Front Endocrinol (Lausanne). 2024 Aug 7;15:1411317. doi: 10.3389/fendo.2024.1411317. eCollection 2024.

ABSTRACT

Cystic fibrosis (CF) is the most common life-threatening genetic disease in the United States and among people of European descent. Despite the widespread distribution of the cystic fibrosis transmembrane conductance regulator (CFTR) along kidney tubules, specific renal phenotypes attributable to CF have not been well documented. Recent studies have demonstrated the downregulation of the apical Cl-/HCO3 - exchanger pendrin (Slc26a4) in kidney B-intercalated cells of CF mouse models. These studies have shown that kidneys of both mice and humans with CF have an impaired ability to excrete excess HCO3 -, thus developing metabolic alkalosis when subjected to excess HCO3 - intake. The purpose of this minireview is to discuss the latest advances on the role of pendrin as a molecule with dual critical roles in acid base regulation and systemic vascular volume homeostasis, specifically in CF. Given the immense prevalence of vascular volume depletion, which is primarily precipitated via enhanced chloride loss through perspiration, we suggest that the dominant presentation of metabolic alkalosis in CF is due to the impaired function of pendrin, which plays a critical role in systemic vascular volume and acid base homeostasis.

PMID:39170739 | PMC:PMC11335532 | DOI:10.3389/fendo.2024.1411317

Clin Chem Lab Med. 2024 Aug 19. doi: 10.1515/cclm-2024-0909. Online ahead of print.

NO ABSTRACT

PMID:39166745 | DOI:10.1515/cclm-2024-0909

Pediatr Pulmonol. 2024 Aug 21. doi: 10.1002/ppul.27184. Online ahead of print.

ABSTRACT

Newborn screening for cystic fibrosis (CF) occasionally results in an inconclusive diagnosis of this disease, and these individuals are designated as CFTR-related metabolic syndrome (CRMS) in the United States, and CF Screen Positive Inconclusive Diagnosis (CFSPID) in other countries. Some of these asymptomatic individuals will progress to symptomatic disease, but risk factors associated with disease progression are not well understood. This scoping review was conducted to comprehensively map nonbiological risk factors in the CRMS/CFSPID literature and to identify understudied topics. Six electronic databases were systematically searched, resulting in 2951 studies. Forty nine eligible works were identified as including information on nonbiological risk factors related to CRMS/CFPSID. Eligible studies were published from 2002 to 2024, most prevalently in the United States (36.7%), and as quantitative data (81.6%). Of the 49 eligible works, 23 articles contributed only intellectual conjecture, while 26 articles contained original data, which underwent full-text qualitative content analysis. Key themes identified in descending order of content coverage included Psychological Impact, Management Care, Newborn Screening and Diagnostics, Communicating Diagnosis, and Lifestyle and External Exposures. This scoping review identified that while nonbiological risk factors are being studied in the CRMS/CFSPID literature, there was nearly equal distribution of works gathering original data to those citing previously published information. These findings indicate a critical need for original data collection on these risk factors, particularly on understudied topics identified herein.

PMID:39166713 | DOI:10.1002/ppul.27184

J Bras Pneumol. 2024 Aug 19;50(3):e20240218. doi: 10.36416/1806-3756/e20240218.

NO ABSTRACT

PMID:39166596 | DOI:10.36416/1806-3756/e20240218

Eur J Hum Genet. 2024 Aug 20. doi: 10.1038/s41431-024-01683-y. Online ahead of print.

ABSTRACT

The main limitation to long-term lung transplant (LT) survival is chronic lung allograft dysfunction (CLAD), which leads to irreversible lung damage and significant mortality. Individual factors can impact CLAD, but no large genetic investigation has been conducted to date. We established the multicentric Genetic COhort in Lung Transplantation (GenCOLT) biobank from a rich and homogeneous sub-part of COLT cohort. GenCOLT collected DNA, high-quality GWAS (genome-wide association study) genotyping and robust HLA data for donors and recipients to supplement COLT clinical data. GenCOLT closely mirrors the global COLT cohort without significant variations in variables like demographics, initial disease and survival rates (P > 0.05). The GenCOLT donors were 45 years-old on average, 44% women, and primarily died of stroke (54%). The recipients were 48 years-old at transplantation on average, 45% women, and the main underlying disease was chronic obstructive pulmonary disease (45%). The mean follow-up time was 67 months and survival at 5 years was 57.3% for the CLAD subgroup and 97.4% for the non-CLAD subgroup. After stringent quality controls, GenCOLT gathered more than 7.3 million SNP and HLA genotypes for 387 LT pairs, including 91% pairs composed of donor and recipient of European ancestry. Overall, GenCOLT is an accurate snapshot of LT clinical practice in France and Belgium between 2009 and 2018. It currently represents one of the largest genetic biobanks dedicated to LT with data available simultaneously for donors and recipients. This unique cohort will empower to run comprehensive GWAS investigations of CLAD and other LT outcomes.

