Pediatr Pulmonol. 2023 Sep 13. doi: 10.1002/ppul.26671. Online ahead of print.

ABSTRACT

OBJECTIVE: To evaluate the psychometric properties of the Spanish versions of the child- and parent-report cystic fibrosis questionnaire-revised (CFQ-R).

METHODS: A Spanish adaptation of the CFQ-R was performed; 68 children with CF (6-13 years) and their parents completed the child- and parent-report CFQ-R, respectively, and the Revidierter KINDer Lebensqualitätsfragebogen (KINDL) questionnaire. The CFQ-R was completed twice, 7-10 days apart, and its psychometric properties were analyzed.

RESULTS: The internal consistency of both CFQ-R versions was adequate (child-report version, Cronbach's α >.60 for all domains except "Treatment Burden" [α = .42] and "Social Functioning" [α = .57]; parent-report version, α > .60 for all domains except "Social Functioning" [α = .58]). For the child-report version, the lowest measurement error was for "Emotional Functioning" (standard error of measurement [SEM]: 8.3%; minimal detectable change [MDC90 ]: 19.3%), and the highest was for "Body Image" (SEM: 15%; MDC90 : 35%). For the parent-report version, the lowest measurement error was for "Physical Functioning" (SEM: 7.1%; MDC90 : 16.5%), and the highest was for "Weight" (SEM: 17.2%; MDC90 ; 40.1%). The correlation between the versions showed higher agreement for the domains related to observable signs ("Physical Functioning") and lower agreement for "Emotional Functioning." There was a significant correlation between the CFQ-R and KINDL.

CONCLUSION: Both the child- and parent-report versions of the Spanish CFQ-R have adequate reliability and validity for clinical and research purposes. These versions can be administered before and after starting modulator therapy to assess its effect on daily functioning. The MDC90 can help identify, with a high probability, whether real changes have occurred in the quality-of-life subscales in children with CF.

PMID:37701960 | DOI:10.1002/ppul.26671

Pediatr Pulmonol. 2023 Sep 13. doi: 10.1002/ppul.26682. Online ahead of print.

NO ABSTRACT

PMID:37701935 | DOI:10.1002/ppul.26682

J Mater Chem B. 2023 Sep 13. doi: 10.1039/d3tb01489d. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a muco-obstructive lung disease where inflammatory responses due to chronic infection result in the accumulation of neutrophil extracellular traps (NETs) in the airways. NETs are web-like complexes comprised mainly of decondensed chromatin that function to capture and kill bacteria. Prior studies have established excess release of NETs in CF airways increases viscoelasticity of mucus secretions and reduces mucociliary clearance. Despite the pivotal role of NETs in CF disease pathogenesis, current in vitro models of this disease do not account for their contribution. Motivated by this, we developed a new approach to study the pathobiological effects of NETs in CF by combining synthetic NET-like biomaterials, composed of DNA and histones, with an in vitro human airway epithelial cell culture model. To determine the impact of synthetic NETs on airway clearance function, we incorporated synthetic NETs into mucin hydrogels and cell culture derived airway mucus to assess their rheological and transport properties. We found that the addition of synthetic NETs significantly increases mucin hydrogel viscoelasticity. As a result, mucociliary transport in vitro was significantly reduced with the addition of mucus containing synthetic NETs. Given the prevalence of bacterial infection in the CF lung, we also evaluated the growth of Pseudomonas aeruginosa in mucus with or without synthetic NETs. We found mucus containing synthetic NETs promoted microcolony growth and prolonged bacterial survival. Together, this work establishes a new biomaterial enabled approach to study innate immunity mediated airway dysfunction in CF.

PMID:37701932 | DOI:10.1039/d3tb01489d

Bioinformation. 2022 Dec 31;18(12):1122-1125. doi: 10.6026/973206300181122. eCollection 2022.

