The expanded French compassionate programme for elexacaftor-tezacaftor-ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study.

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.

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

Rationale: Limited data exist on the safety and effectiveness of elexacaftor-tezacaftor-ivacaftor (ETI) in people with cystic fibrosis (pwCF) and advanced lung disease. Objectives: 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 percentage predicted forced expiratory volume in 1 second (ppFEV1) ⩽ 40 who initiated ETI from December 2019 to June 2021 in France, was conducted. PwCF were followed until August 8, 2022. Results: ETI was initiated in 434 pwCF with a median ppFEV1 of 30 (interquartile range, 25-35), including 27 with severe cystic fibrosis liver disease and 183 with diabetes. PwCF were followed for a median of 587 (interquartile range, 396-728) days after ETI initiation. Discontinuation of ETI occurred in 12 (2.8%) pwCF and was due mostly to lung transplantation (n = 5) or death (n = 4). Absolute increase in ppFEV1 by a mean of +14.2% (95% confidence interval, 13.1-15.4%) occurred at 1 month and persisted throughout the study. Increase in ppFEV1 in the youngest 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 versus 11.3% at 12 months (P = 0.0001). Increases in serum concentrations of vitamins A and E, but not 25-hydroxy vitamin D3, were observed. Significant reductions in the percentages of pwCF using oxygen therapy, noninvasive ventilation, nutritional support, and inhaled and systemic therapies (including antibiotics) were observed; insulin was discontinued in 12% of patients with diabetes. Conclusions: ETI is safe in pwCF and advanced lung disease, with multisystem pulmonary and extrapulmonary benefits.

Successful lung transplantation in genetic methionyl-tRNA synthetase-related alveolar proteinosis/lung fibrosis without recurrence under methionine supplementation: Medium-term outcome in 4 cases.

Pulmonary alveolar proteinosis (PAP) results from the accumulation of lipoproteinaceous material in the alveoli and alveolar macrophages, and can be associated with pulmonary fibrosis, with a need for lung transplantation (LTx). Causes of PAP are autoimmune (90%-95%), secondary (5%), or hereditary (<1%). Patients with hereditary PAP are generally not considered for isolated LTx, due to the high probability of recurrence after LTx, and only a challenging scenario with sequential LTx followed by hematopoietic stem cell transplantation (HSCT) was reported as successful. Recently, a new genetic cause of PAP linked to mutations in the methionyl-tRNA synthetase (MARS) gene has been reported, with a highly variable clinical presentation. Because clinical correction of the defective MARS activity with methionine supplementation has been reported in nontransplanted children, we reassessed the feasibility of LTx for candidates with MARS-related PAP/fibrosis. We report 3 cases of LTx performed for MARS-related pulmonary alveolar proteinosis-pulmonary fibrosis without recurrence under methionine supplementation, whereas another fourth case transplanted without supplementation had fatal PAP recurrence. These results suggest the effectiveness of methionine in correcting defective MARS activity and also looking for this very rare diagnosis in case of unclassified PAP/fibrosis. It argues for not excluding the feasibility of isolated LTx in patients with MARS mutation.

Theratyping cystic fibrosis patients to guide elexacaftor/tezacaftor/ivacaftor out-of-label prescription.

BACKGROUND: Around 20% of people with cystic fibrosis (pwCF) do not have access to the triple combination elexacaftor/tezacaftor/ivacaftor (ETI) in Europe because they do not carry the F508del allele on the CF transmembrane conductance regulator (CFTR) gene. Considering that pwCF carrying rare variants may benefit from ETI, including variants already validated by the US Food and Drug Administration (FDA), a compassionate use programme was launched in France. PwCF were invited to undergo a nasal brushing to investigate whether the pharmacological rescue of CFTR activity by ETI in human nasal epithelial cell (HNEC) cultures was predictive of the clinical response. METHODS: CFTR activity correction was studied by short-circuit current in HNEC cultures at basal state (dimethyl sulfoxide (DMSO)) and after ETI incubation and expressed as percentage of normal (wild-type (WT)) CFTR activity after sequential addition of forskolin and Inh-172 (ΔI ETI/DMSO%WT). RESULTS: 11 pwCF carried variants eligible for ETI according to the FDA label and 28 carried variants not listed by the FDA. ETI significantly increased CFTR activity of FDA-approved CFTR variants (I601F, G85E, S492F, M1101K, R347P, R74W;V201M;D1270N and H1085R). We point out ETI correction of non-FDA-approved variants, including N1303K, R334W, R1066C, Q552P and terminal splicing variants (4374+1G>A and 4096-3C>G). ΔI ETI/DMSO%WT was significantly correlated to change in percentage predicted forced expiratory volume in 1 s and sweat chloride concentration (p<0.0001 for both). G85E, R74W;V201M;D1270N, Q552P and M1101K were rescued more efficiently by other CFTR modulator combinations than ETI. CONCLUSIONS: Primary nasal epithelial cells hold promise for expanding the prescription of CFTR modulators in pwCF carrying rare mutants. Additional variants should be discussed for ETI indication.

