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BACKGROUND: Outcomes for individuals with cystic fibrosis (CF) have improved due to highly effective modulator therapy (HEMT). However, lung transplant (LTx) remains an important treatment for people with advanced lung disease. This study assessed attitudes and knowledge about LTx in the HEMT era. METHODS: All patients from the University of Washington CF clinic were surveyed March 25-May 30, 2020. Questions addressed self-rated LTx preparedness and knowledge, as well as barriers and facilitators to discussing LTx. Demographic and clinical data were extracted from the electronic health record. RESULTS: There were 159/224 (71%) responses. Respondents had a median forced expiratory volume in one second (FEV1) of 70%, and 142 (89%) were on modulatory therapy. One hundred thirteen (71%) respondents felt that it was moderately or very important to be prepared to make decisions about LTx, though only 56 (35%) felt moderately or very prepared. Only 83 (30%) and 47 (52%) participants correctly answered questions about life expectancy and improved quality of life after LTx, respectively. Respondents with Medicaid insurance less frequently answered questions correctly. The most common barriers to discussing LTx were fear of being a burden on loved ones for 58 respondents (36%) and cost of LTx for 46 (29%). Most participants (94%) trusted their CF doctor, and 75% of participants selected trust as a facilitator for LTx discussions. CONCLUSIONS: Many individuals with CF, especially those with lower socioeconomic status, lacked knowledge and did not feel very prepared for decisions about LTx. Earlier education and discussions about LTx represent an area for improvement in CF care.
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Fibrosis Quística , Conocimientos, Actitudes y Práctica en Salud , Trasplante de Pulmón , Humanos , Fibrosis Quística/cirugía , Fibrosis Quística/psicología , Masculino , Femenino , Adulto , Encuestas y Cuestionarios , Calidad de Vida , Persona de Mediana Edad , Adulto JovenRESUMEN
Elexacaftor/tezacaftor/ivacaftor (ETI) has made a substantial positive impact for people living with CF (pwCF). However, there can be substantial variability in efficacy, and we lack adequate biomarkers to predict individual response. We thus aimed to identify transcriptomic profiles in nasal respiratory epithelium that predict clinical response to ETI treatment. We obtained nasal epithelial samples from pwCF prior to ETI initiation and performed a transcriptome-wide analysis of baseline gene expression to predict changes in FEV1 (∆FEV1), year's best FEV1 (∆ybFEV1), and body mass index (∆BMI). Using the top differentially expressed genes (DEGs), we generated transcriptomic risk scores (TRS) and evaluated their predictive performance. The study included 40 pwCF aged ≥6 years (mean 27.7 [SD=15.1] years; 40% female). After ETI initiation, FEV1 improved ≥5% in 22 (61.1%) participants and ybFEV1 improved ≥5% in 19 (50%). TRS were constructed using top over-expressed and under-expressed genes for each. Adding the ∆FEV1 TRS for to a model with age, sex, and baseline FEV1 increased the AUC from 0.41 to 0.88; the ∆ybFEV1 TRS increased the AUC from 0.51 to 0.88; and the ∆BMI TRS increased the AUC from 0.46 to 0.92. Average accuracy was thus ~85% in predicting the response to the three outcomes. Results were similar in models further adjusted for F508del zygosity and previous CFTR modulator use. In conclusion, we identified nasal epithelial transcriptomic profiles that help accurately predict changes in FEV1 and BMI with ETI treatment. These novel TRS could serve as predictive biomarkers for clinical response to modulator treatment in pwCF.
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Many people with CF (pwCF) desire a reduction in inhaled treatment burden after initiation of elexacaftor/tezacaftor/ivacaftor. The randomized, open-label SIMPLIFY study showed that discontinuing hypertonic saline (HS) or dornase alfa (DA) was non-inferior to continuation of each treatment with respect to change in lung function over a 6-week period. In this SIMPLIFY substudy, we used gamma scintigraphy to determine whether discontinuation of either HS or DA was associated with deterioration in the rate of in vivo mucociliary clearance (MCC) in participants ≥12 years of age. While no significant differences in MCC endpoints were associated with HS discontinuation, significant improvement in whole and peripheral lung MCC was observed after discontinuing DA. These results suggest that pwCF on ETI with mild lung disease do not experience a subclinical deterioration in MCC that could later impact health outcomes after discontinuing HS, and in fact may benefit from improved MCC after stopping DA treatment.