ABSTRACT

The process of testing newborn infants for hormonal, genetic, metabolic, and other disorders is known as newborn screening (NSB). Newborn screening is essential for detecting, diagnosing, and treating disorders that could save serious consequences for a newborn's health. Congenital Hypothyroidism (CH), Cystic Fibrosis (CF), Glucose-6-phosphate dehydrogenase (G6PD) deficiency, and Profound Biotinidase deficiency (BD) are common disorders in India. A retrospective analysis of the results of NBS by Cord blood spots was performed at the department of Obstetrics and Gynecology, 7 Airforce Hospital, Kanpur, Uttar Pradesh, from June 2022 to September 2022. During this period, 26 newborns were screened for four disorders, including CH, CF, G6PD deficiency, and BD. In this investigation, no cases of CH, CF, G6PD deficiency, or BD were found to be positive. The results of the current data provide a distinct opportunity to investigate the birth prevalence of inborn metabolic disorders in the area close to the city of Kanpur.

PMID:37701517 | PMC:PMC10492907 | DOI:10.6026/973206300181122

Mol Ther Methods Clin Dev. 2023 Aug 12;30:593-605. doi: 10.1016/j.omtm.2023.08.006. eCollection 2023 Sep 14.

ABSTRACT

Class Ia/b cystic fibrosis transmembrane regulator (CFTR) variants cause severe lung disease in 10% of cystic fibrosis (CF) patients and are untreatable with small-molecule pharmaceuticals. Genetic replacement of CFTR offers a cure, but its effectiveness is limited in vivo. We hypothesized that enhancing protein levels (using codon optimization) and/or activity (using gain-of-function variants) of CFTR would more effectively restore function to CF bronchial epithelial cells. Three different variants of the CFTR protein were tested: codon optimized (high codon adaptation index [hCAI]), a gain-of-function (GOF) variant (K978C), and a combination of both (hˆK978C). In human embryonic kidney (HEK293T) cells, initial results showed that hCAI and hˆK978C produced greater than 10-fold more CFTR protein and displayed ∼4-fold greater activity than wild-type (WT) CFTR. However, functionality was profoundly different in CF bronchial epithelial cells. Here, K978C CFTR more potently restored essential epithelial functions (anion transport, airway surface liquid height, and pH) than WT CFTR. hCAI and hˆK978C CFTRs had limited impact because of mislocalization in the cell. These data provide a proof of principle showing that GOF variants may be more effective than codon-optimized forms of CFTR for CF gene therapy.

PMID:37701179 | PMC:PMC10494266 | DOI:10.1016/j.omtm.2023.08.006

Monaldi Arch Chest Dis. 2023 Sep 12. doi: 10.4081/monaldi.2023.2718. Online ahead of print.

ABSTRACT

Non-cystic fibrosis (non-CF) bronchiectasis has emerged as a significant respiratory disease in developing countries. Given the variation in causes and clinical characteristics across different regions, it is necessary to conduct studies in regions with limited data such as low-middle income countries (LMIC). The aim of the study was to investigate the underlying causes, clinical presentation, etiology, lung function and imaging in patients with bronchiectasis who sought treatment at a tertiary care hospital in a LMIC. We conducted retrospective observational study at the Aga Khan University, Pakistan. Adult patients diagnosed with non-CF bronchiectasis on high-resolution computed tomography scan between 2000 and 2020 were included. We evaluated the etiology, clinical characteristics, microbiology, radiology and spirometric pattern of these patients. A total of 340 patients were included with 56.5% being female and 44.7% aged over 60 years. Among them, 157 (46.2%) had experienced symptoms for 1-5 years. The most common spirometric pattern observed was obstructive impairment (58.1%). Previous tuberculosis (TB) (52.94%) was the most common etiology followed by allergic bronchopulmonary aspergillosis (7.64%). Bilateral lung involvement on HRCT scan was found in 63.2% of patients. Pseudomonas aeruginosa was the most frequently identified organism (38.75%) among 240 patients with available specimens. Patients with P. aeruginosa infections had a significantly higher number of exacerbations (p=0.016). There was a significant difference (p<0.001) in P. aeruginosa growth among different etiologies. In conclusion, post-TB bronchiectasis was the most common cause of non-CF bronchiectasis in our study population. P. aeruginosa was the predominant organism, and 63.2% of the patients exhibited bilateral lung involvement. Since P. aeruginosa growth and extensive lung involvement have been associated with poor prognosis and increased mortality risk, we recommend close follow ups of these patients to improve quality of life and survival in developing countries like Pakistan.