Nonsense mutations accelerate lung disease and decrease survival of cystic fibrosis children.

RATIONALE: Limited information is available on the clinical status of people with Cystic Fibrosis (pwCF) carrying 2 nonsense mutations (PTC/PTC). The main objective of this study was to compare disease severity between pwCF PTC/PTC, compound heterozygous for F508del and PTC (F508del/PTC) and homozygous for F508del (F508del+/+). METHODS: Based on the European CF Society Patient Registry clinical data of pwCF living in high and middle income European and neighboring countries, PTC/PTC (n = 657) were compared with F508del+/+ (n = 21,317) and F508del/PTC(n = 4254).CFTR mRNA and protein activity levels were assessed in primary human nasal epithelial (HNE) cells sampled from 22 PTC/PTC pwCF. MAIN RESULTS: As compared to F508del+/+ pwCF; both PTC/PTC and F508del/PTC pwCF exhibited a significantly faster rate of decline in Forced Expiratory Volume in 1 s (FEV1) from 7 years (-1.33 for F508del +/+, -1.59 for F508del/PTC; -1.65 for PTC/PTC, p < 0.001) until respectively 30 years (-1.05 for F508del +/+, -1.23 for PTC/PTC, p = 0.048) and 27 years (-1.12 for F508del +/+, -1.26 for F508del/PTC, p = 0.034). This resulted in lower FEV1 values in adulthood. Mortality of pediatric pwCF with one or two PTC alleles was significantly higher than their F508del homozygous pairs. Infection with Pseudomonas aeruginosa was more frequent in PTC/PTC versus F508del+/+ and F508del/PTC pwCF. CFTR activity in PTC/PTC pwCF's HNE cells ranged between 0% to 3% of the wild-type level. CONCLUSIONS: Nonsense mutations decrease the survival and accelerate the course of respiratory disease in children and adolescents with Cystic Fibrosis.

Results of Lung Transplantation for Cystic Fibrosis With Selected Donors Over 65 Years Old.

Lung transplantation is limited by the shortage of suitable donors. Many programs have begun to use extended criteria donors. Donors over 65 years old are rarely reported, especially for young cystic fibrosis recipients. This monocentric study was conducted for cystic fibrosis recipients from January 2005 to December 2019, comparing two cohorts according to lung donor age (<65 years or ≥65 years). The primary objective was to assess the survival rate at 3 years using a Cox multivariable model. Of the 356 lung recipients, 326 had donors under 65 years, and 30 had donors over 65 years. Donors' characteristics did not differ significantly in terms of sex, time on mechanical ventilation before retrieval, and partial pressure of arterial oxygen/fraction of inspired oxygen ratio. There were no significant differences in post-operative mechanical ventilation duration and incidence of grade 3 primary graft dysfunction between the two groups. At 1, 3, and 5 years, the percentage of predicted forced expiratory volume in 1 s (p = 0.767) and survival rate did not differ between groups (p = 0.924). The use of lungs from donors over 65 years for cystic fibrosis recipients allows extension of the donor pool without compromising results. Longer follow-up is needed to assess the long-term effects of this practice.

The French Compassionate Program of elexacaftor-tezacaftor-ivacaftor in people with cystic fibrosis with advanced lung disease and no F508del CFTR variant.