PMID:39164465 | DOI:10.1038/s41431-024-01683-y

Nat Microbiol. 2024 Aug 20. doi: 10.1038/s41564-024-01778-8. Online ahead of print.

ABSTRACT

Salmonella translocate to the gut epithelium via microfold cells lining the follicle-associated epithelium (FAE). How Salmonella localize to the FAE is not well characterized. Here we use live imaging and competitive assays between wild-type and chemotaxis-deficient mutants to show that Salmonella enterica serotype Typhimurium (S. Typhimurium) localize to the FAE independently of chemotaxis in an ex vivo mouse caecum infection model. Electrical recordings revealed polarized FAE with sustained outward current and small transepithelial potential, while the surrounding villus is depolarized with inward current and large transepithelial potential. The distinct electrical potentials attracted S. Typhimurium to the FAE while Escherichia coli (E. coli) localized to the villi, through a process called galvanotaxis. Chloride flux involving the cystic fibrosis transmembrane conductance regulator (CFTR) generated the ionic currents around the FAE. Pharmacological inhibition of CFTR decreased S. Typhimurium FAE localization but increased E. coli recruitment. Altogether, our findings demonstrate that bioelectric cues contribute to S. Typhimurium targeting of specific gut epithelial locations, with potential implications for other enteric bacterial infections.

PMID:39164392 | DOI:10.1038/s41564-024-01778-8

mBio. 2024 Aug 20:e0085224. doi: 10.1128/mbio.00852-24. Online ahead of print.

ABSTRACT

Pseudomonas aeruginosa is an opportunistic pathogen that thrives in environments associated with human activity, including soil and water altered by agriculture or pollution. Because L-lactate is a significant product of plant and animal metabolism, it can serve as a carbon source for P. aeruginosa in the diverse settings that it inhabits. In this study, we evaluate the production and use of two redundant P. aeruginosa L-lactate dehydrogenases, termed LldD and LldA. We confirm that the protein LldR represses lldD and identify a new transcription factor, called LldS, that activates lldA; these distinct regulators and the genomic contexts of lldD and lldA contribute to their differential expression. We demonstrate that the lldD and lldA genes are conditionally controlled in response to lactate isomers as well as to glycolate and ɑ-hydroxybutyrate, which, like lactate, are ɑ-hydroxycarboxylates. We also show that lldA is induced when iron availability is low. Our examination of lldD and lldA expression across depth in biofilms indicates a complex pattern that is consistent with the effects of glycolate production, iron availability, and cross-regulation on enzyme preference. Finally, macrophage infection assays reveal that both lldD and lldA contribute to persistence within host cells, underscoring the potential role of L-lactate as a carbon source during P. aeruginosa-eukaryote interactions. Together, these findings help us understand the metabolism of a key resource that may promote P. aeruginosa's success as a resident of contaminated environments and animal hosts.IMPORTANCEPseudomonas aeruginosa is a major cause of lung infections in people with cystic fibrosis, of hospital-acquired infections, and of wound infections. It consumes L-lactate, which is found at substantial levels in human blood and tissues. In this study, we investigated the spatial regulation of two redundant enzymes, called LldD and LldA, which enable L-lactate metabolism in P. aeruginosa biofilms. We uncovered mechanisms and identified compounds that control the preference of P. aeruginosa for LldD versus LldA. We also showed that both enzymes contribute to its ability to survive within macrophages, a behavior that is thought to augment the chronicity and recalcitrance of infections. Our findings shed light on a key metabolic strategy used by P. aeruginosa and have the potential to inform the development of therapies targeting bacterial metabolism during infection.

