ABSTRACT
BACKGROUND: Reducing treatment burden is a priority for people with cystic fibrosis, whose health has benefited from using new modulators that substantially increase CFTR protein function. The SIMPLIFY study aimed to assess the effects of discontinuing nebulised hypertonic saline or dornase alfa in individuals using the CFTR modulator elexacaftor plus tezacaftor plus ivacaftor (ETI). METHODS: The SIMPLIFY study included two parallel, multicentre, open-label, randomised, controlled, non-inferiority trials at 80 participating clinics across the USA in the Cystic Fibrosis Therapeutics Development Network. We included individuals with cystic fibrosis aged 12-17 years with percent predicted FEV1 (ppFEV1) of 70% or more, or those aged 18 years or older with ppFEV1 of 60% or more, if they had been taking ETI and either (or both) mucoactive therapies (≥3% hypertonic saline or dornase alfa) for at least 90 days before screening. Participants on both hypertonic saline and dornase alfa were randomly assigned to one of the two trials, and those on a single therapy were assigned to the applicable trial. All participants were then randomly assigned 1:1 to continue or discontinue therapy for 6 weeks using permuted blocks of varying size, stratified by baseline ppFEV1 (week 0; ≥90% or <90%), single or concurrent use of hypertonic saline and dornase alfa, previous SIMPLIFY study participation (yes or no), and age (≥18 or <18 years). For participants randomly assigned to continue their therapy during a given trial, this therapy was instructed to be taken at least once daily according to each participant's pre-existing, clinically prescribed regimen. Hypertonic saline concentration was required to be at least 3%. The primary objective for each trial was to determine whether discontinuing was non-inferior to continuing, measured by the 6-week change in ppFEV1 in the per-protocol population. We established a non-inferiority margin of -3% for the difference between groups in the 6-week change in ppFEV1. Safety outcomes were analysed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT04378153. FINDINGS: From Aug 25, 2020, to May 25, 2022, a total of 672 unique participants were screened for eligibility for one or both trials, resulting in 847 total random assignments across both trials with 594 unique participants. 370 participants were randomly assigned in the hypertonic saline trial and 477 in the dornase alfa trial. Participants across both trials had an average ppFEV1 of 96·9%. Discontinuing treatment was non-inferior to continuing treatment with respect to the absolute 6-week change in ppFEV1 in both the hypertonic saline trial (-0·19% [95% CI -0·85 to 0·48] in the discontinuation group [n=133] vs 0·14% [-0·51 to 0·78] in the continuation group [n=140]; between-group difference -0·32% [-1·25 to 0·60]) and dornase alfa trial (0·18% [-0·38 to 0·74] in the discontinuation group [n=199] vs -0·16% [-0·73 to 0·41] in the continuation group [n=193]; between-group difference 0·35% [-0·45 to 1·14]), with consistent results in the intention-to-treat populations. In the hypertonic saline trial, 64 (35%) of 184 in the discontinuation group versus 44 (24%) of 186 participants in the continuation group and, in the dornase alfa trial, 89 (37%) of 240 in the discontinuation group versus 55 (23%) of 237 in the continuation group had at least one adverse event. INTERPRETATION: In individuals with cystic fibrosis on ETI with relatively well preserved pulmonary function, discontinuing daily hypertonic saline or dornase alfa for 6 weeks did not result in clinically meaningful differences in pulmonary function when compared with continuing treatment.