BACKGROUND: The European Medicines Agency has approved the cystic fibrosis transmembrane conductance regulator (CFTR) modulator combination elexacaftor-tezacaftor-ivacaftor (ETI) for people with cystic fibrosis (pwCF) carrying at least one F508del variant. The United States Food and Drug Administration (FDA) also approved ETI for pwCF carrying one of 177 rare variants. METHODS: An observational study was conducted to evaluate the effectiveness of ETI in pwCF with advanced lung disease that were not eligible to ETI in Europe. All patients with no F508del variant and advanced lung disease (defined as having a percent predicted forced expiratory volume (ppFEV1)<40 and/or being under evaluation for lung transplantation) and enrolled in the French Compassionate Program initiated ETI at recommended doses. Effectiveness was evaluated by a centralized adjudication committee at 4-6 weeks in terms of clinical manifestations, sweat chloride concentration and ppFEV1. RESULTS: Among the first 84 pwCF included in the program, ETI was effective in 45 (54%) and 39 (46%) were considered to be non-responders. Among the responders 22/45 (49%) carried a CFTR variant that is not currently approved by FDA for ETI eligibility. Important clinical benefits, including suspending the indication for lung transplantation, a significant decrease in sweat chloride concentration by a median [IQR] -30 [-14;-43]mmol·l-1 (n=42; p<0.0001) and an improvement in ppFEV1 by+10.0 [6.0; 20.5] (n=44, p<0.0001), were observed in those for whom treatment was effective. CONCLUSION: Clinical benefits were observed in a large subset of pwCF with advanced lung disease and CFTR variants not currently approved for ETI.

2022 Update of indications and contraindications for lung transplantation in France.

Lung transplantation (LTx) is a steadily expanding field. The considerable developments have been driven over the years by indefatigable work conducted at LTx centers to improve donor and recipient selection, combined with multifaceted efforts to overcome challenges raised by the surgical procedure, perioperative care, and long-term medical complications. One consequence has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. The Francophone Pulmonology Society (Société de Pneumology de Langue Française, SPLF) set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force examined the most recent literature and evaluated the risk factors that limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while also improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

Impact of the COVID-19 pandemic and associated lockdown measures on the management, health, and behavior of the cystic fibrosis population in France during 2020 (MUCONFIN).

Background: Most of the studies on cystic fibrosis (CF) focused on SARS-CoV-2 prevalence and suggested a low incidence of infection in this population. We aimed to assess the impact of the pandemic and related lockdown measures implemented in May 2020 in response to the first wave of SARS-CoV-2 infection on healthcare access, health, and behavior in CF patients. Methods: A national questionnaire opened online from May 15th, 2020 to June 11th, 2020 was completed by 751 CF-patients, aged 14 years and over. It comprised questions about access to healthcare, anxiety and depression, smoking, alcohol, drug and psychotropic drug consumption, adherence to CF treatment, and constraints. A semi-structured comprehensive interview was performed no later than 1 month after the end of the lockdown in 16 CF-patients. Results: The mean age of the population was 28.0 [interquartile range (IQR) 20.0-37.0] years old. More than 75% of in-person consultations scheduled during the lockdown were canceled. Alternatively, 27% were postponed, and telehealth consultations were proposed and accepted in almost 40% of cases. More than 75% of the scheduled physiotherapy sessions were canceled and replaced mainly by self-drainage. Annual follow-up clinic visits were consistently postponed whereas required hospitalizations at CF centers for exacerbation were maintained in most cases. While 43.2% CF-patients had signs of anxiety, 51.0% presented symptoms of depression, both associated with increased use of psychotic medications and inversely correlated to COVID-19 prevalence. Among the lower and lower middle classes, very little medical information was obtained or requested by the patient, participation to sports or other activities was low, while excessive home confinement and isolation were more frequent. In contrast, in the upper middle and upper classes, individuals solicitated help to their CF centre, had more physical activities, and maintained contact with friends or families. Conclusion: The first lockdown in France had only minimal impact on the management care of CF-patients but was associated with increased symptoms of anxiety and depression, together with behavioral changes that varied with social class. Trial registration: NCT04463628.

Amikacin Liposomal Inhalation Suspension in the Treatment of Mycobacterium abscessus Lung Infection: A French Observational Experience.

