinical trials leading to approval of the highly effective CFTR modulator, elexacaftor-tezacaftor-ivacaftor (ETI), with a focus on the safety and efficacy of this treatment in children aged 6 to 11 years.

EXPERT OPINION: The use of ETI in variant-eligible children aged 6-11 is associated with marked clinical improvements with a favorable safety profile. We anticipate that introduction of ETI in early childhood may result in the prevention of pulmonary, gastrointestinal and endocrine complications from CF, consequently leading to previously unimaginable gains in the quality and quantity of life. However, there is an urgent need to develop effective treatments for the remaining 10% of people with CF who are not eligible or unable to tolerate ETI treatment, and to increase access of ETI to more pwCF across the world.

PMID:36803356 | DOI:10.1080/17476348.2023.2179989

Acta Radiol. 2022 Sep 14:2841851221126833. doi: 10.1177/02841851221126833. Online ahead of print.

ABSTRACT

BACKGROUND: Hemoptysis is a severe complication of cystic fibrosis (CF) for which bronchial artery embolization (BAE) is an efficient primary therapeutic option. However, recurrence is more frequent than for other etiologies of hemoptysis.

PURPOSE: To assess the safety and efficacy of BAE in patients with CF and hemoptysis and predictive factors for recurrent hemoptysis.

MATERIAL AND METHODS: This retrospective study reviewed all adult patients with CF treated by BAE for hemoptysis in our center from 2004 to 2021. The primary endpoint was the recurrence of hemoptysis after bronchial artery embolization. Secondary endpoints were overall survival and complications. We introduced the vascular burden (VB) defined as the sum of all bronchial artery diameters measured on pre-procedural enhanced computed tomography (CT) scans.

RESULTS: A total of 48 BAE were performed in 31 patients. A total of 19 recurrences occurred with a median recurrence-free survival of 3.9 years. In univariate analyzes, percentage of unembolized VB (%UVB) (hazard ratio [HR] = 1.034, 95% confidence interval [CI=1.016-1.052; P < 0.001) and %UVB vascularizing the suspected bleeding lung (%UVB-lat) (HR = 1.024, 95% CI=1.012-1.037; P < 0.001) were associated with recurrence. In multivariate analyzes, only %UVB-lat remained significantly associated with recurrence (HR = 1.020, 95% CI=1.002-1.038; P = 0.030). One patient died during follow-up. No complication of grade 3 or higher was reported according to the CIRSE classification system for complications.

CONCLUSION: When possible, unilateral BAE seems sufficient in patients with CF with hemoptysis even in such a diffuse disease involving both lungs. The efficiency of BAE could be improved by thoroughly targeting all arteries vascularizing the bleeding lung.

PMID:36802809 | DOI:10.1177/02841851221126833

Ann Am Thorac Soc. 2023 Feb 17. doi: 10.1513/AnnalsATS.202210-852OC. Online ahead of print.

ABSTRACT

Rationale: The clinical significance of Aspergillus fumigatus (Af) detection in the absence of allergic bronchopulmonary aspergillosis in cystic fibrosis (CF) airways remains unclear. Yet, some clinicians initiate antifungal therapy for Af positive respiratory cultures out of concern for infection in people with CF. Objective: To determine the association between the presence of Af and respiratory outcomes in individuals with CF. Methods: We conducted a prospective longitudinal cohort study of 206 adults and adolescents (age 14 and older) with CF and collected sputum for selective fungus culture. We assessed clinical outcome measurements, including patient reported outcomes (measured by the Cystic Fibrosis Questionnaire-Revised), spirometry, and number of pulmonary exacerbations (PEx) for a one-year period. We used mixed-effects linear models to determine the association between positive Af culture, defined as Af detection in sputum culture at the study visit, with both respiratory domain score and forced expiratory volume in one second (FEV1) percent predicted, adjusted for confounders. Mixed-effects Poisson regression models were employed to examine the association between positive Af culture and PEx events. We explored the association between Af history, defined as Af detection at baseline or within two years of enrollment, and respiratory outcomes. Results: Af prevalence was 10.3% (95% CI 6.8,15.7) at baseline. Forty-eight (23.3%, 95% CI 17.7, 29.7) participants had at least one Af positive culture during the study period. Positive Af culture was not associated with a lower respiratory domain score. However, Af history was associated with a 6.48 point lower respiratory domain score, reflective of worse respiratory quality of life (95% CI -11.96, -0.99, p=0.02). Positive Af culture was associated with a 2.54% lower FEV1 percent predicted (95% CI -4.64, -0.44, p=0.02) and a 1.71-fold increase in severe PEx incidence (95% CI 1.05, 2.76, p=0.03). Conclusion: Positive Af culture was not associated with lower patient-reported respiratory-related QOL. Yet, positive Af culture was associated with both lower FEV1 percent predicted and increased frequency of severe PEx warranting intravenous antibiotics in adolescents and adults with CF. Future studies are required to better understand the direct role of Af in lung disease progression in CF.

