RESUMEN
BACKGROUND: Elexacaftor-tezacaftor-ivacaftor is a small-molecule cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be efficacious in patients with at least one Phe508del allele, which indicates that this combination can modulate a single Phe508del allele. In patients whose other CFTR allele contains a gating or residual function mutation that is already effectively treated with previous CFTR modulators (ivacaftor or tezacaftor-ivacaftor), the potential for additional benefit from restoring Phe508del CFTR protein function is unclear. METHODS: We conducted a phase 3, double-blind, randomized, active-controlled trial involving patients 12 years of age or older with cystic fibrosis and Phe508del-gating or Phe508del-residual function genotypes. After a 4-week run-in period with ivacaftor or tezacaftor-ivacaftor, patients were randomly assigned to receive elexacaftor-tezacaftor-ivacaftor or active control for 8 weeks. The primary end point was the absolute change in the percentage of predicted forced expiratory volume in 1 second (FEV1) from baseline through week 8 in the elexacaftor-tezacaftor-ivacaftor group. RESULTS: After the run-in period, 132 patients received elexacaftor-tezacaftor-ivacaftor and 126 received active control. Elexacaftor-tezacaftor-ivacaftor resulted in a percentage of predicted FEV1 that was higher by 3.7 percentage points (95% confidence interval [CI], 2.8 to 4.6) relative to baseline and higher by 3.5 percentage points (95% CI, 2.2 to 4.7) relative to active control and a sweat chloride concentration that was lower by 22.3 mmol per liter (95% CI, 20.2 to 24.5) relative to baseline and lower by 23.1 mmol per liter (95% CI, 20.1 to 26.1) relative to active control (P<0.001 for all comparisons). The change from baseline in the Cystic Fibrosis Questionnaire-Revised respiratory domain score (range, 0 to 100, with higher scores indicating better quality of life) with elexacaftor-tezacaftor-ivacaftor was 10.3 points (95% CI, 8.0 to 12.7) and with active control was 1.6 points (95% CI, -0.8 to 4.1). The incidence of adverse events was similar in the two groups; adverse events led to treatment discontinuation in one patient (elevated aminotransferase level) in the elexacaftor-tezacaftor-ivacaftor group and in two patients (anxiety or depression and pulmonary exacerbation) in the active control group. CONCLUSIONS: Elexacaftor-tezacaftor-ivacaftor was efficacious and safe in patients with Phe508del-gating or Phe508del-residual function genotypes and conferred additional benefit relative to previous CFTR modulators. (Funded by Vertex Pharmaceuticals; VX18-445-104 ClinicalTrials.gov number, NCT04058353.).
Asunto(s)
Aminofenoles/uso terapéutico , Benzodioxoles/uso terapéutico , Agonistas de los Canales de Cloruro/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Indoles/uso terapéutico , Pirazoles/uso terapéutico , Piridinas/uso terapéutico , Quinolinas/uso terapéutico , Adolescente , Adulto , Aminofenoles/efectos adversos , Benzodioxoles/efectos adversos , Niño , Agonistas de los Canales de Cloruro/efectos adversos , Cloruros/análisis , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Método Doble Ciego , Combinación de Medicamentos , Femenino , Genotipo , Humanos , Indoles/efectos adversos , Masculino , Pirazoles/efectos adversos , Piridinas/efectos adversos , Quinolinas/efectos adversos , Sudor/químicaRESUMEN
Diagnosing cystic fibrosis (CF) in adulthood is not a rare occurrence for CF centers despite the popular belief that the diagnosis is achieved almost universally in childhood by means of newborn screening or early clinical presentation. The purpose of this review article is to highlight specific considerations of adult diagnosis of CF. Obtaining a diagnosis of CF at any age is exceptionally important to ensure optimal treatment, monitoring, and support. In the new era of more personalized treatment with the advent of transformative therapies targeting the underlying protein defect, accurate diagnosis is of increasing importance. This review highlights the diagnostic algorithm leading to a new diagnosis of CF in adults. The diagnosis is usually confirmed in the presence of a compatible clinical presentation, evidence of cystic fibrosis transmembrane conductance regulator (CFTR) protein dysfunction, and/or identification of variants in the CFTR gene believed to alter protein function. Achieving the diagnosis, however, is not always straightforward as CFTR protein function exists on a continuum with different organs displaying varying sensitivity to diminution in function. We highlight the current knowledge regarding the epidemiology of CF diagnosed in adults and outline the various clinical presentations, including pulmonary and extrapulmonary, which are more common in this population. We expand on the stepwise testing procedures that lead to diagnosis, paying particular attention to additional levels of testing which may be required to achieve an accurate diagnosis. There continues to be an important need for both pulmonary and other specialists to be aware of the potential for later presentation of CF, as the improvements in treatment over decades have had large positive impacts on prognosis for people with this condition.