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Aminofenoles , Benzodioxoles , Fibrosis Quística , Desoxirribonucleasa I , Indoles , Depuración Mucociliar , Pirazoles , Quinolonas , Humanos , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/fisiopatología , Depuración Mucociliar/efectos de los fármacos , Masculino , Benzodioxoles/uso terapéutico , Femenino , Solución Salina Hipertónica/administración & dosificación , Aminofenoles/uso terapéutico , Desoxirribonucleasa I/uso terapéutico , Desoxirribonucleasa I/administración & dosificación , Indoles/uso terapéutico , Quinolonas/uso terapéutico , Adulto , Adolescente , Pirazoles/uso terapéutico , Proteínas Recombinantes/administración & dosificación , Pirroles/administración & dosificación , Resultado del Tratamiento , Piridinas/uso terapéutico , Adulto Joven , Agonistas de los Canales de Cloruro/uso terapéutico , Combinación de Medicamentos , Niño , Pruebas de Función Respiratoria , PirrolidinasRESUMEN
BACKGROUND: The cystic fibrosis transmembrane conductance regulator (CFTR) modulator elexacaftor/tezacaftor/ivacaftor (E/T/I) is highly effective clinically for those with at least one F508del-CFTR allele. The effects of E/T/I on mucociliary clearance (MCC) and sputum properties are unknown. We, therefore, sought to characterize the effects of E/T/I on in vivo MCC and sputum characteristics hypothesized to impact mucus transport. METHODS: Forty-four participants ≥12 years of age were enrolled into this prospective, observational trial prior to initiation of E/T/I and had baseline measurement of MCC and characterization of induced sputum and exhaled breath condensate (EBC) samples. Study procedures were repeated after 1 month of E/T/I treatment. RESULTS: Average age was 27.7 years with baseline forced expiratory volume in 1 second (FEV1) of 78.2 % predicted. 52 % of subjects had previously been treated with a 2-drug CFTR modulator combination. The average whole lung MCC rate measured over 60 min (WLAveClr60) significantly improved from baseline to post-E/T/I (14.8 vs. 22.8 %; p = 0.0002), as did other MCC indices. Sputum% solids also improved (modeled mean 3.4 vs. 2.2 %; p<0.0001), whereas non-significant reductions in sputum macrorheology (G', G") were observed. No meaningful changes in exhaled breath condensate endpoints (sialic acid:urea ratio, pH) were observed. CONCLUSIONS: E/T/I improved the hydration of respiratory secretions (% solids) and markedly accelerated MCC. These data confirm the link between CFTR function, mucus solid content, and MCC and help to define the utility of MCC and mucus-related bioassays in future efforts to restore CFTR function in all people with CF.
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Fibrosis Quística , Indoles , Pirazoles , Piridinas , Pirrolidinas , Quinolonas , Humanos , Adulto , Fibrosis Quística/diagnóstico , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Depuración Mucociliar , Estudios Prospectivos , Aminofenoles/uso terapéutico , Benzodioxoles/uso terapéutico , Moco , Mutación , Agonistas de los Canales de Cloruro/uso terapéuticoRESUMEN
People with CF (PwCF), particularly those with advanced lung disease (ALD), experience frequent respiratory symptoms. A major CF breakthrough was the approval of elexacaftor/tezacaftor/ivacaftor (ETI) in 2019, which has been shown to improve symptoms and lung function in the CF population, and decrease pulmonary exacerbations. The purpose of this study was to analyze longitudinal changes in respiratory symptoms over 24 months in ETI-treated and untreated PwCF with ALD Symptoms were measured among CF adults with ppFEV1 < 40% (N = 48, 24 ETI-treated, 24 untreated) using the CFRSD-CRISS and the CFQ-R [respiratory]. Two multilevel growth models assessed the rate of change in symptoms overall and within the ETI-treated and untreated groups. PwCF on ETI had significantly lower symptom severity over 24 months than those not on ETI as measured by the CRISS and CFQ-R. The ETI-treated group maintained an -11.7 and +19.3 point difference(p<0.01) in CRISS and CFQ-R scores over the study compared to the non-ETI group, achieving minimal clinically important differences on average between groups on both instruments. No change in the symptom burden trajectory between groups was observed (p = 0.58). Even with ALD, ETI-treated PwCF have a lower respiratory burden than those not on ETI. This may be confounded by survivorship bias in the non-ETI group. Of note, in this ALD cohort, neither instrument demonstrated ceiling effects. Our results suggest that, while ETI has significantly improved the lived experience, PwCF with ALD are still plagued by respiratory symptoms.