PMID:36800434 | DOI:10.1513/AnnalsATS.202210-852OC

Inflamm Bowel Dis. 2023 Feb 17:izad018. doi: 10.1093/ibd/izad018. Online ahead of print.

ABSTRACT

BACKGROUND: Few drugs have been studied for patients with very early onset inflammatory bowel disease (VEOIBD). This study aimed to evaluate the efficacy and tolerance of thalidomide in children with VEOIBD compared with children with pediatric-onset IBD (pIBD).

METHODS: A retrospective cohort study with a control group was conducted. Propensity score 1:1 matching was used to identify control subjects. The treatment persistence; the causes of drug withdrawal; the rate of clinical remission and mucosal healing at 1, 2, and 3 years; and adverse events (AEs) were evaluated in children with VEOIBD treated with thalidomide and compared with children with pIBD.

RESULTS: Thirty-nine courses of treatment with thalidomide in VEOIBD and pIBD patients were compared. The treatment persistence at 1, 2, and 3 years was 68.2% (95% confidence interval [CI], 50.8%-80.6%), 57.0% (95% CI, 39.6%-71.1%), and 50.9% (95% CI, 33.7%-65.8%) for VEOIBD patients and 81.7% (95% CI, 65.3%-90.9%), 60.0% (95% CI, 41.7%-74.3%) and 33.0% (95% CI, 17.4%-49.5%) for pIBD patients, respectively (P = .12). A significantly higher proportion of VEOIBD patients discontinued therapy due to lack of efficacy (48.2% vs 17.2%; P = .03), while AEs were the main reason for discontinuation in pIBD patients. Clinical remission and mucosal healing rates did not significantly differ between VEOIBD and pIBD patients. A significatively lower number of VEOIBD patients experienced AEs compared with pIBD patients (14 [35.9%] vs 30 [76.9%]; P = .0005).

CONCLUSIONS: Thalidomide is an effective and tolerated treatment in children with VEOIBD. Discontinuation due to lack of efficacy is more frequent, but AEs are less common than in children with pIBD.

PMID:36799567 | DOI:10.1093/ibd/izad018

Liver Int. 2023 Feb 16. doi: 10.1111/liv.15544. Online ahead of print.

ABSTRACT

BACKGROUND: Novel cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapies (elexacaftor/tezacaftor/ivacaftor - ETI) promise clinically significant and sustained improvements for patients with cystic fibrosis (CF). In this study, we investigated the impact of ETI therapy on liver stiffness and bile acid metabolism in a cohort of children and young adults with CF.

METHODS: A prospective observational study (NCT05576324) was conducted from September 2020 to November 2021 enrolling CF patients naive to ETI. Standard laboratory chemistry, sweat test, lung function, share wave velocity (SWV) derived by Acoustic Radiation Force Impulse Imaging (ARFI) and serum bile acid profiles were assessed before and 6 months after induction of ETI therapy.

RESULTS: A total of 20 patients (10 aged <20 years) completed the study. While lung function and BMI improved after ETI therapy, ARFI SWV increased in CF patients < 20 years of age (from 1.27 to 1.43 m/s, p = 0.023). Bile acid (BA) profiles revealed a decrease in unconjugated (5.75 vs 1.46, p = 0.007) and increase in glycine-conjugated derivatives (GCDCA) (4.79 vs 6.64 p = 0.016). There was a positive correlation between ARFI SWV values and GCDCA (r = 0.80, p <0.0001). Glycine conjugated BA provided high diagnostic accuracy to predict increased ARFI measurements (AUC 0.90) and clinical (Colombo) CFLD grading (AUC 0.97).

CONCLUSIONS: ARFI SWV and bile acid profiles provide evidence for early increase of liver stiffness and altered bile acid metabolism in young CF patients after initiation of ETI and may serve as synergistic measures for detection of hepatic complications during ETI therapy.

PMID:36797990 | DOI:10.1111/liv.15544

Ital J Pediatr. 2023 Feb 17;49(1):24. doi: 10.1186/s13052-023-01430-x.

ABSTRACT

Abnormalities in position and/or branching of the aortic arch can lead to vascular rings that may cause narrowing of the tracheal lumen due to external compression, or constriction of the oesophagus, causing symptoms that vary in relation to the anatomical vascular pattern and the relationship between these structures. Respiratory morbidity related to external airways compression is a major concern in children affected by vascular rings. Clinical presentation depends on the severity of the tracheal lumen reduction and the presence of associated tracheomalacia. Recurrent respiratory infections, wheezing, atelectasis, and hyperinflation are mostly reported. As they are nonspecific and therefore difficult to recognize, attention should be given to all children with history of respiratory distress, extubation failure, noisy breathing, and recurrent respiratory infections. Early diagnosis and referral to specialized centres can prevent the long-term complications and improve the respiratory outcomes of these patients.

PMID:36797770 | DOI:10.1186/s13052-023-01430-x

J Allergy Clin Immunol. 2023 Feb 13:S0091-6749(23)00035-0. doi: 10.1016/j.jaci.2023.01.004. Online ahead of print.