PMID:37700688 | DOI:10.4081/monaldi.2023.2718

Curr Opin Pulm Med. 2023 Sep 13. doi: 10.1097/MCP.0000000000001019. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Advances in cystic fibrosis (CF) therapies over the past decade pivotally changed the morbidity and mortality of CF with the advent of cystic fibrosis transmembrane conductance regulator (CFTR) modulators that rescue dysfunctional CFTR protein in individuals with eligible genotypes. However, a significant proportion of the CF population is in need of alternative treatment strategies to address CFTR variants that are ineligible for therapeutic protein correction and/or potentiation. Current drug development efforts of nucleic-acid based therapies (i.e., DNA and RNA based therapies) in CF are informed by historic challenges of CF gene therapy trials, recent FDA guidance informed by non-CF gene therapy trials, and advances in therapeutic applications related to severe acute respiratory syndrome coronavirus 2 vaccine development. These historic and timely developments are of significant relevance for advancing genetic therapies in CF.

RECENT FINDINGS: This article reviews the main themes of semi-permanent genetic therapy strategies covering recent literature focused on: adenovirus and adeno-associated virus vector delivery, advances in lentivirus vector use and safety considerations, mRNA delivery and antisense oligonucleotide drug development.

SUMMARY: Currently, drug development and clinical trials for genetic therapies in CF are rapidly progressing. This review aims to increase the foundational knowledge of CF genetic therapies.

PMID:37700667 | DOI:10.1097/MCP.0000000000001019

Lancet Respir Med. 2023 Sep 8:S2213-2600(23)00260-6. doi: 10.1016/S2213-2600(23)00260-6. Online ahead of print.

NO ABSTRACT

PMID:37699422 | DOI:10.1016/S2213-2600(23)00260-6

Lancet Respir Med. 2023 Sep 8:S2213-2600(23)00297-7. doi: 10.1016/S2213-2600(23)00297-7. Online ahead of print.

ABSTRACT

The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics.

PMID:37699421 | DOI:10.1016/S2213-2600(23)00297-7

Lancet Respir Med. 2023 Sep 8:S2213-2600(23)00324-7. doi: 10.1016/S2213-2600(23)00324-7. Online ahead of print.

ABSTRACT

Cystic fibrosis is a multiorgan disease caused by impaired function of the cystic fibrosis transmembrane conductance regulator (CFTR). Since the introduction of the CFTR modulator combination elexacaftor-tezacaftor-ivacaftor (ETI), which acts directly on mutant CFTR to enhance its activity, most people with cystic fibrosis (pwCF) have seen pronounced reductions in symptoms, and studies project marked increases in life expectancy for pwCF who are eligible for ETI. However, modulator therapy has not cured cystic fibrosis and the success of CFTR modulators has resulted in immediate questions about the new state of cystic fibrosis disease and clinical challenges in the care of pwCF. In this Series paper, we summarise key questions about cystic fibrosis disease in the era of modulator therapy, highlighting state-of-the-art research and clinical practices, knowledge gaps, new challenges faced by pwCF and the potential for future health-care challenges, and the pressing need for additional therapies to treat the underlying genetic or molecular causes of cystic fibrosis.

PMID:37699420 | DOI:10.1016/S2213-2600(23)00324-7

Lancet Respir Med. 2023 Sep 8:S2213-2600(23)00328-4. doi: 10.1016/S2213-2600(23)00328-4. Online ahead of print.

NO ABSTRACT

PMID:37699419 | DOI:10.1016/S2213-2600(23)00328-4

Lancet. 2023 Sep 8:S0140-6736(23)01609-4. doi: 10.1016/S0140-6736(23)01609-4. Online ahead of print.

