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BACKGROUND AND OBJECTIVE: Little is known about malignant central airway obstruction (MCAO) complicating the metastatic spread of non-bronchogenic solid cancers (NBC) and their bronchoscopic management. This study aimed to describe the epidemiology of this population and determine prognostic factors before therapeutic bronchoscopy (TB). METHODS: In this multicenter study using the EpiGETIF registry, we analysed patients treated with TB for MCAO caused by NBC between January 2019 and December 2022. RESULTS: From a database of 2389 patients, 436 patients (18%) with MCAO and NBC were identified. After excluding patients with direct local invasion, 214 patients (8.9%) were analysed. The main primaries involved were kidney (17.8%), colon (16.4%), sarcoma (15.4%), thyroid (8.9%) and head and neck (7.9%) cancers. Most patients (63.8%) had already received one or more lines of systemic treatment. Obstructions were purely intrinsic in 58.2%, extrinsic in 11.1% and mixed in 30.8%. Mechanical debulking was used in 73.4% of cases, combined with thermal techniques in 25.6% of cases. Airway stenting was required in 38.4% of patients. Median survival after TB was 11.2 months, influenced by histology (p = 0.002), performance status (p = 0.019), initial hypoxia (HR 1.45 [1.01-2.18]), prior oncologic treatment received (HR 1.82 [1.28-2.56], p < 0.001) and assessment of success at the end of the procedure (HR 0.66 [0.44-0.99], p < 0.001). Complications rate was 8.8%, mostly mild, with no procedure-related mortality. CONCLUSION: TB for MCAO caused by a NBC metastasis provides rapid improvement of symptoms and prolonged survival. Patients should be promptly referred by medical oncologists for bronchoscopic management based on the prognostic factors identified.
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Obstrucción de las Vías Aéreas , Broncoscopía , Sistema de Registros , Humanos , Broncoscopía/métodos , Masculino , Femenino , Obstrucción de las Vías Aéreas/etiología , Obstrucción de las Vías Aéreas/epidemiología , Persona de Mediana Edad , Anciano , Pronóstico , Neoplasias de Cabeza y Cuello/complicaciones , Neoplasias de Cabeza y Cuello/epidemiología , Neoplasias de Cabeza y Cuello/patologíaRESUMEN
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 4-6â 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.
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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 1â 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.
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Fibrosis Quística , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Dimetilsulfóxido , MutaciónRESUMEN
This study aimed to compare continuous glucose monitoring (CGM) in cystic fibrosis (CF) according to pancreatic exocrine status.CGM and oral glucose tolerance testing (OGTT) were realized annually over five years in people with CF (pwCF) aged≥10 years without cystic fibrosis-related diabetes (CFRD). CGM parameters in patients with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and newly diagnosed CFRD were compared according to presence of pancreatic sufficiency (PS) or insufficiency (PI).Overall, 547 OGTTs and 501 CGMs were performed in 147 CF patients, comprising 122 PI and 25 PS. In PS patients, 84% displayed NGT, 12% IGT, and 4% CFRD vs. 58%, 32%, and 10% (p=0.05) in PI. Among participants displaying normal OGTT, time in glucose range (70-140 mg/dl) was significantly increased, 97% (93, 99) vs. 92% (85, 96), p<0.001, and time above glucose range > 140 mg/dl significantly decreased, 1% (0, 2) % vs. 6% (2, 13), in patients with PS compared to those with PI. No significant differences were highlighted in patients with IGT.CGM revealed significant different glucose tolerance abnormalities in PI versus PS, which were undetected by standard 2-hour OGTT glucose.