Subject(s)
Cystic Fibrosis , Humans , Cystic Fibrosis/drug therapy , Cystic Fibrosis Transmembrane Conductance Regulator , Deoxyribonuclease I/adverse effects , Lung , Saline Solution, HypertonicABSTRACT
Obesity and asthma are epidemic in the United States and obesity is an independent risk factor for asthma. Low vitamin D levels (i.e. serum 25-hydroxyvitamin D) have been reported in patients with reduced lung function, more frequent respiratory infections, and asthma exacerbations. Experts have proposed that serum levels > 40 ng/mL are required to offer the immunomodulatory benefits of vitamin D. Low vitamin D levels are common in both obesity and asthma, but it is not known whether supplementation with vitamin D improves asthma symptoms. Guidance for drug development stresses the importance of early phase studies to establish accurate population pharmacokinetics (PK) and drug dosing prior to larger phase 3 trials. The PK of this fat-soluble vitamin in children with increased adiposity are unknown; as are the doses need to reach proposed immunomodulatory levels. The objective of this study is to characterize the PK of vitamin D in children with obesity. Children ages 6--18 years who had physician diagnosed asthma and a body mass index (BMI) >85th percentile will be randomized to receive either standard daily dosing or loading doses followed by standard daily dosing. Blood samples will be obtained to characterize the PK of vitamin D. The results of this study will be used to identify a sufficient dose of vitamin D supplement to raise serum levels above a pre-specified value that may result in anti-inflammatory actions that could improve asthma symptoms.
Subject(s)
Asthma , Vitamin D Deficiency , Adolescent , Asthma/drug therapy , Asthma/epidemiology , Child , Humans , Obesity , Randomized Controlled Trials as Topic , United States , Vitamin D , Vitamin D Deficiency/drug therapy , Vitamin D Deficiency/epidemiology , Vitamins/therapeutic useABSTRACT
Excess adipose tissue predisposes to an enhanced inflammatory state and can contribute to the pathogenesis and severity of asthma. Vitamin D has anti-inflammatory properties and low-serum levels are seen in children with asthma and in children with obesity. Here we review the intersection of asthma, obesity, and hypovitaminosis D in children. Supplementation with vitamin D has been proposed as a simple, safe, and inexpensive adjunctive therapy in a number of disease states. However, little research has examined the pharmacokinetics of vitamin D and its therapeutic potential in children who suffer from obesity-related asthma.
Subject(s)
Asthma , Dietary Supplements , Obesity , Vitamin D , Vitamins , Asthma/blood , Asthma/diet therapy , Asthma/etiology , Child , Humans , Inflammation/blood , Inflammation/diet therapy , Obesity/blood , Obesity/complications , Obesity/diet therapy , Obesity/metabolism , Vitamin D/blood , Vitamin D/pharmacokinetics , Vitamin D/therapeutic use , Vitamin D Deficiency/blood , Vitamin D Deficiency/diet therapy , Vitamins/blood , Vitamins/pharmacokinetics , Vitamins/therapeutic useSubject(s)
Drug Costs , Drug Industry/economics , Orphan Drug Production/economics , Social Justice , Aminophenols/economics , Aminophenols/therapeutic use , Cost Sharing , Cystic Fibrosis/drug therapy , Drug Discovery , Drug Industry/ethics , Health Expenditures , Humans , Quinolones/economics , Quinolones/therapeutic use , United StatesABSTRACT
Cystic fibrosis (CF) is a disease which predisposes individuals to recurrent infective exacerbations of suppurative lung disease; however, empyema is a rare complication in these patients. Empyemas secondary to Staphylococcus aureus and Burkholderia cepacia have been described in patients with CF. We report the case of pleural empyema with mixed S. aureus and Pseudomonas aeruginosa infection in a 34-year-old woman with CF, which was managed with ultrasound-guided pigtail catheter insertion, fibrinolysis, and antibiotic therapy. Physicians should be aware of this unusual complication in CF patients, especially those receiving an immunosuppressive therapy.