ABSTRACT

Following discovery of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in 1989 and subsequent elucidation of the varied CFTR protein abnormalities that result, a new era of cystic fibrosis management has emerged-one in which scientific principles translated from the bench to the bedside have enabled us to potentially treat the basic defect in the majority of children and adults with cystic fibrosis, with a resultant burgeoning adult cystic fibrosis population. However, the long-term effects of these therapies on the multiple manifestations of cystic fibrosis are still under investigation. Understanding the effects of modulators in populations excluded from clinical trials is also crucial. Furthermore, establishing appropriate disease measures to assess efficacy in the youngest potential trial participants and in those whose post-modulator lung function is in the typical range for people without chronic lung disease is essential for continued drug development. Finally, recognising that a health outcome gap has been created for some people and widened for others who are not eligible for, cannot tolerate, or do not have access to modulators is important.

PMID:37699418 | DOI:10.1016/S0140-6736(23)01609-4

Lancet. 2023 Sep 8:S0140-6736(23)01608-2. doi: 10.1016/S0140-6736(23)01608-2. Online ahead of print.

ABSTRACT

With the 2019 breakthrough in the development of highly effective modulator therapy providing unprecedented clinical benefits for over 90% of patients with cystic fibrosis who are genetically eligible for treatment, this rare disease has become a front runner of transformative molecular therapy. This success is based on fundamental research, which led to the identification of the disease-causing CFTR gene and our subsequent understanding of the disease mechanisms underlying the pathogenesis of cystic fibrosis, working together with a continuously evolving clinical research and drug development pipeline. In this Series paper, we focus on advances since 2018, and remaining knowledge gaps in our understanding of the molecular mechanisms of CFTR dysfunction in the airway epithelium and their links to mucus dysfunction, impaired host defences, airway infection, and chronic inflammation of the lungs of people with cystic fibrosis. We review progress in (and the remaining obstacles to) pharmacological approaches to rescue CFTR function, and novel strategies for improved symptomatic therapies for cystic fibrosis, including how these might be applicable to common lung diseases, such as bronchiectasis and chronic obstructive pulmonary disease. Finally, we discuss the promise of genetic therapies and gene editing approaches to restore CFTR function in the lungs of all patients with cystic fibrosis independent of their CFTR genotype, and the unprecedented opportunities to transform cystic fibrosis from a fatal disease to a treatable and potentially curable one.

PMID:37699417 | DOI:10.1016/S0140-6736(23)01608-2

Lancet. 2023 Sep 8:S0140-6736(23)01727-0. doi: 10.1016/S0140-6736(23)01727-0. Online ahead of print.

NO ABSTRACT

PMID:37699416 | DOI:10.1016/S0140-6736(23)01727-0

Sci Rep. 2023 Sep 12;13(1):15030. doi: 10.1038/s41598-023-41868-x.

ABSTRACT

Cystic fibrosis transmembrane conductance regulator modulators have revolutionized cystic fibrosis (CF) care in the past decade. This study explores the CF-related mortality trends in the US from 1999 to 2020. We extracted CF-related mortality data from the CDC WONDER database. CF age-standardized mortality rates (ASMRs) were identified by ICD-10 code E84 and were stratified by demographic and geographical variables. Temporal trends were analyzed using Joinpoint modeling. CF-related ASMRs decreased from 1.9 to 1.04 per million population (p = 0.013), with a greater reduction in recent years. This trend was replicated in both sexes. The median age of death increased from 24 to 37 years. CF mortality rates decreased across sex, white race, non-Hispanic ethnicity, census regions, and urbanization status. Incongruent trends were reported in non-white races and Hispanic ethnicity. A lower median age of death was observed in women, non-white races, and Hispanic ethnicity. SARS-CoV-2 infection was the primary cause of death in 1.7% of CF decedents in 2020. The national CF-related mortality rates declined and the median age of death among CF decedents increased significantly indicating better survival in the recent years. The changes were relatively slow during the earlier period of the study, followed by a greater decline lately. We observed patterns of sex, ethnic, racial, and geographical disparities associated with the worsening of the gap between ethnicities, narrowing of the gap between races and rural vs. urban counties, and closing of the gap between sexes over the study period.