PMID:39162563 | DOI:10.1128/mbio.00852-24

mSphere. 2024 Aug 20:e0043424. doi: 10.1128/msphere.00434-24. Online ahead of print.

ABSTRACT

Chelsey VanDrisse works in the field of microbial physiology, studying how acylation of small molecules and proteins affects the development of Pseudomonas biofilms. In this mSphere of Influence article, she reflects on the paper "Community composition shapes microbial-specific phenotypes in a cystic fibrosis polymicrobial model system" by Jean-Pierre et al. This paper prompted her to reassess her approach to studying antibiotic tolerance and her design of experiments that search for disease-relevant mutants and phenotypes in the laboratory.

PMID:39162472 | DOI:10.1128/msphere.00434-24

Eur Clin Respir J. 2024 Aug 16;11(1):2381307. doi: 10.1080/20018525.2024.2381307. eCollection 2024.

ABSTRACT

OBJECTIVE: Initiated by the Severe Asthma Network Italy (SANI), this study aims to explore asthma patients' perceptions of disease severity, differentiating between mild and severe asthma. The objective is to identify factors influencing tailored treatment strategies for varying disease severities and to provide insights into asthma care in Italy.

METHODS: Conducted between November 2020 and January 2021, a survey using Computer-Assisted Personal Interviewing (CAPI) collected data from 308 Italian adults, representing the population. A 25 item multiple choice questionnaire covered asthma diagnosis, symptoms, treatment approaches, associated conditions, and quality of life.

RESULTS: Among participants, 83.8% reported having mild asthma, while 16.2% had severe asthma. Severe asthma patients had longer disease durations, more severe symptoms, frequent exacerbations, and higher hospital/ER visits. Although treatment adherence and symptom profiles generally aligned with international guidelines for self reported severe asthma, 22% of self identified mild asthmatics experienced severe respiratory symptoms. Oral corticosteroid (OCS) use was observed in 50% of severe cases and 22% of mild cases. Adherence was higher in severe asthma patients (76%) versus mild asthma patients (28%). Both groups experienced comorbidities, with 96% of severe asthmatics and 72% of mild asthmatics reporting impaired quality of life.

CONCLUSION: This study highlights the disparity between clinical categorization and patient perceptions of asthma severity. The prevalence of self reported severe asthma exceeds literature data. The burden of mild asthma remains significant, with treatment approaches not fully aligned, particularly regarding disproportionate OCS use. Addressing this gap requires enhancing patient education, improving diagnostic practices, and promoting adherence.

PMID:39161972 | PMC:PMC11332286 | DOI:10.1080/20018525.2024.2381307

J Med Microbiol. 2024 Aug;73(8). doi: 10.1099/jmm.0.001869.

ABSTRACT

Introduction. Mycobacterium abscessus (MABS) is a pathogenic bacterium that can cause severe lung infections, particularly in individuals with cystic fibrosis. MABS colonies can exhibit either a smooth (S) or rough (R) morphotype, influenced by the presence or absence of glycopeptidolipids (GPLs) on their surface, respectively. Despite the clinical significance of these morphotypes, the relationship between GPL levels, morphotype and the pathogenesis of MABS infections remains poorly understood.Gap statement. The mechanisms and implications of GPL production and morphotypes in clinical MABS infections are unclear. There is a gap in understanding their correlation with infectivity and pathogenicity, particularly in patients with underlying lung disease.Aim. This study aimed to investigate the correlation between MABS morphology, GPL and infectivity by analysing strains from cystic fibrosis patients' sputum samples.Methodology. MABS was isolated from patient sputum samples and categorized by morphotype, GPL profile and replication rate in macrophages. A high-content ex vivo infection model using THP-1 cells assessed the infectivity of both clinical and laboratory strains.Results. Our findings revealed that around 50 % of isolates displayed mixed morphologies. GPL analysis confirmed a consistent relationship between GPL content and morphotype that was only found in smooth isolates. Across morphotype groups, no differences were observed in vitro, yet clinical R strains were observed to replicate at higher levels in the THP-1 infection model. Moreover, the proportion of infected macrophages was notably higher among clinical R strains compared to their S counterparts at 72 h post-infection. Clinical variants also infected THP-1 cells at significantly higher rates compared to laboratory strains, highlighting the limited translatability of lab strain infection data to clinical contexts.Conclusion. Our study confirmed the general correlation between morphotype and GPL levels in smooth strains yet unveiled more variability within morphotype groups than previously recognized, particularly during intracellular infection. As the R morphotype is the highest clinical concern, these findings contribute to the expanding knowledge base surrounding MABS infections, offering insights that can steer diagnostic methodologies and treatment approaches.

