ABSTRACT
BACKGROUND: Eluforsen is an antisense oligonucleotide designed to bind to the mRNA region around the F508-encoding deletion and restore the cystic fibrosis transmembrane conductance regulator (CFTR) protein function in the airway epithelium. We assessed the safety and tolerability, pharmacokinetics and exploratory measures of efficacy of inhaled eluforsen in cystic fibrosis (CF) patients homozygous for the F508del-CFTR mutation. METHODS: This randomised, double-blind, placebo-controlled, dose escalation 1b study recruited adult CF subjects with a FEV1â¯>â¯70% predicted in four single ascending dose cohorts and four multiple ascending dose cohorts. Primary objectives were safety and tolerability. Secondary endpoints included pharmacokinetics, percent predicted forced expiratory volume in 1â¯s (ppFEV1), and Cystic Fibrosis Questionnaire-Revised (CFQ-R) Respiratory Symptom Score (RSS). RESULTS: Single and multiple doses of inhaled eluforsen up to 50â¯mg were safe and well tolerated. A maximum tolerated dose was not established. Systemic exposure was low in all cohorts and lung function remained stable throughout the study. Three of four eluforsen-treated groups in the MAD study demonstrated an improvement in CFQ-R RSS at end of treatment with adjusted mean change from baseline values ranging from 6.4 to 12.7 points. In comparison, there was a mean decrease of 6.5 points in the placebo group from baseline to end of treatment. CONCLUSIONS: Inhaled eluforsen up to 50â¯mg dosed 3 times per week for 4â¯weeks was safe and well tolerated, showed low systemic exposure, and demonstrated improvement in CFQ-R RSS, a relevant measure of clinical benefit in CF patients.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis , Dose-Response Relationship, Drug , Oligonucleotides , Respiratory Function Tests/methods , Symptom Assessment/methods , Administration, Inhalation , Adult , Cross-Over Studies , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Cystic Fibrosis/physiopathology , Double-Blind Method , Drug Monitoring/methods , Female , Humans , Male , Mutation , Oligonucleotides/administration & dosage , Oligonucleotides/adverse effects , Oligonucleotides, Antisense/administration & dosage , Oligonucleotides, Antisense/adverse effects , Treatment OutcomeABSTRACT
Cystic fibrosis (CF) is caused by mutations in the gene encoding the epithelial chloride channel CF transmembrane conductance regulator (CFTR) protein. The most common mutation is a deletion of three nucleotides leading to the loss of phenylalanine at position 508 (p.Phe508del) in the protein. This study evaluates eluforsen, a novel, single-stranded, 33-nucleotide antisense oligonucleotide designed to restore CFTR function, in in vitro and in vivo models of p.Phe508del CF. The aims of the study were to demonstrate cellular uptake of eluforsen, and its efficacy in functional restoration of p.Phe508del-CFTR both in vitro and in vivo. In vitro, the effect of eluforsen was investigated in human CF pancreatic adenocarcinoma cells and human bronchial epithelial cells. Two mouse models were used to evaluate eluforsen in vivo. In vitro, eluforsen improved chloride efflux in CF pancreatic adenocarcinoma cell cultures and increased short-circuit current in primary human bronchial epithelial cells, both indicating restoration of CFTR function. In vivo, eluforsen was taken up by airway epithelium following oro-tracheal administration in mice, resulting in systemic exposure of eluforsen. In female F508del-CFTR mice, eluforsen significantly increased CFTR-mediated saliva secretion (used as a measure of CFTR function, equivalent to the sweat test in humans). Similarly, intranasal administration of eluforsen significantly improved nasal potential difference (NPD), and therefore CFTR conductance, in two CF mouse models. These findings indicate that eluforsen improved CFTR function in cell and animal models of p.Phe508del-CFTR-mediated CF and supported further development of eluforsen in human clinical trials, where eluforsen has also been shown to improve CFTR activity as measured by NPD.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/drug therapy , Epithelial Cells/drug effects , Oligonucleotides, Antisense/therapeutic use , Animals , Cell Line, Tumor , Cystic Fibrosis/genetics , Disease Models, Animal , Humans , Mice , Oligonucleotides, Antisense/pharmacologyABSTRACT