PMID:37699961 | DOI:10.1038/s41598-023-41868-x

Clin Transplant. 2023 Sep 12:e15130. doi: 10.1111/ctr.15130. Online ahead of print.

ABSTRACT

Cirrhosis is usually regarded as a contraindication to isolated lung transplantation (ILT). We sought to determine which patients with cirrhosis could safely undergo ILT. Based on a retrospective analysis of patients with cirrhosis who underwent ILT at our center between 2007 and 2020, we developed an exclusionary algorithm (PENS-CEPT: Pittsburgh ExclusioN Score in Cirrhotics Evaluated for Pulmonary Transplant) to help determine which patients can undergo ILT with minimal incurred risk from their underlying liver disease. The score utilizes a combination of readily available clinical data and the presence (or absence) of spontaneous portosystemic shunts on preoperative cross-sectional imaging. Sixteen patients underwent ILT with a diagnosis of cirrhosis: nine with cystic fibrosis. On univariate analysis, only our model was able to predict 1 year survival. Of the nine patients that would have been approved using our model, there was only one short term death. Of the seven patients that would have been rejected by the model, all but one died within the first year with six dying of complications from liver failure. We are proposing a simple score utilizing routine clinical parameters and pre-operative imaging to determine the safety of ILT in cirrhotic patients. Further studies are required to validate this scoring system with the goal of safely increasing the opportunity for cirrhotic patients who would otherwise be rejected for ILT.

PMID:37698469 | DOI:10.1111/ctr.15130

Eur Respir J. 2023 Sep 11:2300110. doi: 10.1183/13993003.00110-2023. Online ahead of print.

ABSTRACT

OBJECTIVES: Around 20% of people with Cystic Fibrosis (pwCF) do not have access to the triple combination Elexacaftor/Tezacaftor/Ivacaftor (ETI) in Europe because they do not carry the F508del allele on the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the Food and Drug Administration (FDA), a compassionate use program was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in Human Nasal Epithelial Cell (HNEC) cultures was predictive of the clinical response.

METHODS: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (DMSO) and after ETI incubation and expressed as % of normal CFTR activity after sequential addition of Forskolin and Inh-172 (ΔIETI/DMSO%WT).

RESULTS: Eleven pwCF carried variants eligible for ETI according to the FDA label and twenty-eight variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101 K, R347P, R74W;V201M;D1270N, and H1085R). We point out ETI correction of non FDA-approved variants including N1303 K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A, 4096-3C>G). ΔIETI/DMSO%WT was significantly correlated to change in ppFEV1 and sweat chloride concentration (p<0.0001 for both). R74W; V201M; D1270N; G85E, Q552P and M1101 K were rescued more efficiently by other CFTR modulator combinations than ETI.

CONCLUSION: Primary nasal epithelial cells hold promise for expanding CFTR modulators prescription in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

PMID:37696564 | DOI:10.1183/13993003.00110-2023

Am J Respir Crit Care Med. 2023 Sep 11. doi: 10.1164/rccm.202305-0818OC. Online ahead of print.

ABSTRACT

RATIONALE: "CFTR modulator" drugs restore function to mutant channels in cystic fibrosis (CF) patients and lead to improvements in body-mass index and lung function especially in younger patients. While it is anticipated that early treatment with CFTR modulators will significantly delay the onset of advanced lung disease, lung neutrophils and inflammatory cytokines remain high in modulator-treated CF patients with established lung disease, underscoring the need to identify and ultimately target the source of this inflammation in CF lung.

OBJECTIVES: To examine the stem cell heterogeneity of CF lung to identify stem cell variants that might underlie the chronic lung inflammation in CF and the impact of CFTR genetic complementation or CFTR modulators on the inflammatory properties of the stem cell variants identified herein.