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Fibrosis Quística , Pirrolidinas , Adulto , Humanos , Fibrosis Quística/complicaciones , Fibrosis Quística/tratamiento farmacológico , Pirazoles , Piridinas , Pulmón , Regulador de Conductancia de Transmembrana de Fibrosis Quística , Mutación , Aminofenoles , Benzodioxoles/uso terapéuticoRESUMEN
BACKGROUND: Chronic rhinosinusitis (CRS) is common in individuals with cystic fibrosis (CF) and is marked by chronic inflammation and episodes of infection that negatively impact quality of life. Several studies have shown that elexacaftor-tezacaftor-ivacaftor (ETI) improves symptoms and examination findings in CF-CRS. The current study determines the effect of ETI on the sinonasal microbiota in CF. METHODS: Sinonasal samples were collected under endoscopic visualization before and after starting ETI. Samples were subjected to 16S amplicon sequencing and sequences were processed with the QIIME2 pipeline with subsequent analysis using the vegan R-package. RESULTS: Twenty-nine individual baseline samples and 23 sample pairs pre-/post-ETI were available. At baseline, the cohort had samples dominated by Staphylococcus, and alpha diversity was lower than that of a published reference set of individuals without sinonasal disease. Individuals with prior sinus surgery had lower alpha diversity as measured by Shannon Index, Observed Richness, and Faith's phylogenetic diversity Index. Beta diversity differed between individuals with and without allergic rhinitis, with higher Staphylococcus abundance in those with allergic rhinitis. No change in alpha or beta diversity was seen after a median of 9 months on ETI. With ETI, the Pseudomonas genus and the genus containing Burkholderia decreased in samples containing these taxa at baseline. Pseudomonas abundance decreased with treatment as measured by qPCR. Core sinonasal microbiome members Staphylococcus, Corynebacterium, and Streptococcus were unchanged, while Moraxella increased with ETI. CONCLUSIONS: Treatment with ETI leads to a reduction in Pseudomonas abundance within the sinonasal microbiome of individuals with Pseudomonas at baseline.
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Nearly one-half of patients with cystic fibrosis (CF) carry the homozygous F508del mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene but exhibit variable lung function phenotypes. How adaptive immunity influences their lung function remains unclear, particularly the serological antibody responses to antigens from mucoid Pseudomonas in sera from patients with CF with varying lung function. Sera from patients with CF with reduced lung function show higher anti-outer membrane protein I (OprI) immunoglobulin G1 (IgG1) titers and greater antibody-mediated complement deposition. Induction of anti-OprI antibody isotypes with complement activity enhances lung inflammation in preclinical mouse models. This enhanced inflammation is absent in immunized Rag2-/- mice and is transferrable to unimmunized mice through sera. In a CF cohort undergoing treatment with elexacaftor-tezacaftor-ivacaftor, the declination in anti-OprI IgG1 titers is associated with lung function improvement and reduced hospitalizations. These findings suggest that antibody responses to specific Pseudomonas aeruginosa (PA) antigens worsen lung function in patients with CF.