PMID:39158416 | DOI:10.1099/jmm.0.001869

Clin Microbiol Rev. 2024 Aug 19:e0021521. doi: 10.1128/cmr.00215-21. Online ahead of print.

ABSTRACT

SUMMARYThis guidance presents recommendations for clinical microbiology laboratories for processing respiratory samples from people with cystic fibrosis (pwCF). Appropriate processing of respiratory samples is crucial to detect bacterial and fungal pathogens, guide treatment, monitor the epidemiology of cystic fibrosis (CF) pathogens, and assess therapeutic interventions. Thanks to CF transmembrane conductance regulator modulator therapy, the health of pwCF has improved, but as a result, fewer pwCF spontaneously expectorate sputum. Thus, the collection of sputum samples has decreased, while the collection of other types of respiratory samples such as oropharyngeal and bronchoalveolar lavage samples has increased. To optimize the detection of microorganisms, including Pseudomonas aeruginosa, Staphylococcus aureus, Haemophilus influenzae, and Burkholderia cepacia complex; other less common non-lactose fermenting Gram-negative bacilli, e.g., Stenotrophomonas maltopholia, Inquilinus, Achromobacter, Ralstonia, and Pandoraea species; and yeasts and filamentous fungi, non-selective and selective culture media are recommended for all types of respiratory samples, including samples obtained from pwCF after lung transplantation. There are no consensus recommendations for laboratory practices to detect, characterize, and report small colony variants (SCVs) of S. aureus, although studies are ongoing to address the potential clinical impact of SCVs. Accurate identification of less common Gram-negative bacilli, e.g., S. maltopholia, Inquilinus, Achromobacter, Ralstonia, and Pandoraea species, as well as yeasts and filamentous fungi, is recommended to understand their epidemiology and clinical import.

PMID:39158301 | DOI:10.1128/cmr.00215-21

World Allergy Organ J. 2024 Jul 24;17(8):100933. doi: 10.1016/j.waojou.2024.100933. eCollection 2024 Aug.

ABSTRACT

BACKGROUND: Type 2 inflammation is the principal determinant of asthma in children, and it leads to the downstream activation of eosinophils (EOS), the production of immunoglobulin-E (IgE), and increased levels of fraction of exhaled nitric oxide (FeNO). Dupilumab received the approval for the treatment of uncontrolled severe Type 2 asthma in children.

OBJECTIVE: The aim of this analysis was to calculate the Type 2 severe asthma paediatric population who would be eligible for treatment with dupilumab in Italy and characterize them by expected biomarker status.

METHODS: The calculation of the dupilumab-eligible population employed a two-phase approach: 1) estimating the total number of children aged 6-11 years with uncontrolled severe asthma; and 2) stratifying the severe uncontrolled asthma population, based on appropriate biomarker levels, thus identifying patients eligible for treatment with dupilumab. The VOYAGE study provided the data for this analysis.

RESULTS: The two-phase approach utilizing VOYAGE data revealed that the average number of paediatric patients with uncontrolled severe asthma was N = 1007. Stratification of these patients, as per VOYAGE data, indicated that the majority (N = 740; 73.5%) would have ≥2 elevated biomarkers, and over one-third patients (N = 434, 43.1%) would exhibit simultaneously elevated levels of EOS, FeNO and IgE. Of the paediatric patients, N = 864 were identified as eligible to dupilumab treatment, constituting 85.8% of the target population. Notably, nearly half eligible patients (N = 454) displayed elevated levels of both EOS and FeNO biomarkers, while the substantial majority (81.1%) exhibited at least an increase of EOS levels (N = 817). Patients with increased FeNO levels without a concurrent increase in EOS were less frequent (N = 47; 5.4% of the eligible population).