Background: Mycobacterium abscessus infections remain difficult to manage in both cystic fibrosis (CF) and non-CF patients and reported clinical outcomes are largely unsatisfactory. Clinical trial data are limited and no approved therapies are currently available for the management of M abscessus lung diseases. As an alternative, cohort studies may provide insightful information into the management of M abscessus pulmonary disease. Methods: Based on a retrospective observational cohort study, we investigated the safety and efficacy of amikacin liposome inhaled suspension (ALIS) as an adjunct to a standard antibiotic regimen for M abscessus lung infection in both CF and non-CF patients. We also assessed the association of patient drug compliance with culture conversion and clinical outcomes. Results: Twenty-six patients had long-term follow-up data available. Culture conversion was achieved in 54% (14/26) of the patients with no difference between CF and non-CF patients after an average treatment duration of 10 months. Patient treatment compliance was significantly better in the converter group compared to nonconverters with an odds ratio of 44.78 associated with good compared to poor patient compliance. Overall, 9 patients (35%) experienced an adverse event that led to treatment discontinuation. Conclusions: ALIS appears beneficial in both CF and non-CF populations with M abscessus lung disease.

Feasibility and efficacy of combined pancreatic islet-lung transplantation in cystic fibrosis-related diabetes-PIM study: A multicenter phase 1-2 trial.

Cystic fibrosis-related diabetes (CFRD) is a common complication of cystic fibrosis (CF), and restoring metabolic control in these patients may improve their management after lung transplantation. In this multicenter, prospective, phase 1-2 trial, we evaluate the feasibility and metabolic efficacy of combined pancreatic islet-lung transplantation from a single donor in patients with CFRD, terminal respiratory failure, and poorly controlled diabetes. Islets were infused via the portal vein under local anesthesia, 1 week after lung transplantation. At 1 year, the primary outcome was transplant success as evaluated by a composite score including four parameters (weight, fasting glycemia, HbA1c, and insulin requirements). Ten participants (age: 24 years [17-31], diabetes duration: 8 years [4-12]) received a combined islet-lung transplant with 2892 IEQ/kg [2293-6185]. Transplant success was achieved in 7 out of 10 participants at 1-year post transplant. Fasting plasma C-peptide increased from 0.91 µg/L [0.56-1.29] to 1.15 µg/L [0.77-2.2], HbA1c decreased from 7.8% [6.5-8.3] (62 mmol/mol [48-67]) to 6.7% [5.5-8.0] (50 mmol/mol [37-64]), with 38% decrease in daily insulin doses. No complications related to the islet injection procedure were reported. In this pilot study, combined pancreatic islet-lung transplantation restored satisfactory metabolic control and pulmonary function in patients with CF, without increasing the morbidity of lung transplantation.

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.

A virtual crossmatch-based strategy for perioperative desensitisation in lung transplant recipients with pre-formed donor-specific antibodies: 3-year outcome.

BACKGROUND: Pre-formed donor-specific antibodies (DSAs) are associated with worse outcome after lung transplantation (LTx) and might limit access to LTx. A virtual crossmatch-based strategy for perioperative desensitisation protocol has been used for immunised LTx candidates since 2012 at Foch Hospital (Suresnes, France). We compared the outcome of desensitised LTx candidates with high DSA mean fluorescence intensity and those with low or no pre-formed DSAs, not desensitised. METHODS: For all consecutive LTx recipients (January 2012 to March 2018), freedom from chronic lung allograft dysfunction (CLAD) and graft survival were assessed using Kaplan-Meier analysis and Cox multivariate analysis. RESULTS: We compared outcomes for desensitised patients with high pre-formed DSAs (n=39) and those with no (n=216) or low pre-formed DSAs (n=66). The desensitisation protocol decreased the level of immunodominant DSA (class I/II) at 1, 3 and 6 months post-LTx (p<0.001, p<0.01 and p<0.001, respectively). Freedom from CLAD and graft survival at 3 years was similar in the desensitised group as a whole and other groups. Nevertheless, incidence of CLAD was higher with persistent high-level DSAs than cleared high-level (p=0.044) or no DSAs (p=0.014). Conversely, graft survival was better with cleared high DSAs than persistent high-level, low-level and no pre-formed DSAs (p=0.019, p=0.025 and p=0.044, respectively). On multivariate analysis, graft survival was associated with cleared high DSAs (hazard ratio 0.12, 95% CI 0.02-0.85 versus no DSAs; p=0.035) and CLAD with persistent DSAs (3.04, 1.02-9.17 versus no pre-formed DSAs; p=0.048). CONCLUSION: The desensitisation protocol in LTx recipients with high pre-formed DSAs was associated with satisfactory outcome, with cleared high pre-formed DSAs after desensitisation identified as an independent predictor of graft survival.

"Il faut continuer à poser des questions" patient reported outcome measures in cystic fibrosis: An anthropological perspective.