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Fibrosis Quística , Diabetes Mellitus , Insuficiencia Pancreática Exocrina , Intolerancia a la Glucosa , Glucemia , Automonitorización de la Glucosa Sanguínea , Fibrosis Quística/complicaciones , Diabetes Mellitus/diagnóstico , Insuficiencia Pancreática Exocrina/complicaciones , Glucosa , Intolerancia a la Glucosa/diagnóstico , HumanosRESUMEN
Rationale: Lumacaftor-ivacaftor is a CFTR (cystic fibrosis transmembrane conductance regulator) modulator combination recently approved for patients with cystic fibrosis (CF) homozygous for the Phe508del mutation.Objectives: To evaluate the safety and effectiveness of lumacaftor-ivacaftor in adolescents (≥12 yr) and adults (≥18 yr) in a real-life postapproval setting.Methods: The study was conducted in the 47 CF reference centers in France. All patients who initiated lumacaftor-ivacaftor from January 1 to December 31, 2016, were eligible. Patients were evaluated for lumacaftor-ivacaftor safety and effectiveness over the first year of treatment following the French CF Learning Society's recommendations.Measurements and Main Results: Among the 845 patients (292 adolescents and 553 adults) who initiated lumacaftor-ivacaftor, 18.2% (154 patients) discontinued treatment, often owing to respiratory (48.1%, 74 patients) or nonrespiratory (27.9%, 43 patients) adverse events. In multivariable logistic regression, factors associated with increased rates of discontinuation included adult age group, percent predicted FEV1 (ppFEV1) less than 40%, and numbers of intravenous antibiotic courses during the year before lumacaftor-ivacaftor initiation. Patients with continuous exposure to lumacaftor-ivacaftor showed an absolute increase in ppFEV1 (+3.67%), an increase in body mass index (+0.73 kg/m2), and a decrease in intravenous antibiotic courses by 35%. Patients who discontinued treatment had significant decrease in ppFEV1, without improvement in body mass index or decrease in intravenous antibiotic courses.Conclusions: Lumacaftor-ivacaftor was associated with improvement in lung disease and nutritional status in patients who tolerated treatment. Adults who discontinued lumacaftor-ivacaftor, often owing to adverse events, were found at high risk of clinical deterioration.
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Aminofenoles/uso terapéutico , Aminopiridinas/uso terapéutico , Antibacterianos/uso terapéutico , Benzodioxoles/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Estado Nutricional , Quinolonas/uso terapéutico , Administración Intravenosa , Adolescente , Adulto , Índice de Masa Corporal , Espasmo Bronquial/inducido químicamente , Tos/inducido químicamente , Fibrosis Quística/fisiopatología , Deprescripciones , Combinación de Medicamentos , Disnea/inducido químicamente , Fatiga/inducido químicamente , Femenino , Volumen Espiratorio Forzado , Francia , Enfermedades Gastrointestinales/inducido químicamente , Cefalea/inducido químicamente , Humanos , Modelos Logísticos , Masculino , Metrorragia/inducido químicamente , Análisis Multivariante , Mialgia/inducido químicamente , Vigilancia de Productos Comercializados , Resultado del Tratamiento , Adulto JovenRESUMEN
The clinical and social impacts of the COVID-19 epidemic on lung transplant (LTx) recipients remain poorly known. We aimed to evaluate its social, clinical, and behavioral consequences on the LTx patients followed in Strasbourg university hospital. A questionnaire was used to collect details concerning patients' lifestyles, their protection methods used to avoid COVID-19 contamination, and clinical infection-related information for March 2020. A specific score was created to quantify patients' contacts and the associated risk of infectious contagion. Data were collected from 322 patients (91.2%). A majority reported a higher application than usual of social distancing and barrier measures. 43.8% described infectious-related symptoms and 15.8% needed an anti-infective treatment. There was no difference in symptom onset according to age, native lung disease, diabetes, or obesity. Nineteen patients were tested for COVID-19, and four were diagnosed positive, all with a favorable outcome. The infection risk contact score was higher for symptomatic patients (p: 0.007), those needing extra-medical appointments (p < .001), and those receiving anti-infective treatments (p = .02). LTx patients reported a careful lifestyle and did not seem at higher risk for COVID-19. Our score showed encouraging preliminary results and could become a useful tool for the usual infection-related follow-up of the LTx patients.