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Fibrosis Quística , Humanos , Animales , Ratones , Fibrosis Quística/genética , Pseudomonas , Pseudomonas aeruginosa , Pulmón , Inmunoglobulina GRESUMEN
BACKGROUND: People with cystic fibrosis (CF) are increasingly considering their reproductive goals. We developed MyVoice:CF, a web-based patient-centered reproductive decision support tool and assessed its implementation in CF care. METHODS: We conducted a feasibility trial among 18-44-year-old women with CF and multidisciplinary CF providers. Prior to CF clinic visit, patient participants completed a baseline survey, used MyVoice:CF, and assessed acceptability, appropriateness, and usability. After clinic, participants rated impact on reproductive health communication. At 3 months post-use, participants assessed impact on reproductive health outcomes. Provider participants completed a survey and focus group regarding MyVoice:CF feasibility/implementation. We assessed outcomes descriptively. We compared MyVoice:CF's impact on outcomes from baseline to follow-up using McNemar's and Wilcoxon signed rank tests as appropriate. RESULTS: Forty-three patient participants completed baseline surveys and 40 rated MyVoice:CF's feasibility; 10 providers participated. Patient participants rated MyVoice:CF's acceptability as 4.48±0.50 out of 5, appropriateness as 4.61±0.48 out of 5, and usability as 82.25±11.02 ('A'/excellent). After MyVoice:CF use, participants reported improved reproductive health communication self-efficacy vs. baseline (3.54±1.17vs.3.95±0.93, p<0.001). At baseline, 36% of participants reported any discussion of reproductive goals/plans with their CF team in the past year compared to 59% after first visit post-MyVoice:CF use (p=0.049). Provider participants similarly rated MyVoice:CF as feasible and reported no negative impacts on clinic flow after implementation. CONCLUSIONS: MyVoice:CF is acceptable, appropriate, and usable for those with CF. Preliminary effectiveness evaluation suggests that MyVoice:CF improves self-efficacy in and frequency of reproductive health communication. Future studies should further assess MyVoice:CF's impact on reproductive health communication and outcomes.
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The growing use of modulator therapies aimed at restoring cystic fibrosis transmembrane conductance regulator (CFTR) protein function in people with cystic fibrosis has fundamentally altered clinical trial strategies needed to advance new therapeutics across an orphan disease population that is now divided by CFTR modulator eligibility. The development of a robust pipeline of nucleic acid-based therapies (NABTs)-initially directed towards the estimated 10% of the cystic fibrosis population who are genetically ineligible for, or intolerant of, CFTR modulators-is dependent on the optimisation of restricted trial participant resources across multiple development programmes, a challenge that will preclude the use of gold standard placebo-controlled trials. Advancement of a full pipeline of symptomatic therapies across the entire cystic fibrosis population will be challenged by smaller effect sizes and uncertainty regarding their clinical importance in a growing modulator-treated population with more mild and stable pulmonary disease. In this Series paper, we aim to lay the foundation for clinical trial strategy and community partnership that must deviate from established and familiar precedent to advance the future pipeline of cystic fibrosis therapeutics.
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Fibrosis Quística , Humanos , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Terapia Genética , Calidad de Vida , MutaciónRESUMEN
Idiopathic pulmonary fibrosis lung transplant recipients (IPF-LTRs) are enriched for short telomere length (TL) and telomere gene rare variants. A subset of patients with nontransplant short-TL are at increased risk for bone marrow (BM) dysfunction. We hypothesized that IPF-LTRs with short-TL and/or rare variants would be at increased risk for posttransplant hematologic complications. Data were extracted from a retrospective cohort of 72 IPF-LTRs and 72 age-matched non-IPF-LTR controls. Genetic assessment was done using whole genome sequencing or targeted sequence panel. TL was measured using flow cytometry and fluorescence in-situ hybridization (FlowFISH) and TelSeq software. The majority of the IPF-LTR cohort had short-TL, and 26% of IPF-LTRs had rare variants. Compared to non-IPF controls, short-TL IPF-LTRs were more likely to have immunosuppression agents discontinued due to cytopenias (P = .0375), and BM dysfunction requiring BM biopsy was more prevalent (29% vs 4%, P = .0003). IPF-LTRs with short-TL and rare variants had increased requirements for transfusion and growth factor support. Multivariable logistic regression demonstrated that short-TL, rare variants, and lower pretransplant platelet counts were associated with BM dysfunction. Pretransplant TL measurement and genetic testing for rare telomere gene variants identified IPF-LTRs at increased risk for hematologic complications. Our findings support stratification for telomere-mediated pulmonary fibrosis in lung transplant candidates.
