Ivacaftor improves lung disease in patients with advanced CF carrying CFTR mutations that confer residual function

Salvatore, Donatello; Terlizzi, Vito; Francalanci, Michela; Taccetti, Giovanni; Messore, Barbara; Biglia, Carlotta; Pisi, Giovanna; Calderazzo, Maria Adelaide; Caloiero, Mimma; Pizzamiglio, Giovanna; Majo, Fabio; Cresta, Federico; Leonetti, G; Venuto, D. De

doi:10.1016/j.rmed.2020.106073

Cited by 26 publications

(20 citation statements)

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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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“…Since that time, IVA was approved for several other gating mutations such that by early 2020 ~20% of individuals with CF had access to an efficacious disease modifying oral medication. Several studies have examined the effect of IVA on patients with advanced lung disease and demonstrated similar improvements to what was observed in patients with modest lung disease (2)(3)(4)(5). More recently the second highly effective CFTR modulator therapy, Elexacaftor/Tezacaftor/Ivacaftor (Trikafta®, ETI) was approved for individuals with the F508del CFTR mutation.…”

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confidence: 84%

CFTR Modulators to the Rescue of Individuals with Cystic Fibrosis and Advanced Lung Disease

Myerburg

Pilewski

2021

Am J Respir Crit Care Med

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“…Over the last two decades, CF patients' median survival improved, reaching up to 45 years. Improved treatments, such as LTand CFTR modulators, represented a key factor in this challenge [5,15], and therefore, it is now necessary to evaluate the long-term complications of these therapies. In our study, we showed a reduced renal function (with a reduced eGFR) and an increase in serum nitrogen in LRs compared to the other groups of patients.…”

Section: Discussionmentioning

confidence: 99%

Adult Patients Affected by Cystic Fibrosis in Therapy with Cystic Fibrosis Transmembrane Regulator Modulators and Lung Transplant: Renal Function, Metabolic and Nutritional Status

Lai

Mazzaferro

Mitterhofer

et al. 2020

Journal of Nutrition and Metabolism

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Background. Cystic fibrosis (CF) is one of the most frequent genetic diseases. The discovery and implementation of new therapies prolonged the survival of CF patients in the last years. Evaluation of long-term complications could be useful to improve the outcome of these patients. Aim of the Study. To evaluate renal function, metabolic, nutritional, and inflammatory status in CF patients on cystic fibrosis transmembrane regulator (CFTR) modulators therapy as well as lung transplant recipients (LRs) and patients on conservative therapy (control group). Materials and Methods. We performed a prospective, longitudinal study on 69 CF patients. Clinical and laboratory parameters (metabolic and nutritional indices and inflammatory markers) were evaluated in all patients before starting CFTR therapy or transplant (T0) and after 3 years (T1). Results. We enrolled 69 CF patients (42 males). Patients were distributed into three groups. The average age was 35.01 ± 10.57 years for the control group (group 0), 32.47 ± 9.40 years for patients on CFTR modulators therapy (group 1), and 38.93 ± 7.14 years for LRs (group 2). At T1, we showed a significant difference among the three groups in terms of renal function indices: creatinine, eGFR, serum nitrogen as well as serum uric acid, sodium, and potassium ( p < 0.001 , p < 0.001 , p < 0.001 , p < 0.001 , p < 0.001 , and p < 0.001 , respectively), particularly in LRs patients. Significant differences were found in nutritional status parameters among the three groups: total protein, serum albumin, serum fibrinogen, serum transferrin, and white blood cell counts ( p < 0.001 , p = 0.037 , p = 0.04 , p = 0.003 , and p = 0.007 , respectively), particularly in LRs compared with other groups. Moreover, we found significant differences in metabolic profile (HbA1c, p = 0.026 ) and inflammatory status, with a significant difference in C-reactive protein values, neutrophil counts, and neutrophil-lymphocyte ratio (NLR) among the three groups ( p < 0.001 , p = 0.005 , and p = 0.026 , respectively). Conclusions. Our study showed a reduced renal function and poor nutritional status in LRs, along with worse metabolic control. Moreover, we showed a lower inflammatory status in patients on CFTR modulators therapy. Therefore, we suggest early and careful monitoring of renal function, metabolic, and nutritional parameters in CF patients, whether they are on conservative therapy, CFTR modulators therapy, and LRs patients.

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Ivacaftor improves lung disease in patients with advanced CF carrying CFTR mutations that confer residual function

Cited by 26 publications

References 30 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?

CFTR Modulators to the Rescue of Individuals with Cystic Fibrosis and Advanced Lung Disease

Adult Patients Affected by Cystic Fibrosis in Therapy with Cystic Fibrosis Transmembrane Regulator Modulators and Lung Transplant: Renal Function, Metabolic and Nutritional Status

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