BACKGROUND: People with cystic fibrosis (pwCF) are central in the development of patient-led assessment tools. Qualitative analysis of a frequently used CF-specific patient-reported outcome measure (PROM) sought patient recommendations for development of a new quality of life (QoL) tool. METHODS: We performed an inventory of PROMs, symptom-report and QoL tools used in clinical trials within the European Cystic Fibrosis Society Clinical Trial Network (ECFS-CTN) and in routine clinical practice among Cystic Fibrosis Europe and ECFS members. A qualitative study using cognitive interviews with pwCF and their caregivers reviewed the Cystic Fibrosis Questionnaire (CFQ), the French initial form of the Cystic Fibrosis Questionnaire-Revised (CFQ-R). RESULTS: Survey results from 33 countries revealed over 70 tools used in routine clinical practice, utilized by clinical specialists (n=124), pwCF/parents/carers (n=49) and other allied health professionals (n=60). The CFQ-R was the main PROM used in clinical trials. The qualitative study enrolled 99 pwCF, 6 to 11 years (n=31); 12 to 18 years (n=38); >18 years (n=30) and 26 parents. Inductive thematic analysis based on the CFQ, revealed 19 key themes. Themes common across all cohorts included burden of treatment, impact of disease on day-to-day life, relationships/family, stress/mood, and nutrition. Themes unique to individual groups included, treatment when not symptomatic for the paediatric group; education/studies and planning for the future for adolescents, impact of anxiety and depression on day-to-day life for adults, and for parents, questions addressing anxiety and their role as carers. CONCLUSIONS: Patient-centeredness is paramount in development of an up-to-date PROM in the era of novel therapies.

Rapid Improvement after Starting Elexacaftor-Tezacaftor-Ivacaftor in Patients with Cystic Fibrosis and Advanced Pulmonary Disease.

Rationale: Elexacaftor-tezacaftor-ivacaftor is a CFTR (cystic fibrosis [CF] transmembrane conductance regulator) modulator combination, developed for patients with CF with at least one Phe508del mutation. Objectives: To evaluate the effects of elexacaftor-tezacaftor- ivacaftor in patients with CF and advanced respiratory disease. Methods: A prospective observational study, including all patients aged ⩾12 years and with a percent-predicted FEV1 (ppFEV1) <40 who initiated elexacaftor-tezacaftor-ivacaftor from December 2019 to August 2020 in France was conducted. Clinical characteristics were collected at initiation and at 1 and 3 months. Safety and effectiveness were evaluated by September 2020. National-level transplantation and mortality figures for 2020 were obtained from the French CF and transplant centers and registries. Measurements and Main Results: Elexacaftor-tezacaftor- ivacaftor was initiated in 245 patients with a median (interquartile range) ppFEV1 = 29 (24-34). The mean (95% confidence interval) absolute increase in the ppFEV1 was +15.1 (+13.8 to +16.4; P < 0.0001), and the mean (95% confidence interval) in weight was +4.2 kg (+3.9 to +4.6; P < 0.0001). The number of patients requiring long-term oxygen, noninvasive ventilation, and/or enteral tube feeding decreased by 50%, 30%, and 50%, respectively (P < 0.01). Although 16 patients were on the transplant waiting list and 37 were undergoing transplantation evaluation at treatment initiation, only 2 received a transplant, and 1 died. By September 2020, only five patients were still on the transplantation path. Compared with the previous 2 years, a twofold decrease in the number of lung transplantations in patients with CF was observed in 2020, whereas the number of deaths without transplantation remained stable. Conclusions: In patients with advanced disease, elexacaftor-tezacaftor-ivacaftor is associated with rapid clinical improvement, often leading to the indication for lung transplantation being suspended.

Sputum versus nasopharyngeal samples for the molecular diagnosis of respiratory viral infection in cystic fibrosis: A pilot study.

Viruses are important agents in lung function deterioration in Cystic Fibrosis (CF). To date, no standard operating procedures (SOPs) have been established to determine which sampling method is the most effective for an optimal virological diagnosis of respiratory viral infections in CF. Here we investigated the performances of two sampling sites, sputum samples versus nasopharyngeal (NP) swabs, for thirty participants from three CF centres presenting an acute respiratory infection. Sputum and NP samples were simultaneously collected and multiplex PCR targeting 16 to 18 viruses were performed. Viruses were detected for 18/30 patients (60%). A high concordance between the sputum and NP samples was observed in 25 (83%) paired samples of which 13 tested positive and 12 tested negative. These results highlighted the relevance of sputum sampling for diagnostic of respiratory viruses in CF, which is less invasive and better accepted by CF patients than NP, and allows accurate bacterial detection.