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Fibrosis Pulmonar Idiopática , Telomerasa , Humanos , Estudios Retrospectivos , Receptores de Trasplantes , Telomerasa/genética , Telomerasa/metabolismo , Pulmón/metabolismo , Fibrosis Pulmonar Idiopática/genética , Fibrosis Pulmonar Idiopática/cirugía , Fibrosis Pulmonar Idiopática/patología , Telómero/genética , Telómero/metabolismo , Telómero/patologíaRESUMEN
OBJECTIVES: Systemic sclerosis (SSc) has the highest mortality rate among the rheumatic diseases, with lung fibrosis leading as the cause of death. A characteristic of severe SSc-related lung fibrosis is its progressive nature. Although most research has focused on the pathology of the fibrosis, the mechanism mediating the fibrotic spread remains unclear. We hypothesized that extracellular vesicle (EV) communication drives the propagation of SSc lung fibrosis. METHODS: EVs were isolated from normal (NL) or SSc-derived human lungs and primary lung fibroblasts (pLFs). EVs were also isolated from human fibrotic lungs and pLFs induced experimentally with transforming growth factor-ß (TGFß). Fibrotic potency of EVs was assessed using functional assays in vitro and in vivo. Transmission electron microscopy, nanoparticle tracking analysis, real-time quantitative polymerase chain reaction (RT-qPCR), immunoblotting, and immunofluorescence were used to analyze EVs, their cargo, extracellular matrix (ECM) fractions, and conditioned media. RESULTS: SSc lungs and pLFs released significantly more EVs than NL lungs, and their EVs showed increased fibrotic content and activity. TGFß-stimulated NL lung cores and pLFs increased packaging of fibrotic proteins, including fibronectin, collagens, and TGFß, into released EVs. The EVs induced a fibrotic phenotype in recipient pLFs and in vivo in mouse lungs. Furthermore, EVs interacted with and contributed to the ECM. Finally, suppressing EV release in vivo reduced severity of murine lung fibrosis. CONCLUSIONS: Our findings highlight EV communication as a novel mechanism for propagation of SSc lung fibrosis. Identifying therapies that reduce EV release, activity, and/or fibrotic cargo in SSc patient lungs may be a viable therapeutic strategy to improve fibrosis.
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Vesículas Extracelulares , Fibrosis Pulmonar , Esclerodermia Sistémica , Humanos , Animales , Ratones , Fibrosis Pulmonar/patología , Transducción de Señal , Esclerodermia Sistémica/patología , Fibrosis , Pulmón/patología , Factor de Crecimiento Transformador beta/metabolismo , Vesículas Extracelulares/patología , Fibroblastos/metabolismoRESUMEN
BackgroundNeutropenia is a common complication in lung transplant recipients (LTRs). Filgrastim may be used to treat neutropenia in LTRs, but its consequences on acute cellular rejection (ACR) remain controversial. Objective: The purpose was to examine the association between filgrastim and incidence of ACR 6 months after filgrastim administration in LTRs. Secondary outcomes included burden of ACR, infections, chronic lung allograft dysfunction (CLAD), and survival. Methods: This was a matched cohort study of patients transplanted between January 2010 and October 2019. LTRs who received filgrastim for neutropenia were compared to a cohort who did not. LTRs were matched on transplant indication, sex, age, and time post-transplant and multivariable logistic regression models were used to evaluate the likelihood of ACR. Results: 212 patients were included in the analysis (106 in each group). 50 patients (47.2%) in the filgrastim group experienced ACR compared to 37 patients (34.9%) in the no filgrastim group (P = .070). In multivariable analysis, filgrastim use was not associated with ACR at 6 months (OR 1.409, 95% CI 0.772-2.571). Time to first ACR was shorter (P = .049) and 6-month ACR score was higher in the filgrastim group (.49 vs .33, P = .047). LTRs in the filgrastim group had higher incidence of bacterial pneumonia and 1-year mortality. Conclusions: Although not associated with increased likelihood of ACR at 6 months, our study found that filgrastim is associated with increased ACR burden and decreased time to ACR. This study can help inform clinicians of ACR risk after filgrastim use in LTRs.
