Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry

Salvatore, Donatello; Padoan, Rita; Buzzetti, Roberto; Amato, Annalisa; Giordani, Barbara; Ferrari, Gianluca

doi:10.1002/ppul.24215

Cited by 16 publications

(20 citation statements)

References 15 publications

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“…We studied CRMS/CFSPID infants with at least one copy of the D1152H, because: (i) Such variant has a high frequency in the Italian CF population [ 16 ] and in CRMS/CFSPID subjects [ 11 , 12 ], and (ii) previous data indicated that the clinical expression of CF in patients with the D1152H is heterogeneous and may in part depend on the pathogenic variant in trans [ 15 ]. Furthermore, recent data show that, over time, variants with residual function such as D1152H can determine a markedly reduced life expectancy [ 38 , 39 ] and the Food and Drug Administration approved the use of ivacaftor, a CFTR potentiator, to also treat patients carrying D1152H [ 40 ]. Thus, the identification of CRMS/CFSPID infants at higher risk to evolve in CF and the early diagnosis of the progression could be a useful tool also for the early identification of subjects eligible for the use of CFTR modulators.…”

Section: Discussionmentioning

confidence: 99%

CRMS/CFSPID Subjects Carrying D1152H CFTR Variant: Can the Second Variant Be a Predictor of Disease Development?

et al. 2020

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Background: There are no predictive factors of evolution of cystic fibrosis (CF) screen positive inconclusive diagnosis subjects (CFSPIDs). Aim: to define the role of the second CFTR variant as a predictive factor of disease evolution in CFSPIDs carrying the D1152H variant. Methods: We retrospectively evaluated clinical characteristics and outcome of CFSPIDs carrying the D1152H variant followed at five Italian CF centers. CFSPIDs were divided in two groups: Group A: compound heterozygous for D1152H and a CF-causing variant; Group B: compound heterozygous for D1152H and a: (i) non CF-causing variant, (ii) variant with varying clinical consequences, or (iii) variant with unknown significance. The variants were classified according to CFTR2 mutation database. Results: We enrolled 43 CFSPIDs with at least one D1152H variant: 28 (65.1%) were classified in the group A, and 15 (34.9%) in the Group B. CFSPIDs of group A had the first IRT significantly higher compared to those of group B (p < 0.05) and had a more severe clinical outcome during the follow-up. At the end of the study period, after a mean follow-up of 40.6 months (range 6–91.6), 4 (9.3%) out of 43 CFSPIDs progressed to CFTR-RD or CF. All these subjects were in the group A. Conclusions: The genetic profile could help predict the risk of disease evolution in CFSPIDs carrying D1152H, revealing the subjects that need a more frequent follow-up.

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Section: Discussionmentioning

confidence: 99%

CRMS/CFSPID Subjects Carrying D1152H CFTR Variant: Can the Second Variant Be a Predictor of Disease Development?

et al. 2020

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“…These data were difficult to interpret. The low percentage of women in the F / F group, previously described, 19 and the median age younger than the median age of the F / F men (20.2 vs. 21.3 years, respectively; p = .046) could be partly explained by the gender gap frequently described in CF literature 20,21 . Conversely, the GM group shows a low percentage of males (44%).…”

Section: Discussionmentioning

confidence: 69%

Cystic fibrosis with non‐G551D gating mutations in Italy: Epidemiology and clinical characteristics

Salvatore

Carnovale

Padoan

et al. 2020

Pediatric Pulmonology

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Background: Cystic fibrosis transmembrane conductance regulator (CFTR) gating mutations (GMs) result in CFTR that is present at the cell surface but nonfunctional. Patients with the G551D mutation, the most prevalent worldwide, have been well studied. Italian GM patients have mainly non-G551D mutations. We studied their epidemiology and clinical characteristics in the period spanning the pre/post ivacaftor introduction to the Italian market. Methods: Data from the Italian CF Registry were used to describe patients with GMs and compare them with F508del homozygous (F/F) patients. Results: In total, 186 patients with GMs (median [range] age, 21.96 [0.13-63.38] years) were identified among the 5552 patients included in the study (3.3%). They had lower sweat chloride values at diagnosis than the F/F and a lower ratio of males. In the GM group, examining the data of the years 2012 and 2017 and comparing with F/F, lung infection by Staphylococcus aureus and diabetes became less prevalent, and better FEV 1 and nutritional status were observed in 2017. The cross-sectional evaluation year-by-year from 2012 to 2017 of the GM group showed improving trends in lung function and body mass index, and the decreasing prevalence of diabetes compared with F/F. Longitudinal evaluation of GM patients showed improvement in percent predicted (pp)FEV 1 and nutrition in the 2012-2017 period. These variations correspond to the introduction of treatment with the CFTR potentiator ivacaftor (2014/2015). Conclusions: Italian patients with GMs are few and are characterized by milder phenotypes than F/F patients. Improved outcomes are likely influenced by treatment with ivacaftor.