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COVID-19/etiología , Conductas Relacionadas con la Salud , Trasplante de Pulmón , Complicaciones Posoperatorias , Determinantes Sociales de la Salud , Receptores de Trasplantes/psicología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/diagnóstico , COVID-19/epidemiología , COVID-19/prevención & control , Trazado de Contacto , Epidemias , Femenino , Francia/epidemiología , Hospitales Universitarios , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Cooperación del Paciente/psicología , Cooperación del Paciente/estadística & datos numéricos , Distanciamiento Físico , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/prevención & control , Complicaciones Posoperatorias/psicología , Estudios Retrospectivos , Medición de Riesgo , Factores de Riesgo , Adulto JovenRESUMEN
BACKGROUND: The aim of our study was to describe the lung cancer characteristics in lung transplant recipients at our institution. METHODS: Between January 1, 1992, and August 15, 2017, 463 patients underwent lung transplantation. RESULTS: We found a total of 19 lung cancers (4.10%). Eight patients had lung cancer in the explanted lung, 8 in the native remaining lung, and 3 in the transplanted lung. Histopathological findings were: adenocarcinoma in 10, SCC in 8 patients, and 1 was undetermined. Among lung cancers in the explanted lungs, there were 6 stage I, 1 stage III, 1 stage IV. Among patients with a lung cancer in the remaining native lung, 3 had early stage disease and 5 had stage IV disease. Among lung cancers in the transplanted lung, there were: 1 stage I, 1 stage II and 1 stage IV. Overall median survival in lung transplant recipients without lung cancer was 8.77 ± 0.74 years compared to 6.19 ± 1.4 years in recipients with lung cancer. CONCLUSION: Lung cancer following lung transplantation was uncommon. Early stage lung cancer discovered in the explanted lungs had no impact on survival. Lung cancer occurring in the transplanted or in the native remaining lung had a poor prognosis.
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Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/etiología , Trasplante de Pulmón/efectos adversos , Anciano , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Factores de RiesgoRESUMEN
Cladophialophora bantiana brain abscesses are rare, but are frequently and quickly lethal in transplanted patients. We report the case of a 63-year-old man who had undergone lung transplantation for chronic obstructive pulmonary disease and presented with headaches and a neurological deficit. Magnetic resonance imaging revealed multiple brain abscesses. C. bantiana was identified by DNA sequencing performed directly on cerebral tissue obtained by surgical biopsy. After 6 months of antifungal treatment, the brain abscesses were replaced by ischemic sequelae. The patient died suddenly 2 months later from a pulmonary bacterial infection. This is the second reported case of C. bantiana brain abscesses in a lung transplant recipient, to our knowledge, who experienced a long survival period with medical antifungal treatment alone. We review the literature and discuss our treatment.
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Ascomicetos/aislamiento & purificación , Absceso Encefálico/microbiología , Trasplante de Pulmón/efectos adversos , Enfermedad Pulmonar Obstructiva Crónica/cirugía , Antifúngicos/uso terapéutico , Biopsia , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Absceso Encefálico/diagnóstico por imagen , Absceso Encefálico/tratamiento farmacológico , Absceso Encefálico/patología , Infecciones Fúngicas del Sistema Nervioso Central , Resultado Fatal , Humanos , Hifa/aislamiento & purificación , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Factores de TiempoRESUMEN
INTRODUCTION: The effects of cystic fibrosis (CF) on females' sexuality have not been described. The aims of the present study were to describe and characterize sexual issues in females with CF. METHODS: We included adult (≥18 years) females with CF currently or previously in a sexual relationship from 11 adult CF centres in France. We collected quantitative data using a modified version of the self-administered Pelvic Incontinence Sexual Questionnaire IUGA-Revised (PISQ-IR). We performed one-to-one interviews using a semi-directive framework in volunteer females to further characterize the effects of CF on sexual life. We summarized answers to questionnaire as percentages and analysed interviews by theme according to discourse analysis method. RESULTS: Between November 2019 and July 2021, 212 females completed the PISQR-IR, of whom 15 were interviewed. Of the females who completed the questionnaire, 93.4% were concerned about the discomfort, pain, or unpleasantness they experienced during sexual intercourse. The most frequent cause of sexual difficulties was a lack of vaginal lubrication (78.8%), followed by pain (74.1%) and discomfort. Interviews revealed sexual lives that were uncomfortable or painful, unsatisfying or avoided for most females, with a strong impression of being sexually different, incompetent, and betrayed by their bodies in terms of sexual desire. CONCLUSION: Sexual difficulties faced by females with CF are highly prevalent. Increasing awareness regarding sex life issues in females with CF appears necessary to improve their management by CF multidisciplinary teams.