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BACKGROUND: Chronic lung allograft dysfunction (CLAD) remains a major cause of death after the first year posttransplant, with acute cellular rejection (ACR) being a major risk factor for CLAD. We evaluated the use of rabbit antithymocyte globulin (rATG) for corticosteroid refractory ACR in lung transplant recipients. METHODS: We retrospectively identified 112 adult lung transplant recipients who received rATG for refractory ACR after lung transplantation. The primary endpoint was the incidence of ACR on follow-up transbronchial biopsy. Secondary endpoints included freedom from ACR within 1 y post-rATG, CLAD progression at 1 y post-rATG, and all-cause mortality at 1 y post-rATG. RESULTS: A complete resolution of ACR was observed in 60.2% of patients, an improvement but not complete resolution in 22.1%, and no response on follow-up biopsy in 17.8%. Mean A grade 1 y post-rATG was 0.51 in complete responders, 1.01 in partial responders, and 2.19 in nonresponders ( P < 0.001). Complete responders had significantly less new or worsening CLAD at 1 y than partial responders (17% versus 40%; P = 0.02). All-cause mortality rate was 14.9% in complete responders, 40% in partial responders, and 30% in nonresponders ( P < 0.01). CONCLUSIONS: rATG appears to be an effective treatment of refractory ACR in lung transplant recipients. Failure to respond to rATG carries an increased risk of early CLAD and death.
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Inmunosupresores , Trasplante de Pulmón , Inmunosupresores/efectos adversos , Estudios Retrospectivos , Suero Antilinfocítico/uso terapéutico , Corticoesteroides/uso terapéutico , Trasplante de Pulmón/efectos adversos , Rechazo de Injerto/etiologíaRESUMEN
BACKGROUND: There is increased interest in bacteriophage (phage) therapy to treat infections caused by antibiotic-resistant bacteria. A lung transplant recipient with cystic fibrosis and Burkholderia multivorans infection was treated with inhaled phage therapy for 7 days before she died. METHODS: Phages were given via nebulization through the mechanical ventilation circuit. Remnant respiratory specimens and serum were collected. We quantified phage and bacterial deoxyribonucleic acid (DNA) using quantitative polymerase chain reaction, and tested phage neutralization in the presence of patient serum. We performed whole genome sequencing and antibiotic and phage susceptibility testing on 15 B. multivorans isolates. Finally, we extracted lipopolysaccharide (LPS) from two isolates and visualized their LPS using gel electrophoresis. RESULTS: Phage therapy was temporally followed by a temporary improvement in leukocytosis and hemodynamics, followed by worsening leukocytosis on day 5, deterioration on day 7, and death on day 8. We detected phage DNA in respiratory samples after 6 days of nebulized phage therapy. Bacterial DNA in respiratory samples decreased over time, and no serum neutralization was detected. Isolates collected between 2001 and 2020 were closely related but differed in their antibiotic and phage susceptibility profiles. Early isolates were not susceptible to the phage used for therapy, while later isolates, including two isolates collected during phage therapy, were susceptible. Susceptibility to the phage used for therapy was correlated with differences in O-antigen profiles of an early versus a late isolate. CONCLUSIONS: This case of clinical failure of nebulized phage therapy highlights the limitations, unknowns, and challenges of phage therapy for resistant infections.