CONCLUSION: The simultaneous testing of multiple biomarkers during baseline patient assessment and disease follow-up is highly recommended. Utilizing cost-effective tests, physicians can estimate the prevalence of severe Type 2 asthma, categorize patients into distinct phenotypes (eosinophilic, allergic, or mixed), and consequently identify and prescribe the most suitable therapeutic interventions. This approach also facilitates the ongoing evaluation and adjustment of the treatment strategies based on individual patient responses.

PMID:39156597 | PMC:PMC11327463 | DOI:10.1016/j.waojou.2024.100933

Cureus. 2024 Jul 18;16(7):e64792. doi: 10.7759/cureus.64792. eCollection 2024 Jul.

ABSTRACT

Allergic bronchopulmonary aspergillosis (ABPA) is a multifaceted immune hypersensitivity reaction occurring in the lungs and bronchi, triggered by exposure and colonization of Aspergillus species, commonly Aspergillus fumigatus (A. fumigatus). It typically affects individuals who are immunocompetent but predisposed, such as those with bronchial asthma and cystic fibrosis. Diagnosis involves various methods including chest radiography, computed tomography, identification of eosinophilia, elevated serum IgE (immunoglobulin E) levels, and immunological tests for Aspergillus antigen. Left undiagnosed and untreated, ABPA can advance to bronchiectasis and/or pulmonary fibrosis, leading to significant morbidity and mortality.

PMID:39156318 | PMC:PMC11329887 | DOI:10.7759/cureus.64792

Hum Gene Ther. 2024 Aug 19. doi: 10.1089/hum.2024.064. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is a serious genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Approved small molecule therapies benefit the majority of people with CF (pwCF), but unfortunately not all. Gene addition offers a mutation agnostic treatment option for all pwCF. SP-101 is an adeno-associated virus gene therapy vector (AAV2.5T) that has been optimized for efficient human airway cell transduction, and that contains a functional and regulated shortened human CFTR minigene (hCFTRΔR) with a small synthetic promoter/enhancer. To understand SP-101 airway distribution, activity, and the associated immune response, in vivo studies were performed in wild-type and CF ferrets. After single dose inhaled delivery of SP-101, followed by single dose inhaled doxorubicin (an AAV transduction augmenter) or saline, SP-101 vector genomes were detected throughout the respiratory tract. hCFTRΔR mRNA expression was highest in ferrets also receiving doxorubicin and persisted for the duration of the study (13 weeks). Pre-existing mucus in the CF ferrets did not present a barrier to effective transduction. Binding and neutralizing antibodies to the AAV2.5T capsid were observed regardless of doxorubicin exposure. Only a portion of ferrets exhibited a weak T-cell response to AAV2.5T and no T-cell response was seen against hCFTRΔR. These data strongly support the continued development of inhaled SP-101, followed by inhaled doxorubicin, for the treatment of cystic fibrosis.

PMID:39155828 | DOI:10.1089/hum.2024.064

Hum Gene Ther. 2024 Aug 19. doi: 10.1089/hum.2024.063. Online ahead of print.

ABSTRACT

Cystic fibrosis (CF) is caused by mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein. Although CF affects multiple organs, lung disease is the main cause of morbidity and mortality, and gene therapy is expected to provide a mutation agnostic option for treatment. SP-101 is a recombinant adeno-associated virus (AAV) gene therapy vector carrying a human CFTR minigene, hCFTRΔR, and is being investigated as an inhalation treatment for people with CF. To further understand SP-101 activity, in vitro studies were performed in human airway epithelia derived from multiple CF and non-CF donors. SP-101 restored CFTR-mediated chloride conductance, measured via Ussing chamber assay, at a multiplicity of infection (MOI) as low as 5e2 in the presence of doxorubicin, a small molecule known to augment AAV transduction. Functional correction of CF HAE increased with increasing MOI and doxorubicin concentration and correlated with increasing cell-associated vector genomes and hCFTRΔR mRNA expression. Tropism studies using a fluorescent reporter vector and single-cell mRNA sequencing of SP-101-mediated hCFTRΔR mRNA demonstrated broad expression in all cell types after apical transduction, including secretory, ciliated, and basal cells. In summary, SP-101, particularly in combination with doxorubicin, shows promise for a novel CF treatment strategy, and strongly supports continued development.

PMID:39155805 | DOI:10.1089/hum.2024.063

Arch Dis Child. 2024 Aug 17:archdischild-2023-326447. doi: 10.1136/archdischild-2023-326447. Online ahead of print.