Background: Eluforsen (previously known as QR-010) is a 33-mer antisense oligonucleotide under development for oral inhalation in cystic fibrosis (CF) patients with the delta F508 mutation. Previous work has shown that eluforsen restores CF transmembrane conductance regulator (CFTR) function in vitro and in vivo. To be effective, eluforsen has first to reach its primary target, the lung epithelial cells. Therefore, it has to diffuse through the CF airway surface layer (ASL), which in CF is characterized by the presence of thick and viscous mucus, impaired mucociliary clearance, and persistent infections. The goal of this study was to assess delivery of eluforsen through CF-like ASL. Methods and Results: First, air-liquid interface studies with cultured primary airway epithelial cells revealed that eluforsen rapidly diffuses through CF-like mucus at clinically relevant doses when nebulized once or repeatedly, over a range of testing doses. Furthermore, eluforsen concentrations remained stable in CF patient sputum for at least 48 hours, and eluforsen remained intact in the presence of various inhaled CF medications for at least 24 hours. When testing biodistribution of eluforsen after orotracheal administration in vivo, no differences in lung, liver, trachea, and kidney eluforsen concentration were observed between mice with a CF-like lung phenotype (ENaC-overexpressing mice) and control wild-type (WT) littermates. Also, eluforsen was visualized in the airway epithelial cell layer of CF-like muco-obstructed mice and WT littermates. Finally, studies of eluforsen uptake and binding to bacteria prevalent in CF lungs, and diffusion through bacterial biofilms showed that eluforsen was stable and not absorbed by, or bound to bacteria. In addition, eluforsen was found to be able to penetrate Pseudomonas aeruginosa biofilms. Conclusions: The thickened and concentrated CF ASL does not constitute a significant barrier for delivery of eluforsen, and feasibility of oral inhalation of eluforsen is supported by these data.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/metabolism , Cystic Fibrosis/therapy , Lung/metabolism , Oligonucleotides, Antisense/pharmacology , Oligonucleotides/pharmacology , Administration, Inhalation , Animals , Biofilms , Cells, Cultured , Cystic Fibrosis/genetics , Epithelial Cells/metabolism , Female , Humans , Male , Mice , Mice, Inbred C57BL , Oligonucleotides/administration & dosage , Oligonucleotides/pharmacokinetics , Oligonucleotides, Antisense/administration & dosage , Oligonucleotides, Antisense/pharmacokinetics , Pseudomonas aeruginosa/physiology , Time Factors , Tissue DistributionABSTRACT
BACKGROUND: Cystic fibrosis (CF) is caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. In this study we assessed the effect of antisense oligonucleotide eluforsen on CFTR biological activity measured by Nasal Potential Difference (NPD) in patients with the most common mutation, F508del-CFTR. METHODS: This multi-centre, exploratory, open-label study recruited adults with CF homozygous or compound heterozygous for the F508del-CFTR mutation. Subjects received intranasal eluforsen three times weekly for 4â¯weeks. The primary endpoint was the within-subject change from baseline in total chloride transport (Cl-free+iso), as assessed by NPD. Secondary endpoints included within-subject change from baseline in sodium transport. RESULTS: In the homozygous cohort (nâ¯=â¯7; per-protocol population), mean change (90% confidence interval) in Cl-free+iso was -3.0â¯mV (-6.6; 0.6) at day 15, -4.1â¯mV (-7.8; -0.4, pâ¯=â¯.04) at day 26 (end of treatment) andâ¯-â¯3.7â¯mV (-8.0; 0.6) at day 47. This was supported by improved sodium transport as assessed by an increase in average basal potential difference at day 26 of +9.4â¯mV (1.1; 17.7, pâ¯=â¯.04). The compound heterozygous cohort (nâ¯=â¯7) did not show improved chloride or sodium transport NPD values. Eluforsen was well tolerated with a favourable safety profile. CONCLUSIONS: In F508del-CFTR homozygous subjects, repeated intranasal administration of eluforsen improved CFTR activity as measured by NPD, an encouraging indicator of biological activity.