ABSTRACT
OBJECTIVE: To describe pancreatic function during the first year of life in infants diagnosed with cystic fibrosis (CF) using serial fecal elastase measurements. STUDY DESIGN: This was a longitudinal study of 82 infants diagnosed with CF through newborn screening. Monthly stool samples were sent to a central laboratory for fecal elastase measurements. RESULTS: A total of 61 infants had an initial stool sample obtained at age <3.5 months and a final stool sample obtained at age >9 months. Twenty-six of 29 infants with a fecal elastase value <50 µg/g at study entry had a fecal elastase value <200 µg/g (the accepted cutoff value for pancreatic insufficiency) on all measurements during the year; all 29 had a value <200 µg/g at the end of the study. Of the 48 infants with initial fecal elastase value <200 µg/g, 13 had at least 1 fecal elastase value >200 µg/g but had a final stool fecal elastase value <200 µg/g; however, 4 infants with an initial fecal elastase value <200 µg/g ended the year with a value >200 µg/g. Eleven of 13 infants with an initial fecal elastase value of >200 µg/g still had a value >200 µg/g at the end of the first year. CONCLUSION: Infants with CF exhibit variability in fecal elastase values during the first year. Infants with a fecal elastase level of 50-200 µg/g at diagnosis should be treated with pancreatic enzyme replacement therapy, but fecal elastase should be remeasured at age 1 year to ensure that those with a falsely low value do not continue to receive pancreatic enzyme replacement therapy unnecessarily. Those with a fecal elastase value >200 µg/g initially can become pancreatic insufficient with time.
Subject(s)
Cystic Fibrosis/physiopathology , Pancreatic Function Tests/methods , Cohort Studies , Cystic Fibrosis/complications , Cystic Fibrosis/genetics , Docosahexaenoic Acids/metabolism , Exocrine Pancreatic Insufficiency/diagnosis , Exocrine Pancreatic Insufficiency/genetics , Feces , Female , Genotype , Homozygote , Humans , Infant , Infant, Newborn , Longitudinal Studies , Male , Neonatal Screening , Pancreatic Elastase/metabolismABSTRACT
The pulmonary vasculitides are a heterogeneous group of diseases that often occur as a component of systemic vasculitic diseases. Most frequently, pulmonary vasculitis is observed in vasculitic syndromes that preferentially affect small vessels. Pulmonary involvement may develop because the lung has an extensive vascular and microvascular network. Sensitising antigens can easily reach the lung, and there are large numbers of vasoactive and activated immune cells in the lung. A diagnosis often can be made on the basis of clinical presentation and serologic studies, but biopsy of skin, nose, kidney, or lung may be necessary to ascertain the precise syndrome.
Subject(s)
Respiratory Tract Diseases/etiology , Systemic Vasculitis , Child , Humans , Respiratory Tract Diseases/immunology , Systemic Vasculitis/classification , Systemic Vasculitis/complications , Systemic Vasculitis/diagnosis , Systemic Vasculitis/immunologyABSTRACT
PURPOSE: To use hyperpolarized (HP) (3)He MR imaging to assess functional lung ventilation in subjects with cystic fibrosis (CF) before and after treatment. MATERIALS AND METHODS: We performed HP (3)He static ventilation MRI scans on three subjects, using a Philips 3.0 Tesla (T) Achieva MRI scanner, before and after 11 days of in-patient treatment with combined intravenous and inhaled therapies for pulmonary exacerbations of CF. We also collected spirometry data. We quantified pulmonary ventilation volume measured with HP (3)He MRI using an advanced semi-automated analysis technique. RESULTS: Following 11 days of treatment with intravenous antibiotics, hypertonic saline, and rhDNase, HP (3)He MR images in one subject displayed a 25% increase in total ventilation volume. Total ventilation volume in the other two subjects slightly decreased. All three subjects showed increases in FEV(1) and FVC following treatment. CONCLUSION: In all subjects, the HP (3)He MR images provided detailed information on precisely where in the lungs gas was reaching. These data provide additional support for the conclusion that HP noble gas MRI can be a powerful tool for evaluating lung ventilation in patients with cystic fibrosis, but also raise important questions about the correlation between spirometry and HP gas MRI measurements.