Asunto(s)
Fibrosis Quística , Adulto , Humanos , Fibrosis Quística/diagnóstico , Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Pruebas Genéticas , Mutación , Tamizaje Neonatal , PronósticoRESUMEN
INTRODUCTION: Ivacaftor was the first therapy licensed to address the underlying defect in cystic fibrosis (CF). The improvements in lung function, nutritional status and pulmonary exacerbations in patients carrying a Gly551Asp mutation were greater than previously seen in clinical trials for other therapies. Limited data are available regarding long-term outcomes and adherence to ivacaftor outside clinical trials. METHODS: We conducted a 5-year single-centre retrospective study of people with CF carrying the Gly551Asp mutation who received ivacaftor. Clinical outcome data were extracted from medical notes and databases. Drug delivery data were used to assess medicine possession ratio (MPR). RESULTS: 35 people were included. After commencing ivacaftor, FEV1 improved by 9.6% (SE±1.59%) predicted by 6 months. Thereafter, FEV1 declined, and at 5 years had returned to pre-ivacaftor baseline. Ivacaftor did not alter annual rate of FEV1 decline (1.57% pre vs 1.82% post, p=0.74). Body mass index (BMI) increased for 4 years. There was a significant reduction in inpatient and total intravenous antibiotic days sustained over 5 years. MPR remained high but declined over time (-2.5±0.9% per year, p=0.007). FEV1 was better maintained in patients with higher MPRs. CONCLUSION: The addition of ivacaftor provides acute benefits for people with the Gly551Asp mutation and established lung disease. We report a sustained reduction in intravenous antibiotic use but following acute improvement in lung function, decline continues, and patients will continue to require medical observation and optimisation. Strategies to maintain high adherence should be a priority to prolong the benefits of ivacaftor.
Asunto(s)
Aminofenoles/uso terapéutico , Agonistas de los Canales de Cloruro/uso terapéutico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Quinolonas/uso terapéutico , Adolescente , Adulto , Femenino , Humanos , Masculino , Mutación , Estudios RetrospectivosRESUMEN
PURPOSE OF REVIEW: The purpose of this review is to describe on-going and upcoming real-world studies that will aid the cystic fibrosis (CF) community in understanding the long-term efficacy, safety and challenges in utilizing this therapy and managing care. RECENT FINDINGS: The triple combination of elexacaftor, tezacaftor and ivacaftor (ETI) has been demonstrated to improve lung function, weight and quality of life in children and adults with CF with at least one copy of Phe508del. Treatment with ETI will potentially be available for approximately 90% of the CF population and change the face of CF. SUMMARY: In spite of early demonstrations of short-term efficacy and safety, for medications that may be given for much of someone's life, continued assessment of these outcomes is necessary. Furthermore, the CF community must evaluate and address the issues that arise with increased longevity including parenthood, preventive care management and the potential comorbidities of aging.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística , Fibrosis Quística , Adulto , Aminofenoles/uso terapéutico , Niño , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Combinación de Medicamentos , Humanos , Mutación , Calidad de VidaRESUMEN
This is a selection of papers presented at the 30th North American Cystic Fibrosis Conference held in Orlando in October 2016. The papers discussed are thought to be of particular interest to CF caregivers in the UK. We highlight the major themes covered in the conference including novel therapies, recently published and proposed guidelines and insights from registry studies.
Asunto(s)
Fibrosis Quística , Manejo de Atención al Paciente , Terapias en Investigación , Niño , Fibrosis Quística/epidemiología , Fibrosis Quística/terapia , Humanos , Manejo de Atención al Paciente/organización & administración , Manejo de Atención al Paciente/tendencias , Guías de Práctica Clínica como Asunto , Reino Unido/epidemiologíaRESUMEN
CFTR modulators are a class of drugs which directly target the defective CFTR protein in cystic fibrosis (CF), improving its function with resultant clinical improvements. Currently these drugs are confined to people with a limited selection of genetic mutations. New modulators are in development which will lead to the majority of patients with CF becoming eligible for treatment. CFTR modulators are currently considered contraindicated in patients with a solid organ transplant. This excludes many patients who may benefit from the multisystem effects of CFTR modulator treatment. In this review, we discuss issues regarding drug interactions, organ transplantation and CFTR modulation.