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“…Willingness to initiate CFTRm treatment reaches 69-78% in case of fully expressed disease and exceeds 90% in patients with worsening disease. Interestingly, compared to survey conducted in 2015 13 , intention to initiate CFTRm treatment in F508del homozygous over 12 years of age increased by 8-11% in all severity categories and even doubled for patients in terminal stage, showing increasing confidence of physicians with increasing experience of CFTRm. Nevertheless, some concern on initiating CFTRm in asymptomatic pediatric patients actually exists and this might be related to lack of long term experience of CFTRm in pediatric CF patients.…”

Section: Discussionmentioning

confidence: 82%

“…This new class of drugs called CFTR modulators (CFTRm) rapidly increased with the addition of new combinations targeting additional CF patient groups, ivacaftor/lumacaftor, ivacaftor/tezacaftor and more recently ivacaftor/tezacaftor/elexacaftor, each of them approved for use in patients with specific genotypes 12 . Although genotype does not fully correlate with phenotype, patients homozygous forF508del , the most frequently represented mutation worldwide, generally have a rapidly progressive disease while patients with mutations associated with residual function of the CFTR protein tend to have a slower course of disease 13 . With the increasing availability of compounds addressing the cause of the disease, the possibility to change the course of CF is now within reach and there are high hopes in the community to transform this rapidly lethal disease into a chronic disease.…”

Section: Introductionmentioning

confidence: 99%

Expectations about CFTR modulators among physicians from Italian Cystic fibrosis centers: a survey about the evolution of clinical practice paradigms for cystic fibrosis

Casciaro

Costa

Ros

2021

Preprint

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CFTR modulators (CFTRm) were introduced recently but they are already profoundly changing Cystic Fibrosis (CF) landscape. This survey was conducted in 2018 to evaluate how their perception and use evolved in Italy, with focus on factors that could influence physician treatment decisions. Response rate was 75.6% and the majority of physicians (81%) had been working in CF for over 5 years. While traditional parameters such as lung function and nutritional status remain key evaluation criteria in relation to initiation and monitoring of CFTRm, pulmonary exacerbations ranked at least at the same level of importance in both pediatric and adolescent/adult patients homozygous for F508del, as well as those with residual function mutations. Increasing interest is shown for tools that can help detect early manifestations of disease such as Lung Clearance Index and imaging. Patient-related outcomes, such as ability to conduct daily activities, are also deemed relevant in decision to start and continue CFTRm. Physician decision to initiate treatment according to clinical presentation was similar in all groups, showing that more importance was given to severity/instability of disease rather than mutation type or age range. A relatively low percentage of physicians would treat asymptomatic patients, in particular very young or those with residual function mutations, showing reluctance to treat early in some patient groups in the absence of clear manifestations of CF. Increasing experience with CFTRm will allow to gain more long term evidence and will help shape new guidelines.

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Patients with cystic fibrosis having a residual function mutation: Data from the Italian registry

Cited by 16 publications

References 15 publications

CRMS/CFSPID Subjects Carrying D1152H CFTR Variant: Can the Second Variant Be a Predictor of Disease Development?

CRMS/CFSPID Subjects Carrying D1152H CFTR Variant: Can the Second Variant Be a Predictor of Disease Development?

Cystic fibrosis with non‐G551D gating mutations in Italy: Epidemiology and clinical characteristics

Expectations about CFTR modulators among physicians from Italian Cystic fibrosis centers: a survey about the evolution of clinical practice paradigms for cystic fibrosis

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