Subject(s)
Cystic Fibrosis Transmembrane Conductance Regulator/drug effects , Cystic Fibrosis Transmembrane Conductance Regulator/physiology , Cystic Fibrosis/drug therapy , Cystic Fibrosis/genetics , Oligonucleotides, Antisense/pharmacology , Oligonucleotides, Antisense/therapeutic use , Oligonucleotides/pharmacology , Oligonucleotides/therapeutic use , Adolescent , Adult , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Female , Humans , Male , Middle Aged , Mutation , Young AdultABSTRACT
Since identification of the CFTR gene over 25 years ago, gene therapy for cystic fibrosis (CF) has been actively developed. More recently gene therapy has been joined by other forms of "genetic medicines" including mRNA delivery, as well as genome editing and mRNA repair-based strategies. Proof-of-concept that gene therapy can stabilize the progression of CF lung disease has recently been established in a Phase IIb trial. An early phase study to assess the safety and explore efficacy of CFTR mRNA repair is ongoing, while mRNA delivery and genome editing-based strategies are currently at the pre-clinical phase of development. This review has been written jointly by some of those involved in the various CF "genetic medicine" fields and will summarize the current state-of-the-art, as well as discuss future developments. Where applicable, it highlights common problems faced by each of the strategies, and also tries to highlight where a specific strategy may have an advantage on the pathway to clinical translation. We hope that this review will contribute to the ongoing discussion about the hype versus reality of genetic medicine-based treatment approaches in CF. Pediatr Pulmonol. 2016;51:S5-S17. © 2016 Wiley Periodicals, Inc.
ABSTRACT
The clinical course of pulmonary hypertension (PH) in idiopathic pulmonary fibrosis (IPF) is not known except in advanced disease.488 subjects in a placebo-controlled study of ambrisentan in IPF with mild-moderate restriction in lung volume, underwent right heart catheterisation (RHC) at baseline and 117 subjects (24%) had repeated haemodynamic measurements at 48â weeks. The subjects were categorised into a) World Health Organization (WHO) Group 3 PH (PH associated with pulmonary disease), n=68 (14%); b) WHO Group 2 PH (PH associated with left-sided cardiac disease), n=25 (5%); c) no PH but elevated pulmonary artery wedge pressure (PAWP), n=21 (4%); and d) no PH but without elevation of PAWP, n=374 (77%). The WHO Group 3 PH subjects had a lower diffusion capacity, 6MWD and oxygen saturation compared to the subjects with no PH. There was no significant change in mean pulmonary arterial pressure with ambrisenten or placebo after 12â months. Subjects with IPF associated with WHO Group 3 PH had impaired gas exchange and exercise capacity compared to patients without PH. An additional 9% of the subjects had haemodynamic evidence of subclinical left-ventricular dysfunction. Pulmonary artery pressures remained stable over 1â year in the majority of the cohort.
Subject(s)
Hypertension, Pulmonary/physiopathology , Idiopathic Pulmonary Fibrosis/complications , Lung/physiopathology , Phenylpropionates/administration & dosage , Pulmonary Wedge Pressure/drug effects , Pyridazines/administration & dosage , Aged , Arterial Pressure , Cardiac Catheterization , Double-Blind Method , Female , Humans , Idiopathic Pulmonary Fibrosis/drug therapy , Male , Middle Aged , Ventricular Dysfunction, Left , World Health OrganizationABSTRACT
BACKGROUND: Individuals with Burkholderia spp. infection have historically been excluded from efficacy trials of inhaled antibiotics, including aztreonam for inhalation solution (AZLI). METHODS: A double-blind, placebo-controlled, 24-week trial of continuous AZLI/placebo treatment was undertaken in individuals with cystic fibrosis (CF) and chronic Burkholderia spp. infection. All subjects also received usual medical care (determined by their physicians). Additional antibiotic use was not restricted. RESULTS: Baseline FEV1% predicted values ranged from 15.8% to 114.6%. No significant treatment differences (AZLI vs. placebo) were observed at week 24 for any endpoints, including FEV1% predicted, number of respiratory exacerbations requiring systemic/inhaled antibiotics, or hospitalizations. Continuous AZLI administration was well tolerated. Burkholderia spp. susceptibility to antibiotics commonly used in CF therapy showed little change. CONCLUSIONS: 24-weeks of continuous AZLI treatment did not significantly improve lung function in CF subjects with chronic Burkholderia spp. infection. Non-study antibiotic use may have confounded any potential AZLI effects.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Aztreonam/administration & dosage , Burkholderia Infections/drug therapy , Cystic Fibrosis/microbiology , Administration, Inhalation , Adolescent , Adult , Child , Chronic Disease , Double-Blind Method , Female , Humans , Male , Placebos , Treatment Outcome , Young AdultABSTRACT
In pulmonary hypertension, as in many other diseases, there is a need for a smarter approach to evaluating new treatments. The traditional randomized controlled trial has served medical science well, but constrains the development of treatments for rare diseases. A workshop was established to consider alternative clinical trial designs in pulmonary hypertension and here discusses their merits, limitations and challenges to implementation of novel approaches.