Asunto(s)
Aminofenoles/uso terapéutico , Aminopiridinas/uso terapéutico , Benzodioxoles/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/cirugía , Terapia Molecular Dirigida , Trasplante de Órganos , Quinolonas/uso terapéutico , Agonistas de los Canales de Cloruro/uso terapéutico , Fibrosis Quística/complicaciones , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Combinación de Medicamentos , Humanos , Masculino , Adulto JovenRESUMEN
BACKGROUND AND OBJECTIVE: Acute exacerbations of cystic fibrosis (CF) occur frequently throughout the course of the disease. Dyspnoea is the most common and distressing symptom experienced by patients during these episodes. We tested the hypothesis that pulmonary hyperinflation is an important determinant of dyspnoea severity during acute exacerbations. METHODS: We studied patients during an acute exacerbation of CF. Lung volumes, spirometry and dyspnoea scores were measured at Day 0, Day 7, at the end of treatment (EOT) and 14 days following the EOT. RESULTS: At the start of treatment, mean residual volume (RV)/total lung capacity (TLC) was 54.9%, which decreased significantly with treatment, as did vital capacity (VC), inspiratory capacity (IC) and dyspnoea scores. IC was the only independent predictor of dyspnoea severity. CONCLUSION: Our study demonstrates significant improvements in hyperinflation, spirometry and dyspnoea scores with treatment of acute exacerbations of CF. Hyperinflation, rather than airflow limitation, may contribute towards the increased dyspnoea during exacerbations.
Asunto(s)
Fibrosis Quística , Disnea , Adulto , Fibrosis Quística/complicaciones , Fibrosis Quística/fisiopatología , Disnea/diagnóstico , Disnea/etiología , Disnea/fisiopatología , Femenino , Volumen Espiratorio Forzado/fisiología , Humanos , Capacidad Inspiratoria/fisiología , Pulmón/fisiopatología , Masculino , Índice de Severidad de la Enfermedad , Espirometría/métodos , Estadística como Asunto , Evaluación de Síntomas/métodos , Brote de los Síntomas , Capacidad Vital/fisiologíaRESUMEN
Pneumothorax is a serious but common complication in patients with cystic fibrosis (CF). It has adverse prognostic implications as well as associations with subsequent reduction in lung function and significant risk of recurrence. Management dilemmas frequently occur that are beyond current guidelines. We review the evidence and highlight management difficulties in pneumothoraces in CF.
Asunto(s)
Fibrosis Quística/complicaciones , Neumotórax/etiología , Neumotórax/terapia , Adolescente , Fibrosis Quística/microbiología , Fibrosis Quística/fisiopatología , Diagnóstico por Imagen , Manejo de la Enfermedad , Humanos , Masculino , Neumotórax/diagnóstico por imagen , Neumotórax/fisiopatología , Pronóstico , Pruebas de Función Respiratoria , Factores de RiesgoRESUMEN
The use of non-prescribed anabolic agents amongst non-athletes is increasing with young, adult males with cystic fibrosis (CF) in the highest risk demographic. There is evidence that anabolic agents increase weight and muscle mass in adults with a variety of catabolic conditions but there is no evidence for their use in hormone sufficient adults with CF. We report a case of anabolic agent use in a male adult with CF and review the clinical features of anabolic agent use with a focus on adults with CF.
Asunto(s)
Anabolizantes/uso terapéutico , Peso Corporal/efectos de los fármacos , Fibrosis Quística/tratamiento farmacológico , Adulto , Anabolizantes/efectos adversos , Fibrosis Quística/complicaciones , Humanos , MasculinoRESUMEN
Cystic fibrosis (CF) represents one of the success stories of modern medicine with sustained incremental increases in the survival from one of childhood death to one of adult survival into the middle decades over the past 30 years. Improving survival has focused on multidisciplinary management centered on treating the consequences of this genetic disease. It has been firmly established for more than 20 years that mutations in the CF transmembrane conductance regulator (CFTR) gene result in a defective protein that normally functions as a chloride channel on epithelial cell surfaces. Until recently, modulating CFTR dysfunction was only a research aspiration, however, greater focus placed upon addressing the primary defect of CF has developed several clinical therapeutic strategies in this area. This review highlights the evidence to date on efforts to modulate CFTR and restore robust functional protein to the cell surface. This approach has now led to the licensing of one CFTR potentiator, which has been shown to have significant clinical improvements in a subset of CF patients. This success represents the beginning for CFTR modulation and further research is ongoing which aims to broaden the applicability of these techniques.