METHODS: Stem cell cloning technology was applied to CF lungs. Single cell-derived clones were assessed by RNA-sequencing and xenografting to monitor inflammation, fibrosis, and mucin secretion. The impact of CFTR activity on these variants following gene complementation or exposure to CFTR modulators was assessed by molecular and functional studies.

MEASUREMENTS AND MAIN RESULTS: CF lungs display a stem cell heterogeneity marked by six predominant variants of which three are proinflammatory both at the level of gene expression and their ability to drive neutrophil inflammation in xenografts. The proinflammatory functions of these variants were unallayed by genetic or pharmacological restoration of CFTR activity.

CONCLUSIONS: The emergence of proinflammatory stem cell variants in CF lung may explain the persistence of lung inflammation in CF patients undergoing CFTR modulator therapy.

PMID:37695863 | DOI:10.1164/rccm.202305-0818OC

Curr Opin Pulm Med. 2023 Sep 12. doi: 10.1097/MCP.0000000000001013. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: The nutritional landscape in cystic fibrosis has shifted dramatically in the era of CFTR modulator therapy. In this review, we will critically examine the literature on overweight and obesity in CF, current nutritional care unknowns and opportunities for further investigation or adaptation in clinical care.

RECENT FINDINGS: Results of clinical trial and real-world data reflect marked improvement in nutritional status and quality of life. Clinical outcomes including CF related diabetes and CF related liver disease appear positively impacted. Secondary impacts on cardiometabolic disease have been noted, especially in association with excessive weight gain.

SUMMARY: The prior approaches to optimizing nutrition in cystic fibrosis with caloric excess can likely be safely retired for many. As modulator access expands across the lifespan, a longitudinal focus on health maintenance should be considered.

PMID:37694679 | DOI:10.1097/MCP.0000000000001013

Clin Transplant. 2023 Sep 11:e15122. doi: 10.1111/ctr.15122. Online ahead of print.

ABSTRACT

INTRODUCTION: The postoperative hemodynamic management after lung transplant (LUTX) is guided by limited evidence. We aimed to describe and evaluate risk factors and outcomes of postoperative vasoactive support of LUTX recipients.

METHODS: In a single-center retrospective analysis of consecutive adult LUTX, two cohorts were identified: (1) patients needing prolonged vasoactive support (>12 h from ICU admission) (VASO+); (2) or not (VASO-). Postoperative hemodynamic characteristics were thoroughly analyzed. Risk factors and outcomes of VASO+ versus VASO- cohorts were assessed by multivariate logistic regression and propensity score matching.

RESULTS: One hundred and thirty-eight patients were included (86 (62%) VASO+ versus 52 (38%) VASO-). Vasopressors (epinephrine, norepinephrine, dopamine) were used in the first postoperative days (vasoactive inotropic score at 12 h: 6 [4-12]), while inodilators (dobutamine, levosimendan) later. Length of vasoactive support was 3 [2-4] days. Independent predictors of vasoactive use were: LUTX indication different from cystic fibrosis (p = .003), higher Oto score (p = .020), longer cold ischemia time (p = .031), but not preoperative cardiac catheterization. VASO+ patients showed concomitant hemodynamic and graft impairment, with longer mechanical ventilation (p = .010), higher primary graft dysfunction (PGD) grade at 72 h (PGD grade > 0 65% vs. 31%, p = .004, OR 4.2 [1.54-11.2]), longer ICU (p < .001) and hospital stay (p = .013). Levosimendan as a second-line inodilator appeared safe.

CONCLUSIONS: Vasoactive support is frequently necessary after LUTX, especially in recipients of grafts of lesser quality. Postoperative hemodynamic dysfunction requiring vasopressor support and graft dysfunction may represent a clinical continuum with immediate and long-term consequences. Further studies may elucidate if this represents a possible treatable condition.

PMID:37694497 | DOI:10.1111/ctr.15122