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BACKGROUND: Cystic fibrosis related diabetes (CFRD) is commonly associated with declining lung function and nutritional status. We aimed to evaluate the pulmonary impact of early glucose abnormalities by using 2-h standard oral glucose tolerance testing (OGTT) and continuous glucose monitoring (CGM) in people with cystic fibrosis (PwCF). METHODS: PwCF aged ≥10 years old without known CFRD were included in a five-year prospective multicentre study. Annual evaluation of nutritional status, lung function, OGTT and CGM was set up. Associations between annual rate changes (Δ) in lung function, ΔFEV1 (forced expiratory volume in 1 s) percentage predicted (pp) and ΔFVC (forced vital capacity) pp., and annual rate changes in OGTT or CGM variables were estimated with a mixed model with a random effect for subject. RESULTS: From 2009 to 2016, 112 PwCF (age: 21 ± 11 years, BMI (body mass index) z-score: -0.55 ± 1.09, FEV1pp: 77 ± 24 %, 2-h OGTT glucose: 122 ± 44 mg/dL, AUC (area under curve) >140 mg/dL: 1 mg/dL/day (0.2, 3.0) were included. A total of 428 OGTTs and 480 CGMs were collected. The participants presented annual decline of FVCpp and FEV1pp at -1.0 % per year (-1.6, -0.4), p < 0.001 and - 1.9 % per year (-2.5, -1.3), p < 0.001 respectively without change in BMI z-score during the study. Variation of two-hour OGTT glucose was not associated with declining lung function, as measured by ΔFEV1pp (p = 0.94) and ΔFVCpp (p = 0.90). Among CGM variables, only increase in AUC >140 mg/dL between two annual visits was associated with a decrease in ΔFVCpp (p < 0.05) and ΔFEV1pp (p < 0.05). CONCLUSIONS: This prospective study supports the fact that early glucose abnormalities revealed by CGM predict pulmonary function decline in PwCF, while 2-h standard OGTT glucose is not associated with pulmonary impairment.
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Fibrosis Quística , Diabetes Mellitus , Intolerancia a la Glucosa , Humanos , Niño , Adolescente , Adulto Joven , Adulto , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Estudios Prospectivos , Glucemia , Intolerancia a la Glucosa/complicaciones , Intolerancia a la Glucosa/diagnóstico , Glucosa , Automonitorización de la Glucosa Sanguínea , Monitoreo Continuo de Glucosa , Diabetes Mellitus/diagnóstico , PulmónRESUMEN
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.
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BACKGROUND: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare but serious dermatologic diseases. They can be associated with systemic manifestations such as bronchiolitis obliterans syndrome (BOS). SJS/TEN-induced BOS is associated with a poor prognosis, and no guidelines exist regarding its management. Several case reports have described the association between SJS/TEN and BOS, with few patients undergoing lung transplantation as a last resort therapy. Unfortunately, in the published reports, none of the transplanted patients were observed for a long period of time after the transplantation; therefore, the long-term mortality as well as the risk of recurrence of BOS could not be inferred from these reports. CASE REPORT: We present the case of a young patient diagnosed with SJS complicated by BOS and end-stage respiratory failure refractory to corticosteroid therapy. She underwent bilateral lung transplantation with an outstanding outcome at 5-year follow-up. CONCLUSION: SJS/TEN-induced BOS might have a favorable evolution and long-term outcomes following lung transplantation. However, prospective studies are needed to confirm this finding.
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Bronquiolitis Obliterante/complicaciones , Insuficiencia Respiratoria/complicaciones , Síndrome de Stevens-Johnson/diagnóstico , Corticoesteroides/uso terapéutico , Bronquiolitis Obliterante/etiología , Niño , Epidermis/patología , Femenino , Estudios de Seguimiento , Volumen Espiratorio Forzado , Humanos , Trasplante de Pulmón , Insuficiencia Respiratoria/cirugía , Síndrome de Stevens-Johnson/etiología , Capacidad VitalRESUMEN
Epigenetic changes, including miRNAs deregulation, have been suggested to play a significant role in development of obliterative bronchiolitis (OB) in transplanted lungs. Many studies have tried to identify ideal candidate miRNAs and the downstream pathways implicated in the bronchiolar fibro-obliterative process. Several candidate miRNAs, previously indicated as possibly being associated with OB, were analyzed by combining the quantitative real time-polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH) of lung tissues of OB affected patients. Disease and OB-lesion-specific expression of miR-21-5p was confirmed and by computational analysis we were able to identify the network of genes most probably associated miR-21-5p in the context of OB fibrogenesis. Among all potentially associated genes, STAT3 had a very high probability score. Immunohistochemistry showed that STAT3/miR-21-5p were co-over expressed in OB lesions, thus, suggesting miR-21-5p could regulate STAT3 expression. However, miR-21-5p inhibition in cultures of bronchiolitis obliterans syndrome (BOS) derived myofibroblasts did not significantly affect STAT3 mRNA and protein expression levels. This study demonstrates the specificity of miR-21-5p over-expression in OB lesions and contributes to existing knowledge on the miR-21-5p downstream pathway. Activation of STAT3 is associated with miR-21-5p upregulation, however, STAT-3 network activation is most likely complex and miR-21-5p is not the sole regulator of STAT3.