Asunto(s)
Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Fibrosis Quística/terapia , Terapia Genética , Humanos , MutaciónRESUMEN
Clinical trials have revealed that Ivacaftor significantly reduces sweat chloride in patients with cystic fibrosis who carry the G551D mutation. This finding has been incorporated into the commissioning guidelines in the UK with a sweat chloride reduction of 30% or below 60â mmol/L, specified as the main criteria for continued funding of Ivacaftor for individual patients. In a cohort of 24 adults who were prescribed Ivacaftor, there was no correlation between absolute or relative reductions in sweat chloride and improvements in lung function. This questions the validity of sweat chloride as a surrogate marker of clinical efficacy.
Asunto(s)
Aminofenoles/uso terapéutico , Cloruros/análisis , Fibrosis Quística/tratamiento farmacológico , Quinolonas/uso terapéutico , Sudor/química , Aminofenoles/economía , Biomarcadores/análisis , Estatura , Peso Corporal , Estudios de Cohortes , Fibrosis Quística/genética , Fibrosis Quística/fisiopatología , Flujo Espiratorio Forzado , Humanos , Pulmón/fisiopatología , Estudios Prospectivos , Quinolonas/economía , EspirometríaRESUMEN
Staphylococcus aureus is an important pathogen within the context of cystic fibrosis lung disease. Case reports have identified a strong association between the toxin Panton-Valentine Leukocidin (PVL) and lethal necrotizing pneumonia in healthy immunocompetent patients. PVL+ strains of Staphylococcus aureus have also been identified in patients with cystic fibrosis. We describe a further case of pneumonia in a patient with cystic fibrosis, and outline potential transmission of the organism from healthy family members to this patient. We review the evidence regarding the pathogenicity of PVL toxin with a special reference to patients with cystic fibrosis. We outline current concerns regarding the potential transmission of the organism and possible treatment strategies.
Asunto(s)
Toxinas Bacterianas/biosíntesis , Fibrosis Quística/microbiología , Exotoxinas/biosíntesis , Leucocidinas/biosíntesis , Infecciones Estafilocócicas/complicaciones , Staphylococcus aureus/metabolismo , Humanos , Masculino , Adulto JovenRESUMEN
Bronchial artery embolisation (BAE) is a treatment used to manage haemoptysis. We performed a 7-year review of BAE procedures for haemoptysis at our CF centre aiming to evaluate the incidence and outcomes of patients with neurovascular complications post-BAE. Our review suggests that whilst BAE is an effective method for controlling life-threatening haemoptysis, patients are at risk of developing neurovascular complications with long term residual symptoms, and therefore careful consideration should be given in offering BAE, especially to otherwise well patients with chronic small volume haemoptysis and managing teams should have a low threshold to image symptomatic patients.
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Fibrosis Quística , Embolización Terapéutica , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/terapia , Arterias Bronquiales , Estudios Retrospectivos , Hemoptisis/diagnóstico , Hemoptisis/etiología , Hemoptisis/terapia , Resultado del Tratamiento , Embolización Terapéutica/efectos adversosRESUMEN
Rationale: Cardiopulmonary exercise testing (CPET) provides prognostic information in cystic fibrosis (CF); however, its prognostic value for patients with advanced CF lung disease is unknown. Objectives: To determine the prognostic value of CPET on the risk of death or lung transplant (LTX) within 2 years. Methods: We retrospectively collected data from 20 CF centers in Asia, Australia, Europe, and North America on patients with a forced expiratory volume in 1 second (FEV1) ⩽ 40% predicted who performed a cycle ergometer CPET between January 2008 and December 2017. Time to death/LTX was analyzed using mixed Cox proportional hazards regression. Conditional inference trees were modeled to identify subgroups with increased risk of death/LTX. Results: In total, 174 patients (FEV1, 30.9% ± 5.8% predicted) were included. Forty-four patients (25.5%) died or underwent LTX. Cox regression analysis adjusted for age, sex, and FEV1 revealed percentage predicted peak oxygen uptake ([Formula: see text]o2peak) and peak work rate (Wpeak) as significant predictors of death/LTX: adjusted hazard ratios per each additional 10% predicted were 0.60 (95% confidence interval, 0.43-0.90; P = 0.008) and 0.60 (0.48-0.82; P < 0.001). Tree-structured regression models, including a set of 11 prognostic factors for survival, identified Wpeak to be most strongly associated with 2-year risk of death/LTX. Probability of death/LTX was 45.2% for those with a Wpeak ⩽ 49.2% predicted versus 10.9% for those with a Wpeak > 49.2% predicted (P < 0.001). Conclusions: CPET provides prognostic information in advanced CF lung disease, and Wpeak appears to be a promising marker for LTX referral and candidate selection.