Subject(s)
Cystic Fibrosis/pathology , Helium/chemistry , Lung/pathology , Magnetic Resonance Imaging/methods , Adolescent , Adult , Cystic Fibrosis/therapy , Deoxyribonucleases/chemistry , Female , Forced Expiratory Volume , Gases , Humans , Male , Respiratory Function Tests/methods , Spirometry/methods , Vital CapacityABSTRACT
Melioidosis, an infection caused by the bacterium Burkholderia pseudomallei, is endemic to Southeast Asia and northern Australia but is only very rarely seen in patients in the United States. We report pulmonary B pseudomallei infection in a young girl with cystic fibrosis (CF) who had never traveled to Asia or Australia. Biochemical and epidemiologic investigation determined Aruba as the likely site of disease acquisition. This report highlights the ability of patients with CF to acquire this organism outside of Southeast Asia and describes an aggressive treatment regimen that has kept this patient culture-negative for the organism over a long period of time.
Subject(s)
Burkholderia pseudomallei/isolation & purification , Cystic Fibrosis/complications , Melioidosis/complications , Opportunistic Infections/complications , Sputum/microbiology , Child , Diagnosis, Differential , Female , Humans , Melioidosis/diagnosis , Melioidosis/microbiology , Opportunistic Infections/diagnosis , Opportunistic Infections/microbiology , Radiography, ThoracicABSTRACT
Newborn screening (NBS) for cystic fibrosis (CF) offers the opportunity for early diagnosis and improved outcomes in patients with CF and has been universally available in the state of Massachusetts since 1999 using an immunoreactive trypsinogen (IRT)-DNA algorithm. Ideally, CF NBS is incorporated as part of an integrated NBS system that allows for comprehensive and coordinated education, laboratory screening, clinical follow-up, and evaluation so that evidence-based data can be used to maximize quality improvements and optimize the screening algorithm. The New England Newborn Screening Program (NENSP) retrospectively analyzed Massachusetts's CF newborn screening data that yielded decisions to eliminate a screen-positive category, maintain the IRT cutoff value that prompts the second tier DNA testing, and communicate CF relative risk to primary care providers (PCPs) based on categorization of positive CF NBS results.
Subject(s)
Algorithms , Cystic Fibrosis/diagnosis , Neonatal Screening , Biomarkers/blood , Chlorides/analysis , Cystic Fibrosis/blood , Cystic Fibrosis/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , DNA Mutational Analysis , Genetic Testing , Humans , Immunoassay , Infant, Newborn , Massachusetts , Mutation , Neonatal Screening/methods , Predictive Value of Tests , Primary Health Care , Program Development , Program Evaluation , Quality Indicators, Health Care , Retrospective Studies , Sweat/chemistry , Trypsinogen/bloodABSTRACT
In February 2010, aztreonam for inhalation solution (Cayston; Gilead) - an inhalable formulation of the monobactam antibiotic aztreonam and lysine - was approved by the US FDA to improve respiratory symptoms in patients with cystic fibrosis infected with Pseudomonas aeruginosa.
Subject(s)
Anti-Bacterial Agents/therapeutic use , Aztreonam/therapeutic use , Cystic Fibrosis/complications , Pseudomonas Infections/drug therapy , Administration, Inhalation , Anti-Bacterial Agents/administration & dosage , Anti-Bacterial Agents/adverse effects , Aztreonam/administration & dosage , Aztreonam/adverse effects , Cystic Fibrosis/microbiology , Drug Discovery , Humans , Lysine/chemistry , Pseudomonas Infections/complications , Pseudomonas Infections/microbiology , Pseudomonas aeruginosa/isolation & purification , Treatment OutcomeABSTRACT
There is strong evidence that early, aggressive therapy of lung disease leads to improved quality and quantity of life for patients with cystic fibrosis (CF). The treatment of pulmonary disease associated with CF is multifactorial, encompassing prophylaxis, aggressive treatment of infection, use of antiinflammatory agents, and treatment of severe complications. Chest physiotherapy on a regular basis, perhaps using new modalities that allow patient autonomy, is also crucial. This review covers the pathogenesis of CF lung disease and current approaches to therapy, highlighting guidelines recently published by the Cystic Fibrosis Foundation. Clinicians caring for patients with CF should maximize current therapies with the goal of preserving lung function until the time a more definitive curative or controller medication is developed. Empowering patients in the process of providing their own care is a key to achieving this goal.