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Infecciones por Burkholderia , Complejo Burkholderia cepacia , Fibrosis Quística , Terapia de Fagos , Femenino , Humanos , Antibacterianos/uso terapéutico , Infecciones por Burkholderia/tratamiento farmacológico , Fibrosis Quística/microbiología , ADN/uso terapéutico , Leucocitosis/tratamiento farmacológico , Lipopolisacáridos/uso terapéutico , Pulmón/microbiología , Receptores de Trasplantes , Resultado Fatal , AdultoRESUMEN
There is no consensus on the best model of care for individuals with CF to manage the non-pulmonary complications that persist after lung transplant. The CF Foundation virtually convened a group of international experts in CF and lung-transplant care. The committee reviewed literature and shared the post-lung transplant model of care practiced by their programs. The committee then developed a survey that was distributed internationally to both the clinical and individual with CF/family audiences to determine the strengths, weaknesses, and preferences for various models of transplant care. Discussion generated two models to accomplish optimal CF care after transplant. The first model incorporates the CF team into care and proposes delineation of responsibilities for the CF and transplant teams. This model is reliant on outstanding communication between the teams, while leveraging the expertise of the CF team for management of the non-pulmonary manifestations of CF. The transplant team manages all aspects of the transplant, including pulmonary concerns and management of immunosuppression. The second model consolidates care in one center and may be more practical for transplant programs that have expertise managing CF and have access to CF multidisciplinary care team members (e.g., located in the same institution). The best model for each program is influenced by several factors and model selection needs to be decided between the transplant and the CF center and may vary from center to center. In either model, CF lung transplant recipients require a clear delineation of the roles and responsibilities of their providers and mechanisms for effective communication.
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Fibrosis Quística , Trasplante de Pulmón , Humanos , Fibrosis Quística/cirugía , Fibrosis Quística/complicaciones , Trasplante de Pulmón/efectos adversos , Receptores de Trasplantes , Encuestas y Cuestionarios , ConsensoRESUMEN
Systemic sclerosis (SSc) is a connective tissue disorder that results in fibrosis of the skin and visceral organs. SSc-associated pulmonary fibrosis (SSc-PF) is the leading cause of death amongst SSc patients. Racial disparity is noted in SSc as African Americans (AA) have a higher frequency and severity of disease than European Americans (EA). Using RNAseq, we determined differentially expressed genes (DEGs; q < 0.1, log2FC > |0.6|) in primary pulmonary fibroblasts from SSc lungs (SScL) and normal lungs (NL) of AA and EA patients to characterize the unique transcriptomic signatures of AA-NL and AA-SScL fibroblasts using systems-level analysis. We identified 69 DEGs in "AA-NL vs. EA-NL" and 384 DEGs in "AA-SScL vs. EA-SScL" analyses, and a comparison of disease mechanisms revealed that only 7.5% of DEGs were commonly deregulated in AA and EA patients. Surprisingly, we also identified an SSc-like signature in AA-NL fibroblasts. Our data highlight differences in disease mechanisms between AA and EA SScL fibroblasts and suggest that AA-NL fibroblasts are in a "pre-fibrosis" state, poised to respond to potential fibrotic triggers. The DEGs and pathways identified in our study provide a wealth of novel targets to better understand disease mechanisms leading to racial disparity in SSc-PF and develop more effective and personalized therapies.
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Esclerodermia Sistémica , Transcriptoma , Humanos , Pulmón/patología , Esclerodermia Sistémica/patología , Fibrosis , Fibroblastos/metabolismo , Piel/metabolismoRESUMEN
OBJECTIVES: Lung fibrosis is the leading cause of death in SSc, with no cure currently available. Antifibrotic Endostatin (ES) production does not reach therapeutic levels in SSc patients, suggesting a deficit in its release from Collagen XVIII by the main cleavage enzyme, Cathepsin L (CTSL). Thus, elucidating a potential deficit in CTSL expression and activity unravels an underlying molecular cause for SSc-driven lung fibrosis. METHODS: Fibrosis was induced experimentally using TGF-ß in vitro, in primary human lung fibroblasts (pLFs), and ex vivo, in human lung tissues. ES and CTSL expression was quantified using ELISA, RT-qPCR, immunoblotting or immunofluorescence. Recombinant NC1-FLAG peptide was used to assess CTSL cleavage activity. CTSL expression was also compared between SSc vs normal (NL)-derived pLFs and lung tissues. RESULTS: ES levels were significantly reduced in media conditioned by TGF-ß-induced pLFs. TGF-ß-stimulated pLFs significantly reduced expression and secretion of CTSL into the extracellular matrix (ECM). CTSL was also sequestered in its inactive form into extracellular vesicles, further reducing its availability in the ECM. Media conditioned by TGF-ß-induced pLFs showed reduced cleavage of NC1-Flag and reduced release of the antifibrotic ES fragment. SSc-derived pLFs and lung tissues expressed significantly lower levels of CTSL compared with NL. CONCLUSIONS: Our findings identify CTSL as a protein protective against lung fibrosis via its activation of antifibrotic ES, and whose expression in SSc pLFs and lung tissues is suppressed. Identifying strategies to boost CTSL endogenous levels in SSc patients could serve as a viable therapeutic strategy.