Asunto(s)
Fibrosis Quística , Trasplante de Pulmón , Humanos , Prueba de Esfuerzo , Pronóstico , Estudios RetrospectivosRESUMEN
BACKGROUND: Elexacaftor/tezacaftor/ivacaftor (E/T/I) therapy has resulted in substantial improvements in health status for many with cystic fibrosis. Monitoring of liver tests is recommended due to observed rises in transaminases in trials and cases of hepatotoxicity. Comprehensive data in large populations of unselected individuals and those with established CF related liver disease (CFLD) is lacking. METHODS: Patients prescribed E/T/I at a large, adult centre had liver tests monitored at least 3 monthly for 12 months. Changes in individual liver tests were analysed and abnormalities were compared in those with and without CFLD. RESULTS: 255 of 267 eligible patients were included. Mild rises in median ALT, AST and bilirubin from baseline to 3 months (all p < 0.001) within normal limits were noted which were sustained. There were no differences in changes in liver tests between those with or without CFLD. There was a significant difference in alkaline phosphatase for those with raised levels at baseline versus those with normal baseline level (-18.5 vs +2.0 IU/L, p = 0.002). Clinically significant rises in ALT and AST occurred in 8 (3.1%) and 6 (2.4%) cases respectively, with derangements in 2 individuals attributed to therapy. CONCLUSIONS: E/T/I leads to a mild, likely clinically insignificant increase in ALT, AST and bilirubin after 3 months which is sustained but does not appear to increase further in the vast majority. Underlying CFLD should not be a barrier to treatment. Although there was a reduction in ALP when elevated at baseline, this was not unique to those with pre-existing CFLD.
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Fibrosis Quística , Humanos , Adulto , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Aminofenoles/efectos adversos , Benzodioxoles/efectos adversos , Bilirrubina , Hígado , MutaciónRESUMEN
BACKGROUND: There are limited studies to date on the effects of elexacaftor/tezacaftor/ivacaftor (E/T/I) on markers of liver fibrosis in adults with cystic fibrosis (CF). This study aims to analyse changes in makers of liver fibrosis before and after initiation of E/T/I in CF adults. METHODS: Outcome measures of liver fibrosis, including liver stiffness measurement (LSM) using FibroScan, AST-to-platelet-ratio index (APRI) and gamma-GT-to-platelet-ratio (GPR) were available in 74 CF adults following initiation of E/T/I. This was compared to historical data collected in 2018 prior to UK availability of E/T/I. RESULTS: The median duration of E/T/I therapy at the time liver fibrosis markers were repeated was 21 (IQR: 17-25) months. There was an increase in APRI from historical measurement to follow-up but no change in LSM or GPR. There were no differences in change in fibrosis markers according to CF liver disease (CFLD) status, although those with a raised LSM at baseline (>6.8 kPa) (n = 14) had a significant reduction in LSM from historical measurement to follow-up versus those with a normal historical value (-3.3 kPa vs 0.25 kPa, p < 0.01). CONCLUSIONS: Apart from APRI, we found no changes in liver fibrosis outcomes after initiation of E/T/I in adults with CF. Those with a historical diagnosis of CFLD had no significant worsening or improvement of liver fibrosis markers. We did observe a reduction in LSM in those with liver nodularity, with an initial highest result suggesting a potential positive treatment effect of E/T/I in this category of those with severe CFLD.