Subject(s)
Cystic Fibrosis/therapy , Lung Diseases/therapy , Respiratory Tract Infections/drug therapy , Cystic Fibrosis/complications , Cystic Fibrosis/physiopathology , Humans , Lung Diseases/etiology , Lung Diseases/physiopathology , Personal Autonomy , Practice Guidelines as Topic , Quality of Life , Respiratory Function Tests , Respiratory Therapy/methods , Respiratory Tract Infections/etiology , Respiratory Tract Infections/microbiologyABSTRACT
Cystic fibrosis is the most common lethal genetic disease in white populations. The outlook for patients with the disease has improved steadily over many years, largely as a result of earlier diagnosis, more aggressive therapy, and provision of care in specialised centres. Researchers now have a more complete understanding of the molecular-biological defect that underlies cystic fibrosis, which is leading to new approaches to treatment. One of these treatments, hypertonic saline, is already in use, whereas others are in advanced stages of development. We review clinical care for cystic fibrosis and discuss recent advances in the understanding of its pathogenesis, implementation of screening of neonates, and development of therapies aimed at treating the basic defect.
Subject(s)
Cystic Fibrosis , Animals , Cystic Fibrosis/diagnosis , Cystic Fibrosis/epidemiology , Cystic Fibrosis/genetics , Cystic Fibrosis/therapy , Cystic Fibrosis Transmembrane Conductance Regulator/genetics , Cystic Fibrosis Transmembrane Conductance Regulator/physiology , Disease Models, Animal , Early Diagnosis , Genetic Testing/methods , Genetic Therapy/methods , Humans , Infant, Newborn , Life Expectancy , Lung Transplantation , Mutation/genetics , Neonatal Screening/methods , Nutritional Support/methods , Practice Guidelines as Topic , Prevalence , Prognosis , Respiratory Therapy/methods , Saline Solution, Hypertonic , Treatment OutcomeABSTRACT
OBJECTIVE: The purpose of this preliminary study was to determine normal oropharyngeal flora in healthy, non-CF infants in order to help care givers better interpret culture results obtained from infants with CF. METHODS: Oropharyngeal cultures were obtained from 104 healthy infants <12 months old. Cultures were obtained using the same methods as for CF patients and were inoculated onto routine CF culture media. Approximately 20 infants from each of 5 age groups (0-2 days, 3 days to <3 months, 3 months to <6 months, 6 months to <9 months or 9 months to <1 year) were included in the well child sample. In addition, we reviewed serial results of upper airway cultures obtained during the first year of life from 20 CF-affected infants whose diagnosis was suggested by newborn screening. RESULTS: Well infants in the first 48 hr of life had very few pathogenic organisms found in their oropharyngeal cultures; 1/21 had S. aureus. Of the 83 samples from infants over 48 hr of age, we found that 27% (23/83) had S. aureus in their oropharyngeal cultures. Many infants had polymicrobial cultures. Eleven percent of culture samples had E. coli, E. cloacae, H. influenzae, or M. catarrhalis. Three of 83 cultures were positive for non-mucoid Ps. aeruginosa (3.6%), while 2 others were positive for Ps. putida. CONCLUSION: Healthy infants can have multiple gram-negative and gram-positive organisms recovered from their oropharynx. S. aureus and enteric gram-negative organisms, including non-mucoid Ps. aeruginosa, can be found in the oropharynx of well children up to 1 year of age. Care should be taken to not over interpret the presence of some of these organisms in the oropharyngeal cultures of asymptomatic CF infants.