ABSTRACT
Chronic biofilm formation by Pseudomonas aeruginosa in cystic fibrosis (CF) lungs is a major cause of morbidity and mortality for patients with CF. To gain insights into effectiveness of novel anti-infective therapies, the inhibitory effects of fosfomycin, tobramycin, and a 4:1 (wt/wt) fosfomycin/tobramycin combination (FTI) on Pseudomonas aeruginosa biofilms grown on cultured human CF-derived airway cells (CFBE41o-) were investigated. In preformed biofilms treated for 16 h with antibiotics, P. aeruginosa CFU per mL were reduced 4 log10 units by both FTI and tobramycin at 256 mg L(-1) , while fosfomycin alone had no effect. Importantly, the FTI treatment contained five times less tobramycin than the tobramycin-alone treatment. Inhibition of initial biofilm formation was achieved at 64 mg L(-1) FTI and 16 mg L(-1) tobramycin. Fosfomycin (1024 mg L(-1)) did not inhibit biofilm formation. Cytotoxicity was also determined by measuring lactate dehydrogenase (LDH). Intriguingly, sub-inhibitory concentrations of FTI (16 mg L(-1)) and tobramycin (4 mg L(-1)) and high concentrations of fosfomycin (1024 mg L(-1)) prevented bacterially mediated airway cell toxicity without a corresponding reduction in CFU. Overall, it was observed that FTI and tobramycin demonstrated comparable activity on biofilm formation and disruption. Decreased administration of tobramycin upon treatment with FTI might lead to a decrease in negative side effects of aminoglycosides.
Subject(s)
Anti-Bacterial Agents/pharmacology , Biofilms/drug effects , Epithelial Cells/microbiology , Fosfomycin/pharmacology , Pseudomonas aeruginosa/drug effects , Tobramycin/pharmacology , Cell Survival/drug effects , Cells, Cultured , Colony Count, Microbial , Drug Synergism , Epithelial Cells/drug effects , Humans , Microbial Sensitivity TestsABSTRACT
Edema is a common side effect of endothelin receptor antagonists. Ambrisentan is an endothelin type A-selective endothelin receptor antagonist approved for the treatment of pulmonary arterial hypertension. We examined the clinical outcomes of patients who developed edema with and without ambrisentan treatment in 2 phase III, randomized placebo-controlled trials, ambrisentan for the treatment of pulmonary arterial hypertension: results of the ambrisentan in pulmonary arterial hypertension, randomized, double-blind, placebo-controlled, multicenter, efficacy (ARIES) study 1 and 2 (ARIES-1 and ARIES-2) (n = 393). Edema-related adverse events were extracted using broad adverse event search terms. The present post hoc analysis included 132 placebo patients and 261 ambrisentan patients. Of these patients, 14% of the placebo patients and 23% of the ambrisentan patients experienced edema-related adverse events. Overall, the patients who experienced edema tended to have a worse baseline World Health Organization (WHO) functional class (edema 76%, WHO functional class III-IV; no edema 56%, WHO functional class III-IV). In the ambrisentan patients, those with edema were older (mean age 58 ± 13 years) and heavier (mean weight 75 ± 19 kg) than those without edema (mean age 49 ± 15 years; mean weight 70 ± 17 kg). At week 12 of treatment, the ambrisentan patients had significantly increased their 6-minute walk distance (6MWD) by 34.4 m compared to the placebo patients in whom the 6MWD had deteriorated by -9.0 m (p <0.001). Among the ambrisentan patients, those without edema had a 6MWD increase of 38.9 m and those with edema had a 6MWD increase of 19.4 m. Ambrisentan significantly improved the brain natriuretic peptide levels by -34% compared to the brain natriuretic peptide levels in the placebo group that had worsened by +11% (p <0.001). Ambrisentan reduced the brain natriuretic peptide concentrations similarly in patients with and without edema. In conclusion, the present subanalysis of patients with pulmonary arterial hypertension has revealed that ambrisentan therapy provides clinical benefit compared to placebo, even in the presence of edema.