Posaconazole Tablets in Real-Life Lung Transplantation: Impact on Exposure, Drug-Drug Interactions, and Drug Management in Lung Transplant Patients, Including Those with Cystic Fibrosis.

Appropriate exposure to posaconazole (PSZ) has been limited until the recent approval of the delayed-release oral tablet formulation. Our goal was to determine the exposure obtained by using the standard dose of 300 mg once a day in lung transplant (LT) patients, including patients with cystic fibrosis (CF). PSZ trough concentrations (C0) were determined using a liquid chromatography-tandem mass spectrometry assay. Indicative thresholds of interest were <0.7 mg/liter for prophylaxis and 1 to 3 mg/liter for cure. The tacrolimus (TRL) and everolimus (ERL) C0 measured during PSZ exposure were also collected. The interaction with proton-pump inhibitors (PPI) was evaluated. We recorded the results for 21 CF patients with LT (CFLT patients), 11 non-CF patients with LT (NCFLT patients), and 27 nontransplant (NT) patients in pneumology departments. The weights of the NCFLT, CFLT, and NT patients were 59.2 ± 8.4, 48.8 ± 8.4, and 63.7 ± 16.6 kg, respectively (P = 0.001* [asterisk means that statistical test is significant]), and the PSZ C0 exposures for these patients were 1.9 ± 1.5, 1.1 ± 0.8, and 2.4 ± 1.8 mg/liter, respectively (P < 0.00001*). More than 60% of the concentrations were in the therapeutic range. In CFLT patients, the administration of one 300-mg PSZ tablet quickly achieved an exposure similar to that achieved with the PSZ oral suspension formulation (OSF) administered 3 or 4 times a day for several months. The TRL C0/dose ratio (C0/D) was 7.4 ± 4.4 mg/liter with PSZ tablets, whereas it was 4.6 ± 0.8 mg/liter with the PSZ oral solution (P = 0.034*). The ERL C0/D was similar with both formulations. PPI had no impact on the PSZ concentration (1.49 ± 1.07 mg/liter without PPI versus 1.33 ± 1.17 mg/liter with PPI; P = 0.4134*). Despite the high levels of exposure, PSZ remained well tolerated (one case of diarrhea and one case of fatigue were reported). PSZ tablet administration allows satisfactory exposure, even in CFLT patients, with a dosage lower than that of the PSZ OSF. This once-a-day formulation was not impacted by PPI, which are extensively used in CF patients.

Omalizumab treatment for allergic bronchopulmonary aspergillosis in young patients with cystic fibrosis.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is a severe lung disease complication caused by an Aspergillus fumigatus-induced hypersensitivity that affects 2-15% of patients with cystic fibrosis (CF). The mainstay treatment consists of a combination of corticosteroids and antifungals. However, repeated or long-term corticosteroid therapies can lead to serious side effects. The monoclonal anti-IgE antibody, omalizumab, has demonstrated its efficacy in allergic asthma. As ABPA results from a hypersensitivity to a specific allergen, omalizumab might benefit CF patients with ABPA. Therefore, we conducted a retrospective study to investigate the effects of omalizumab on ABPA in CF patients. METHODS: We retrospectively analyzed the clinical records of young patients with CF treated with omalizumab for an ABPA in several French CF centers. The clinical data were collected 3 months before the start of omalizumab treatment, at initiation, and every 3 months up to 12 following initiation. These data comprised clinical, biological, nutritional, and functional parameters. RESULTS: Eighteen patients were included (mean age: 17.1 ± 5.2 yrs). Under omalizumab was observed a stabilization of the lung function decline associated with a significant decrease in the corticosteroid daily dose (p = 0.0007) and an improvement in the nutritional status (p = 0.01). No serious side effect of omalizumab was reported. CONCLUSIONS: This study suggests that omalizumab might be an interesting therapeutic strategy in ABPA, associated with less side effects compared to long-term corticosteroids. Further randomized-controlled trials are needed to ascertain the efficacy of omalizumab in CF patients with ABPA.