ABSTRACT

Discerning the genetics and epigenetics of chronic rhinosinusitis (CRS) may optimize outcomes through early diagnostics, personalized and novel therapeutics, and early prognostication. CRS associated with cystic fibrosis and primary ciliary dyskinesia has well-characterized genetic mutations. Most CRS subjects, however, do not exhibit identifiable monogenic alterations. Clustering in related individuals is seen in CRS with nasal polyps. Spouses of subjects with CRS without nasal polyps also may be at increased risk of the same disease. These observations generate questions on genetic and environmental influences in CRS. Genome-wide association studies have identified variations and polymorphisms between CRS and control subjects in genes related to innate and adaptive immunity. Candidate gene and transcriptomics studies have investigated and identified genetic variations related to immunity, inflammation, epithelial barrier function, stress-response, antigen processing, T-cell regulation, and cytokines in CRS. Epigenetic studies have identified mechanisms through which environmental factors may affect these gene functions. However, causality is not determined for most variations. Inferences drawn from these data must be measured because most investigations report unreplicated results from small study populations. Large, replicated studies in tight cohorts across diverse populations remain a pressing need in studying CRS genetics.

PMID:36797169 | DOI:10.1016/j.jaci.2023.01.004

Handb Clin Neurol. 2023;192:119-130. doi: 10.1016/B978-0-323-85538-9.00006-7.

ABSTRACT

Cystic fibrosis (CF), first described in 1938, is a common, life-limiting monogenetic disease. The discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 was crucial in advancing our understanding of disease pathogenesis and paving the road for treatment aimed at the fundamental molecular defect. With the delineation of over 2000 variations in the CFTR gene, a sound understanding of the individual variations in cell biology, and electrophysiological abnormalities conferred by the most common defects propelled the advent of targeted disease-modifying therapeutics beginning in 2012. Since then, CF care has transformed beyond just symptomatic treatment to include a variety of small-molecule therapies that address the basic electrophysiologic defect and cause profound improvements in physiology, clinical manifestations, and long-term outcomes, designed to differentially address six genetic/molecular subtypes. This chapter illustrates the progress made toward how fundamental science and translational initiatives enabled personalized, mutation specific treatment. We highlight the importance of preclinical assays and mechanistically-driven development strategies that were coupled with sensitive biomarkers and a clinical trial cooperative to provide a platform for successful drug development. This convergence of academic and private partnerships, and formation of multidisciplinary care teams directed by evidence-based initiatives provide a seminal example of addressing the needs of individuals with a rare, but fatal genetic disease.

PMID:36796937 | DOI:10.1016/B978-0-323-85538-9.00006-7

Eur Respir J. 2023 Feb 16:2202437. doi: 10.1183/13993003.02437-2022. Online ahead of print.

ABSTRACT

BACKGROUND: The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants.

METHODS: An observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)<40 and/or being under evaluation for lung transplantation) and enrolled in the French Compassionate Program initiated ETI at recommended doses. Effectiveness was evaluated by a centralized adjudication committee at 4-6 weeks in terms of clinical manifestations, sweat chloride concentration and ppFEV1.

RESULTS: Among the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried a CFTR variant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] -30 [-14;-43]mmol·l-1 (n=42; p<0.0001) and an improvement in ppFEV1 by+10.0 [6.0; 20.5] (n=44, p<0.0001), were observed in those for whom treatment was effective.

CONCLUSION: Clinical benefits were observed in a large subset of pwCF with advanced lung disease and CFTR variants not currently approved for ETI.

PMID:36796836 | DOI:10.1183/13993003.02437-2022

Int J Biol Macromol. 2023 Feb 14:123662. doi: 10.1016/j.ijbiomac.2023.123662. Online ahead of print.

ABSTRACT

The proper functioning of any protein depends on its three dimensional conformation which is achieved by the accurate folding mechanism. Keeping away from the exposed stress conditions leads to cooperative unfolding and sometimes partial folding, forming the structures like protofibrils, fibrils, aggregates, oligomers, etc. leading to several neurodegenerative diseases like Parkinson's disease, Alzheimer's, Cystic fibrosis, Huntington, Marfan syndrome, and also cancers in some cases, too. Hydration of proteins is necessary, which may be achieved by the presence of organic solutes called osmolytes within the cell. Osmolytes belong to different classes in different organisms and play their role by preferential exclusion of osmolytes and preferential hydration of water molecules and achieves the osmotic balance in the cell otherwise it may cause problems like cellular infection, cell shrinkage leading to apoptosis and cell swelling which is also the major injury to the cell. Osmolyte interacts with protein, nucleic acids, intrinsically disordered proteins by non-covalent forces. Stabilizing osmolytes increases the Gibbs free energy of the unfolded protein and decreases that of folded protein and vice versa with denaturants (urea and guanidinium hydrochloride). The efficacy of each osmolyte with the protein is determined by the calculation of m value which reflects its efficiency with protein. Hence osmolytes can be therapeutically considered and used in drugs.

PMID:36796566 | DOI:10.1016/j.ijbiomac.2023.123662