Subject(s)
Edema/chemically induced , Edema/epidemiology , Hypertension, Pulmonary/drug therapy , Phenylpropionates/administration & dosage , Pyridazines/administration & dosage , Adult , Age Factors , Aged , Analysis of Variance , Confidence Intervals , Dose-Response Relationship, Drug , Double-Blind Method , Drug Administration Schedule , Edema/physiopathology , Familial Primary Pulmonary Hypertension , Female , Follow-Up Studies , Humans , Hypertension, Pulmonary/diagnosis , Incidence , Male , Middle Aged , Natriuretic Peptide, Brain/analysis , Natriuretic Peptide, Brain/drug effects , Phenylpropionates/adverse effects , Pyridazines/adverse effects , Reference Values , Risk Assessment , Safety Management , Severity of Illness Index , Sex Factors , Treatment OutcomeSubject(s)
Antihypertensive Agents/administration & dosage , Antihypertensive Agents/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Endothelin A Receptor Antagonists , Hypertension, Pulmonary/drug therapy , Liver/drug effects , Phenylpropionates/administration & dosage , Phenylpropionates/adverse effects , Pyridazines/administration & dosage , Pyridazines/adverse effects , Adult , Aged , Alanine Transaminase/blood , Aspartate Aminotransferases/blood , Chemical and Drug Induced Liver Injury/enzymology , Chemical and Drug Induced Liver Injury/epidemiology , Drug Administration Schedule , Endothelins/antagonists & inhibitors , Female , Humans , Incidence , Liver/enzymology , Liver/pathology , Liver/physiopathology , Liver Function Tests , Male , Middle Aged , Risk Factors , United States/epidemiologyABSTRACT
IMPORTANCE OF THE FIELD: Chronic endobronchial infection in cystic fibrosis (CF) leads to progressive lung function loss and respiratory failure. Most adult CF patients are infected with Pseudomonas aeruginosa, an important predictor of mortality. Suppressing chronic P. aeruginosa infection with inhaled antibiotics is standard of care for CF patients. AREAS COVERED IN THIS REVIEW: This review describes the development (2003 - 2010) of aztreonam lysine 75 mg powder and solvent for nebulizer solution (AZLI; Cayston), an aerosolized formulation of the monobactam antibiotic aztreonam. WHAT THE READER WILL GAIN: AZLI was studied in patients with CF and chronic P. aeruginosa airway infection. In placebo-controlled trials, AZLI improved respiratory symptoms, increased forced expiratory volume in 1 sec (FEV(1)), decreased sputum P. aeruginosa density, and was well tolerated. An open-label follow-on trial of nine 'on/off' courses showed that AZLI was safe and the effect durable with repeated administration. AZLI was recently approved for use in CF patients in Australia and the USA, and conditionally approved in Canada and the European Union. AZLI is given three times daily for 28 days (2 - 3 min/dose), followed by 28 days off-drug. AZLI is used only with the Altera Nebulizer System, which provides appropriate particle size and small airway deposition, and has excellent portability. TAKE HOME MESSAGE: AZLI is a new therapy that is safe and effectively improves respiratory symptoms and FEV(1) in patients with CF.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Aztreonam/administration & dosage , Cystic Fibrosis/drug therapy , Pseudomonas Infections/drug therapy , Administration, Inhalation , Aerosols , Anti-Bacterial Agents/pharmacokinetics , Aztreonam/pharmacokinetics , Controlled Clinical Trials as Topic , Cystic Fibrosis/microbiology , Cystic Fibrosis/physiopathology , Drug-Related Side Effects and Adverse Reactions/etiology , Drug-Related Side Effects and Adverse Reactions/physiopathology , Humans , Nebulizers and Vaporizers , Pseudomonas Infections/complications , Pseudomonas aeruginosa/drug effects , Respiratory Function Tests , Treatment OutcomeABSTRACT
