Multisystemic Effects of Elexacaftor-Tezacaftor-Ivacaftor in Adults with Cystic Fibrosis and Advanced Lung Disease.

RATIONALE: Limited data exist on safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. OBJECTIVE: To evaluate the effects of ETI in an unselected population of pwCF and advanced lung disease. METHODS: A prospective observational study, including all adults, aged 18 years and older, with a percent predicted FEV1 (ppFEV1)≤ 40 who initiated ETI from December 2019 to June 2021 in France was conducted. PwCF were followed until August 8th, 2022. RESULTS: ETI was initiated in 434 pwCF with a median [interquartile range, IQR] ppFEV1=30 [25; 35], including 27 with severe CF liver disease and 183 with diabetes. PwCF were followed for a median [IQR] 587 [396; 728] days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was mostly due to lung transplantation (n=5) or death (n=4). Absolute increase in ppFEV1 by a mean +14.2% (95% CI, 13.1-15.4) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the younger age quartile was almost twice that of the oldest quartile (P<0.001); body mass index <18.5 kg/m2 was found in 38.6% at initiation vs. 11.3% at 12 months (P=0.0001). Increase in serum concentrations of vitamin A and E, but not 25OHD3, was observed. Significant reduction in the % of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of diabetics. CONCLUSION: ETI is safe in pwCF and advanced lung disease with multisystem pulmonary and extrapulmonary benefits.

CT imaging shows specific pancreatic abnormalities in persons with cystic fibrosis related diabetes.

Cystic fibrosis related diabetes (CFRD) is observed in 20-50% of adults with cystic fibrosis (CF). Pancreas abnormalities on imaging, e.g. pancreas lipomatosis, are frequent in subjects with CF. We hypothesized that specific abnormalities may characterize patients with CFRD. We performed a retrospective study comparing the computed tomography (CT) of participants with CF with or without diabetes ("CFRD" and "CF control" groups). We classified the pancreas on imaging according to 3 categories: normal, partial lipomatosis and complete lipomatosis of the pancreas. We also assessed the presence or absence of pancreatic calcifications. Forty-one CFRD and 53 CF control participants were included. Only 2% of the patients with CFRD had a normal pancreas, as compared with 30% of the participants from the CF control group (p = 0.0016). Lipomatosis was more frequent in subjects with CFRD and was related to exocrine pancreatic insufficiency (EPI) and to severe CFTR mutations (classes I to III). Nine participants with diabetes (22%) presented with pancreatic calcifications, versus none of the control participants (p = 0.0003). In conclusion, pancreas imaging was almost always abnormal in subjects with CFRD, while it was normal in a third of the CF control subjects. Pancreatic calcifications were specific of subjects with CFRD.

The Changing Epidemiology of Cystic Fibrosis: The Implications for Adult Care.

Cystic fibrosis (CF) is a genetic disease in which mutations in the gene encoding for the CF transmembrane conductance regulator protein result in a multisystem disease dominated by digestive and respiratory manifestations. In the mid-20th century, CF caused death within the first years of life. Over the past decades, advances in disease management, which includes systematic neonatal screening, multidisciplinary symptomatic CF care, lung transplantation and, more recently, highly effective CF transmembrane conductance regulator modulators, have transformed the prognosis of people with CF markedly. In most countries with well-established CF care, adults now outnumber children, and life expectancy is expected to increase further, narrowing the survival gap with the general population. However, marked differences in the prognosis of CF exist not only among high-, low-, and middle-income countries but also among high-income countries, based on the presence and quality of a specialized CF care provision network. Current evidence suggests that differences in patient clinical status and survival could be attributable not only to intrinsic disease severity but also to disparities in access to high-quality specialized care. Because CF is generally a progressive disease, adults with CF often show increased pulmonary severity and complications and increased occurrence of comorbidities, which highlights the need for specialized adult CF centers. This article seeks to describe the evolution of CF demography over the past decades, predict future trends, and anticipate the future provision of adult CF care.

CFTR Modulators in People with Cystic Fibrosis: Real-World Evidence in France.

Cystic fibrosis (CF) is a rare genetic multisystemic disease, the manifestations of which are due to mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) protein and can lead to respiratory insufficiency and premature death. CFTR modulators, which were developed in the past decade, partially restore CFTR protein function. Their clinical efficacy has been demonstrated in phase 3 clinical trials, particularly in terms of lung function and pulmonary exacerbations, nutritional status, and quality of life in people with gating mutations (ivacaftor), homozygous for the F508del mutation (lumacaftor/ivacaftor and tezacaftor/ivacaftor), and in those with at least one F508del mutation (elexacaftor/tezacaftor/ivacaftor). However, many questions remain regarding their long-term safety and effectiveness, particularly in patients with advanced lung disease, liver disease, renal insufficiency, or problematic bacterial colonization. The impact of CFTR modulators on other important outcomes such as concurrent treatments, lung transplantation, chest imaging, or pregnancies also warrants further investigation. The French CF Reference Network includes 47 CF centers that contribute patient data to the comprehensive French CF Registry and have conducted nationwide real-world studies on CFTR modulators. This review seeks to summarize the results of these real-world studies and examine their findings against those of randomized control trials.

Sustained effectiveness of elexacaftor-tezacaftor-ivacaftor in lung transplant candidates with cystic fibrosis.