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Fibrosis Pulmonar , Esclerodermia Sistémica , Humanos , Catepsina L/metabolismo , Células Cultivadas , Fibroblastos/metabolismo , Fibrosis , Fibrosis Pulmonar/patología , Esclerodermia Sistémica/patología , Piel/patología , Factor de Crecimiento Transformador beta/metabolismoRESUMEN
Background: Cystic fibrosis (CF) is a progressive genetic disease characterized by multisystem symptom burden. Specialist palliative care (PC), as a model of care, has been shown to be effective in improving quality of life and reducing symptom burden in other conditions, but has not been tested in CF. Objectives: To develop and test the feasibility and acceptability of a specialist PC intervention embedded within an outpatient CF clinic. Design: Single-site, equal-allocation randomized pilot study comparing usual care with addition of four protocolized quarterly visits with a PC nurse practitioner. Participants: Adults with CF age ≥18 years with any of the following: FEV1% predicted ≤50, ≥2 CF-related hospitalizations in the past 12 months, supplemental oxygen use, or noninvasive mechanical ventilation use, and moderate-or-greater severity of any symptoms on the Edmonton Symptom Assessment Scale. Measurements: Randomization rate, intervention visit completion, data completements, participant ratings of intervention acceptability and benefit, and intervention delivery fidelity. Results: We randomized 50 adults with CF of 65 approached (77% randomization rate) to intervention (n = 25) or usual care (n = 25), mean age 38, baseline mean FEV1% predicted 41.8 (usual care), and 41.2 (intervention). No participants withdrew, five were lost to follow-up, and two died (88% retention). In the intervention group, 23 of 25 completed all study visits; 94% stated the intervention was not burdensome, and 97.6% would recommend the intervention to others with CF. More than 90% of study visits addressed topics prescribed by intervention manual. Conclusions: Adding specialist PC to standard clinic visits for adults with CF is feasible and acceptable.
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Fibrosis Quística , Adulto , Humanos , Adolescente , Fibrosis Quística/terapia , Cuidados Paliativos , Calidad de Vida , Proyectos Piloto , Estudios de FactibilidadRESUMEN
Lung transplantation provides a treatment option for many individuals with advanced lung disease due to cystic fibrosis (CF). Since the first transplants for CF in the 1980s, survival has improved and the opportunity for transplant has expanded to include individuals who previously were not considered candidates for transplant. Criteria to be a transplant candidate vary significantly among transplant programs, highlighting that the engagement in more than one transplant program may be necessary. Individuals with highly resistant CF pathogens, malnutrition, osteoporosis, CF liver disease, and other comorbidities may be suitable candidates for lung transplant, or if needed, multi-organ transplant. The transplant process involves several phases, from discussion of prognosis and referral to a transplant center, to transplant evaluation, to listing, transplant surgery, and care after transplant. While the availability of highly effective CF transmembrane conductance regulator (CFTR) modulators for many individuals with CF has improved lung function and slowed progression to respiratory failure, early discussion regarding transplant as a treatment option and referral to a transplant program are critical to maximizing opportunity and optimizing patient and family experience. The decision to be evaluated for transplant and to list for transplant are distinct, and early referral may provide a treatment option that can be urgently executed if needed. Survival after transplant for CF is improving, to a median survival of approximately 10 years, and most transplant survivors enjoy significant improvement in quality of life.