RATIONALE: Pseudomonas aeruginosa lung infection in patients with bronchiectasis, a chronic airway disease that is characterized by episodes of exacerbation, is associated with more severe disease and a higher utilization of health-care resources. Inhaled tobramycin solution reduces the number of acute exacerbations in patients with cystic fibrosis (CF)-related bronchiectasis with P aeruginosa infection but remains untested in the treatment of exacerbations in patients with non-CF bronchiectasis. OBJECTIVES: This study tested the effect of adding inhaled tobramycin solution to oral ciprofloxacin (Cip) for the treatment of acute exacerbations of non-CF bronchiectasis in patients with P aeruginosa infection. METHODS: A double-blind, randomized, active comparator, parallel-design study conducted at 17 study centers (5 in the United Kingdom, and 12 in the United States) compared 2 weeks of therapy with Cip with either an inhaled tobramycin solution or placebo in 53 adults with known P aeruginosa infection who were having acute exacerbations of bronchiectasis. MEASUREMENTS: Clinical symptoms, pulmonary function, clinical efficacy, and sputum microbiology were investigated prospectively. MAIN RESULTS: An inhaled solution of Cip with tobramycin, compared to placebo, achieved greater microbiological response but no statistically significant difference in clinical efficacy at days 14 or 21. Clinical and microbiological outcomes at the test of cure (ie, the clinical outcome assessment at day 21) were concordant when an inhaled tobramycin solution was added to therapy with Cip and compared to placebo (p = 0.01). Both subject groups had similar overall adverse event rates, but subjects receiving therapy with an inhaled tobramycin solution reported an increased frequency of wheeze (50%; placebo group, 15%). CONCLUSIONS: The addition of an inhaled tobramycin solution to therapy with oral Cip for the treatment of acute exacerbations of bronchiectasis due to P aeruginosa improved microbiological outcome and was concordant with clinical outcome; the inability to demonstrate an additional clinical benefit may have been due to emergent wheeze resulting from treatment.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Bronchiectasis/complications , Bronchiectasis/drug therapy , Bronchiectasis/microbiology , Ciprofloxacin/therapeutic use , Pseudomonas Infections/drug therapy , Tobramycin/therapeutic use , Administration, Inhalation , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Ciprofloxacin/administration & dosage , Ciprofloxacin/adverse effects , Double-Blind Method , Drug Administration Schedule , Drug Therapy, Combination , Female , Humans , Lung/microbiology , Lung/pathology , Lung/physiopathology , Male , Middle Aged , Pseudomonas Infections/etiology , Pseudomonas aeruginosa/pathogenicity , Tobramycin/administration & dosage , Tobramycin/adverse effects , Treatment Outcome , United Kingdom , United StatesABSTRACT
BACKGROUND: Bronchiectasis and pulmonary infection with nontuberculous mycobacteria (NTM) may be associated with disease-causing mutations in the cystic fibrosis transmembrane regulator (CFTR). METHODS: Fifty adult patients at Stanford University Medical Center with a diagnosis of bronchiectasis and/or pulmonary NTM infection were prospectively characterized by sweat chloride measurement, comprehensive mutational analysis of CFTR, and sputum culture results. RESULTS: A de novo diagnosis of cystic fibrosis (CF) was established in 10 patients (20%). Patients with CF were more likely than those without CF to have mucus plugging seen on chest high-resolution CT, and women with a CF diagnosis were thinner, with a significantly lower mean body mass index than the non-CF subjects. Thirty CFTR mutations were identified in 24 patients (50% prevalence). Sweat chloride concentration was elevated > 60 mEq/dL (diagnostic of CF) in seven patients (14%), and from 40 to 60 mEq/dL in eight patients (16%). The frequency of CFTR mutations was elevated above that expected in the general population: heterozygous DeltaF508 (12% vs 3%), R75Q (14% vs 1%), and intron 8 5T (17% vs 5 to 10%). Other known CFTR mutations identified were V456A, G542X, R668C, I1027T, D1152, R1162L, W1282X, and L183I. Three novel CFTR mutations were identified: A394V, F650L, and C1344S. CONCLUSIONS: Mutations in CFTR that alter RNA splicing and/or functional chloride conductance are common in this population, and are likely to contribute to the susceptibility and pathogenesis of adult bronchiectasis and pulmonary NTM infection. Careful clinical evaluation for disease cause should be undertaken in this clinical context.