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Bronquiolitis Obliterante/genética , Bronquiolitis Obliterante/metabolismo , Trasplante de Pulmón , MicroARNs/genética , Adolescente , Adulto , Anciano , Femenino , Humanos , Pulmón/metabolismo , Trasplante de Pulmón/métodos , Masculino , Persona de Mediana Edad , Factor de Transcripción STAT3/genética , Regulación hacia Arriba , Adulto JovenRESUMEN
BACKGROUND: Phase 3 trials have demonstrated the safety and efficacy of lumacaftor-ivacaftor (LUMA-IVA) in patients with cystic fibrosis (CF) homozygous for the Phe508del CFTR mutation and percent predicted forced expiratory volume in 1 s (ppFEV1) between 40 and 90. Marketing authorizations have been granted for patients at all levels of ppFEV1. METHODS: To evaluate the safety and effectiveness of LUMA-IVA over the first year of treatment in patients with ppFEV1<40 or ppFEV1≥90 in comparison with those with ppFEV1 [40-90[. Analysis of data collected during a real world study, which included all patients aged ≥12 years who started LUMA-IVA in 2016 across all 47 French CF centers. RESULTS: 827 patients were classified into 3 subgroups according to ppFEV1 at treatment initiation (ppFEV1<40, n = 121; ppFEV1 [40-90[, n = 609; ppFEV1≥90, n = 97). Treatment discontinuation rate was higher in ppFEV1<40 patients (28.9%) than in those with ppFEV1 [40-90[(16.4%) or ppFEV1≥90 (17.5%). In patients with uninterrupted treatment, significant increase in ppFEV1 occurred in the ppFEV1 [40-90[subgroup (+2.9%, P<0.001), and in those ppFEV1<40 (+0.5%, P = 0.03) but not in those with ppFEV1≥90 (P = 0.46). Compared with the year prior to initiation, the number of days of intravenous antibiotics were reduced in all subgroups, although 72% of patients with ppFEV1<40 still experienced at least one exacerbation/year under LUMA-IVA. Comparable increase in body mass index was seen in the three subgroups. CONCLUSION: Phe508del homozygous CF patients benefit from LUMA-IVA at all levels of baseline lung function, but the characteristics and magnitude of the response vary depending on ppFEV1 at baseline.
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Aminofenoles/uso terapéutico , Aminopiridinas/uso terapéutico , Benzodioxoles/uso terapéutico , Agonistas de los Canales de Cloruro/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Quinolonas/uso terapéutico , Adolescente , Adulto , Progresión de la Enfermedad , Combinación de Medicamentos , Femenino , Francia , Humanos , Masculino , Pruebas de Función RespiratoriaRESUMEN
INTRODUCTION: The cystic fibrosis (CF) clinical profile and associated CFTR mutation spectrum is poorly understood in the South Asian population. This is likely due to the lack of diagnostic resources and the absence of a centralised CF database and screening programme, despite a relatively large proportion of the global population. METHODS: Following identification of a previously unreported CFTR mutation (c.2805_2810delinsTCAGA; p.(Pro936Ginfs*6)) in a newly diagnosed patient of Indian descent, we interrogated national registries for other cases. RESULTS: We identified three European-born subjects of South Asian descent with CF due to a novel CFTR mutation. All three subjects presented in infancy and each had a severe phenotype with intestinal complications as a presenting feature. Two subjects were diagnosed prior to the advent of universal screening. Preliminary genetic screening failed to identify the causative mutation in all three patients. CONCLUSION: Our work highlights the value of extended or targeted genotyping in selected populations. It also demonstrates the benefit of routine collaboration between national registries. This will promote the identification of novel mutations; leading to greater understanding of genotype-phenotype associations, improved individual prognostication and ultimately the improved availability of novel precision therapies. This collaboration is essential if we are to achieve health equality for people with CF living in resource-limited settings.