BACKGROUND: Elexacaftor-tezacaftor-ivacaftor induces rapid clinical improvement in patients with cystic fibrosis (CF) and advanced pulmonary disease, often leading to suspend the indication for lung transplantation. Yet no long-term data is available in lung transplant candidates. METHODS: Lung transplant candidates (defined as being waitlisted for lung transplantation or considered for listing within 3 months) who have initiated elexacaftor-tezacaftor-ivacaftor were identified in the French cohort of patients with CF and advanced pulmonary disease. Patients were prospectively followed to evaluate treatment safety and effectiveness from initiation to July 20th, 2021. RESULTS: Among the 331 patients with advanced CF pulmonary disease who initiated elexacaftor-tezacaftor-ivacaftor, 65 were lung transplant candidates (17 listed for transplantation, 48 considered for listing within 3 months). Median [IQR] follow-up time was 363 [329; 377] days. At the end of the follow-up period, two patients were transplanted five and 11 days following treatment initiation, two were listed for transplantation, and 61 no longer met transplantation criteria. Improvement in percent predicted forced expiratory volume in 1 s (ppFEV1) at one month was +13.4% (95% confidence interval, 10.3%-16.5%; P < 0.0001) and remained stable thereafter. Treatment burden decreased substantially, with an 86% decrease in the need for intravenous antibiotics, 59% for oxygen therapy and 62% for non-invasive ventilation. CONCLUSION: In lung transplant candidates eligible for elexacaftor-tezacaftor-ivacaftor, the rapid improvement following initiation of treatment persisted over one year with a reduction in treatment burden and lung transplantation could be safely deferred in most patients.

Nurse coordinator roles in the management of patients with hepatocellular carcinoma: A French national survey.

Hepatocellular carcinoma (HCC) mostly occurs in patients with chronic liver disease (CLD). HCC treatment may have a direct impact on CLD prognosis. HCC management can therefore become complex, involving multiple health care providers, such as oncologists, hepatologists, radiologists, and surgeons. In France, dedicated nurses have been involved in patient care pathways. Their impact is poorly documented. PURPOSE: To determine the country-wide distribution of HCC nurse coordinators in French health care settings and to describe their roles and responsibilities. PATIENTS AND METHODS: A survey using a multi-item questionnaire (including center characteristics, nurse coordinator characteristics, and quality indicators such as patient care pathway initiation timeline, scheduled length of hospital stay, diagnostic disclosure process) was conducted. All French liver cancer centers planning to participate in a prospective national cohort study for patients with HCC (CHIEF Cohort) were invited to take part in the survey. Bivariate analysis compared centers with a nurse coordinator to those without. RESULTS: Among the 42 of 72 centers that replied, 14 treated fewer than 75 HCC patients. Treatment mostly took place in hepatology units (34/42). Sixteen nurse coordinators were part of the health care team in 13 of the 42 centers. Among these 13 centers, 11 were university hospitals and 11 followed more than 75 patients per year. The median number of patients followed in these centers was 300 (min-max 44-600) in 2017. All nurse coordinators were involved in providing patient information and counseling. Other roles included treatment monitoring (13/16), care coordination (12/16), psychological support (12/16) and treatment planning (11/16). Thirteen nurse coordinators conducted diagnostic disclosure nurse consultations; seven conducted initial patient contact consultations; and six held outpatient nurse consultations, with wide heterogeneity between centers. The presence of a nurse coordinator was associated with completion of the full diagnostic disclosure process (p = 0.045). CONCLUSION: In France, nurse coordinators for HCC patient pathway management are present mainly in university hepatology units with a caseload of more than 75 patients per year. All provide patient information and counseling but their roles in care coordination, patient support and holistic assessment are heterogeneous and not standardized.

A prospective analysis of unplanned patient-initiated contacts in an adult cystic fibrosis centre.

BACKGROUND: Timely response should be provided when patients contact the cystic fibrosis (CF) centre in between scheduled visits. Little data exist on unplanned patient-initiated contacts in CF adults. METHODS: A two-stage prospective study was undertaken from 1 January to 31 December 2015 at Cochin Hospital, Paris (France). The first stage included all adults (≥18 years) who initiated unplanned contacts to the CF centre over four months. Four physicians and three nurses systematically recorded unplanned patient-initiated contacts. The data was analysed to determine why and how patients contacted the CF centre and time spent responding to their request(s). The second stage (one physician, three nurses) lasted twelve months and explored whether high contact frequency was associated with disease severity, using multivariate logistic regression. RESULTS: In the first stage, 259 of 410 patients (63%) initiated at least one unplanned contact, corresponding to 1067 contacts over 4 months. Patients favoured email with physicians (61% of contacts) and telephone with nurses (87% of contacts). Total time spent by the 7 caregivers on providing responses was 8 h/work week. Reasons for contacting the CF centre varied greatly, but <20% of contacts were directly related to symptom management. In the second stage, 180 of 212 patients (85%) initiated 1876 contacts over 12 months. Factors associated with ≥5 contacts/year were female sex, FEV1 ≤ 30% predicted, ≥5 physician visits/year, and ≥ 1 hospital admission/year. CONCLUSIONS: Answering unplanned patient-initiated contacts represented a significant workload for CF caregivers. Increased disease severity was associated with high contact frequency.