Subject(s)
Bronchiectasis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis/genetics , DNA Mutational Analysis , Lung Diseases/genetics , Mycobacterium avium-intracellulare Infection/genetics , Adult , Aged , Aged, 80 and over , Body Mass Index , Bronchiectasis/diagnosis , Chloride Channels/genetics , Chlorides/analysis , Cystic Fibrosis/diagnosis , Exons , Female , Genetic Carrier Screening , Genotype , Humans , Introns , Lung Diseases/diagnosis , Male , Middle Aged , Mycobacterium avium-intracellulare Infection/diagnosis , Polymerase Chain Reaction , RNA Splicing/genetics , Sweat/chemistry , Tomography, Spiral ComputedABSTRACT
RATIONALE: The optimal timing for listing of cystic fibrosis patients for lung transplantation is controversial. OBJECTIVES: We conducted a retrospective cohort study of 343 patients listed for lung transplantation at four academic medical centers to identify risk factors for death while awaiting transplantation. METHODS: Data on possible risk factors were abstracted from medical records. MEASUREMENTS: Time to death, patient demographic characteristics, and risk factors for death while awaiting transplantation were assessed. Univariate and multivariate survival analyses were performed using Cox regression. RESULTS: By univariate analyses, FEV1 < or = 30% predicted (HR, 3.8; 95% CI, 2.0-7.5), Pa(CO2) > or = 50 mm Hg (HR, 1.85; 95% CI, 1.1-3.0), and shorter height (HR, 1.8; 95% CI, 1.1-3.0) were associated with a higher risk of death. Referral from an accredited cystic fibrosis center was associated with a lower risk (HR, 0.53; 95% CI, 0.30-0.92). The final multivariate model included referral from an accredited cystic fibrosis center (HR, 0.5; 95% CI, 0.3-1.0) and listing year after 1996 (HR, 0.4; 95% CI, 0.2-0.7); both were associated with a lower risk of death. FEV1 < or = 30% predicted (HR, 6.8; 95% CI, 2.4-19.3), Pa(CO2) > or = 50 mm Hg (HR, 6.9; 95% CI, 1.5-32.1), and use of a nutritional intervention (HR, 2.3; 95% CI, 1.3-4.1) were associated with increased risk. Patients with FEV1 > 30% predicted had a higher risk of death only when their Pa(CO2) was > or = 50 mm Hg (HR, 7.0; 95% CI, 1.5-32), while the increased risk of death with FEV1 < or = 30% was not further influenced by the presence of hypercapnia. CONCLUSIONS: We identified risk factors for waiting list mortality that could impact on transplant listing and allocation guidelines.
Subject(s)
Cystic Fibrosis/mortality , Lung Transplantation , Waiting Lists , Adult , Cause of Death/trends , Child , Cystic Fibrosis/physiopathology , Cystic Fibrosis/surgery , Female , Follow-Up Studies , Forced Expiratory Volume , Humans , Male , Prognosis , Proportional Hazards Models , Retrospective Studies , Risk Factors , Severity of Illness Index , Survival Rate/trendsABSTRACT
BACKGROUND: Over the past 3 decades, the field of lung transplantation has been refined. However, many barriers exist that limit long-term success. The purpose of this study was to review a single institution's long-term experience with single and double lung transplantation and to assess the effect of different immunosuppressive therapies on outcomes. METHODS: Lung transplant recipients, both single and double, were reviewed, retrospectively. Patients were divided into five groups: group I, all lung transplants (n = 127); group II, single lung transplants (n = 73); group III, double lung transplants (n = 54); group IV, OKT3 induction therapy recipients (n = 27); and group V, RATG induction therapy recipients (n = 100). Rates of survival, rejection, bronchiolitis obliterans syndrome (BOS) and infection were analyzed at 1, 3, and 5 years. RESULTS: There were no significant differences in survival, acute rejection rate, freedom from BOS, nor infection between single and double lung transplant recipients. Induction therapy with RATG (group V) was associated with significantly improved survival and freedom from acute rejection, BOS, and infection when compared to OKT3 induction therapy (group IV). CONCLUSIONS: An earlier impression that RATG is superior to OKT3 induction therapy has borne true in terms of overall survival and incidence of BOS, acute rejection and infection rates. Lung transplantation, using RATG induction therapy, remains an important modality for end-stage pulmonary disease.