NO ABSTRACT

PMID:39153747 | DOI:10.1136/archdischild-2023-326447

Microb Pathog. 2024 Aug 14:106854. doi: 10.1016/j.micpath.2024.106854. Online ahead of print.

ABSTRACT

BACKGROUND: P. aeruginosa, a biofilm-forming bacteria, is the main cause of pulmonary infection in CF patients. We applied ZnO-np as a therapeutic agent for eradicating multi-drug resistance and biofilm-forming P. aeruginosa isolated from young CF patients.

METHODS: A total of 73 throat and sputum samples taken from young CF patients were inquired. ZnO-np was synthesized and characterized in terms of size, shape, and structure for anti-bacterial activity. The antibiotic susceptibility of isolates before and after the addition of 16 μg/ml of ZnO was evaluated using disc diffusion and microtiter methods, respectively. The gene expression level of QS genes was assessed after treatment with 16 μg/ml ZnO-np.

RESULTS: The optimum concentration of ZnO-np with a higher inhibitory zone was 16 μg/ml (MIC) and 32 μg/ml (MBC). All isolates were resistant to applied antibiotics, and about 45 % of isolates were strong biofilm-forming bacteria. After treatment with 16 μg/ml ZnO-np, all strains became susceptible to the applied antibiotic except for amikacin, which confers an intermediate pattern. About 63 % and 20 % of isolates were, respectively, non-biofilm and weak biofilm-forming bacteria following the addition of ZnO-np. Relative gene expression of gacA, lasR, and rhlR genes were downregulated significantly (P<0.001). Although the retS did not have a significant reduction (P=0.2) CONCLUSION: ZnO-np at a concentration of 16 μg/ml could significantly reduce the P. aeruginosa infection by altering the antibiotic susceptibility pattern and inhibiting biofilm formation. Due to their photocatalytic properties and their ability to penetrate the extracellular polysaccharide layer, ZnO nanoparticles can produce ROS, which increases their susceptibility to antibiotics. Nasal delivery of ZnO-np in the form of aerosol can be considered a potential strategy to decrease the mortality rate in CF patients at an early age.

PMID:39151738 | DOI:10.1016/j.micpath.2024.106854

Medicine (Baltimore). 2024 Aug 16;103(33):e39224. doi: 10.1097/MD.0000000000039224.

ABSTRACT

BACKGROUND: To examine the burden of exocrine pancreatic insufficiency (EPI), specifically the clinical impact of EPI on patients, their quality of life (QoL) and the cost-effectiveness of existing treatments.

METHODS: A systematic literature review was conducted using key search terms for the clinical, economic, and humanistic burden. Databases were searched from 2010 to 2022, with articles screened independently by 2 reviewers at abstract and full-text stage against pre-defined eligibility criteria.

RESULTS: Seventy-one publications were identified that reported relevant clinical, humanistic, and economic data. Prevalence and incidence of EPI varied across identified studies; EPI appears to be especially prevalent as a comorbid condition in patients with cystic fibrosis. EPI has a large impact on QoL, with lower QoL scores in patients with EPI compared with those without EPI. The instruments used to assess QoL, however, were inconsistent across studies. Where reported, economic burden studies highlighted that patients with EPI have higher healthcare resource utilization compared with those without, with costs increasing with disease severity.

CONCLUSION: This systematic literature review highlights that patients with EPI have higher treatment costs and lower QoL scores than patients without EPI. The prevalence of EPI as a comorbid condition is high, particularly in patients with cystic fibrosis.

PMID:39151540 | DOI:10.1097/MD.0000000000039224

Lancet Respir Med. 2024 Aug 13:S2213-2600(24)00243-1. doi: 10.1016/S2213-2600(24)00243-1. Online ahead of print.

NO ABSTRACT

PMID:39151435 | DOI:10.1016/S2213-2600(24)00243-1

Lancet Respir Med. 2024 Aug 13:S2213-2600(24)00208-X. doi: 10.1016/S2213-2600(24)00208-X. Online ahead of print.

ABSTRACT

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response.

METHODS: The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France's 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses.

FINDINGS: The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV1 (ppFEV1) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor.

INTERPRETATION: In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population.

FUNDING: Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.

PMID:39151434 | DOI:10.1016/S2213-2600(24)00208-X