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Pueblo Asiatico/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/genética , Adolescente , Adulto , Fibrosis Quística/complicaciones , Fibrosis Quística/diagnóstico , Fibrosis Quística/patología , Insuficiencia Pancreática Exocrina/diagnóstico , Insuficiencia Pancreática Exocrina/etiología , Femenino , Estudios de Asociación Genética , Pruebas Genéticas/normas , Genotipo , Humanos , Lactante , Obstrucción Intestinal/diagnóstico , Obstrucción Intestinal/etiología , Obstrucción Intestinal/cirugía , Masculino , Íleo Meconial/diagnóstico , Íleo Meconial/etiología , Íleo Meconial/cirugía , Mutación , Fenotipo , Sudor/químicaRESUMEN
Long term survival post lung transplantation (LTx) is limited by the occurrence of bronchiolitis obliterans syndrome (BOS). One mechanism involved is the epithelial-mesenchymal transition (EMT). Membrane microparticles (MPs) are known to be involved in some respiratory diseases and in other organs allograft rejection episodes. We hypothesized that leukocyte-derived MPs likely contribute to EMT. To emphasize this physiological concept, our objectives were to: (1) confirm the presence of EMT on explanted lungs from patients who underwent a second LTx for BOS; 2) characterize circulating MPs in transplanted patients, with or without BOS; (3) evaluate in vitro the effect of monocyte-derived MPs in EMT of human bronchial epithelial cells. Our IHC analysis on explanted graft lungs revealed significant pathological signs of EMT with an inhomogeneous destruction of the bronchial epithelium, with decreased expression of the epithelial protein E-cadherin and increased expression of the mesenchymal protein Vimentin. The immunophenotyping of MPs demonstrated that the concentration of MPs carrying E-cadherin was lower in patients affected by BOS (p = .007). In vitro, monocyte-derived MPs produced with LPS were associated with decreased E-cadherin expression (p < .05) along with significant morphological and functional cell modifications. MPs may play a role in EMT onset in bronchial epithelium following LTx.
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Bronquiolitis Obliterante/metabolismo , Micropartículas Derivadas de Células/metabolismo , Trasplante de Pulmón , Pulmón/patología , Monocitos/metabolismo , Complicaciones Posoperatorias/metabolismo , Mucosa Respiratoria/metabolismo , Adulto , Bronquiolitis Obliterante/etiología , Bronquiolitis Obliterante/patología , Cadherinas/metabolismo , Regulación hacia Abajo , Transición Epitelial-Mesenquimal , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/patología , Complicaciones Posoperatorias/patología , Mucosa Respiratoria/patologíaRESUMEN
BACKGROUND Although central airway stenosis (CAS) is a common complication after lung transplantation, its consequences have been poorly evaluated. The objective of our study was to evaluate the impact of CAS on lung function after lung transplantation. MATERIAL AND METHODS All lung transplant recipients from June 2009 to August 2014 in a single center (Strasbourg, France) were retrospectively reviewed. RESULTS A total of 191 lung transplantations were performed: 175 bilateral, 15 single, and 1 heart-lung transplantation. Of the 161 bilateral lung-transplanted patients who survived >3 months, 22 (13.6%) developed CAS requiring endobronchial treatment. All these patients were treated by endoscopic balloon dilatation, and 9 additionally needed endobronchial stents. Respiratory function tests demonstrated persistent obstructive ventilatory pattern despite endoscopic treatment in recipients with CAS compared to those without CAS at 6, 12, and 18 months post-transplant. At 18 months, CAS patients had significantly lower post-transplant FEV1 (1.96±0.60 L versus 2.57±0.76 L, p=0.001) and FEV1/FVC (61±14% versus 81±13%, p<0.001). The percentage of patients hospitalized for respiratory infections and number of hospital days were significantly increased in recipients with CAS (20 [91%] versus 92 [66%] p=0.036, and 144±110 days versus 103±83 days p=0.042, respectively). Survival in transplant recipients did not significantly differ between those with CAS and those without. CONCLUSIONS CAS after lung transplantation was not associated with worse survival, but it did have a significant and persistent effect on lung function, and was associated with increased rate of respiratory infection.