Subject(s)
Graft Rejection/prevention & control , Lung Transplantation , Adult , Antilymphocyte Serum/therapeutic use , Bronchiolitis Obliterans/epidemiology , Bronchiolitis Obliterans/etiology , Cystic Fibrosis/epidemiology , Cystic Fibrosis/therapy , Female , Follow-Up Studies , Graft Rejection/epidemiology , Graft Rejection/etiology , Humans , Immunosuppressive Agents/therapeutic use , Male , Muromonab-CD3/therapeutic use , Postoperative Complications/epidemiology , Postoperative Complications/etiology , Pulmonary Disease, Chronic Obstructive/epidemiology , Pulmonary Disease, Chronic Obstructive/therapy , Retrospective Studies , Survival Analysis , Treatment OutcomeABSTRACT
Induced sputum has been used to study airway inflammation. We sought to determine whether markers of infection and inflammation in induced sputum were a useful and safe outcome measure in cystic fibrosis. We hypothesized that bacterial density and inflammatory content of induced sputum would decrease after antibiotic therapy. Induced sputum was assayed for bacterial density, cell count, and differential and inflammatory markers before and after treatment with intravenous antibiotics. Fifty-five of the 72 subjects enrolled (mean age +/- SD 18.2 +/- 7.9 years) completed the study. FEV1 increased by an average 0.3 +/- 0.3 L (10.4 +/- 8.7% predicted FEV1), p<0.0001; density of Pseudomonas aeruginosa and Staphylococcus aureus decreased by 2.4 +/- 3.1 log10 cfu/g (p<0.0005) and 4.0 +/- 2.3 log10 cfu/ml (p<0.0001), respectively; neutrophil count decreased by 0.4 +/- 0.6 log10 cells/ml (p<0.0001), interleukin-8 concentration by 0.5 +/- 1.3 log10 pg/ml (p<0.05), and neutrophil elastase by 0.4 +/- 0.7 log10 microg/ml (p<0.005). Seven of 127 (6%) sputum induction procedures showed a decrease in FEV1 of 20% or more. We conclude that markers in induced sputum may be useful, noninvasive outcome measures to assess response to therapies in cystic fibrosis studies.
Subject(s)
Anti-Bacterial Agents/administration & dosage , Bacteria/isolation & purification , Biomarkers/analysis , Bronchial Provocation Tests , Cystic Fibrosis/drug therapy , Cystic Fibrosis/immunology , Sputum/immunology , Administration, Inhalation , Adolescent , Adult , Bronchial Provocation Tests/methods , Child , Colony Count, Microbial , Female , Humans , Infusions, Intravenous , Male , Saline Solution, Hypertonic/administration & dosage , Sputum/chemistry , Sputum/microbiology , Treatment OutcomeABSTRACT
Degenerative neuromuscular diseases are characterized by a gradual decline of motor function leading to respiratory collapse, while the patients retain consciousness and cognition. The ethical challenges of caring for such patients result from the need to implement various combinations of initiating, withholding, and withdrawing life-sustaining interventions. In caring for this population of patients physicians should adhere to the ethical principles of autonomy, beneficence, nonmaleficence, and justice. A central goal of care is to avoid a decisional impasse by anticipating end-of-life issues in discussion with patients and families. The evolution of these diseases is usually slow enough to allow ample patient education, and thus physicians should foster early and frank discussions and encourage the patient to set up advance directives, designate a durable power of attorney for health care, and plan end-of-life care. Competent patients have the right to accept or refuse life-sustaining therapies, and such requests should be honored. In delivering palliative care, adequate sedation and analgesia must be provided when needed. If a decision to withhold or withdraw life support is made, patient comfort and dignity are the ultimate objectives.