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Artigo em Inglês | MEDLINE | ID: mdl-35771568

RESUMO

RATIONALE: Previous phase 3 trials showed treatment with lumacaftor/ivacaftor was safe and efficacious in people aged ≥2 years with cystic fibrosis homozygous for F508del-CFTR (F/F genotype). OBJECTIVES: To assess the safety, pharmacokinetics, and pharmacodynamics of lumacaftor/ivacaftor in children aged 1 to <2 years with the F/F genotype. METHODS: This open-label, phase 3 study consisted of two parts (Part A [N = 14] and Part B [N = 46]) that enrolled two cohorts based on age (Cohort 1: 18 to <24 months and Cohort 2: 12 to <18 months). For the 15-day treatment period in Part A, lumacaftor/ivacaftor dose was based on weight at screening. Pharmacokinetic data from Part A were used to determine dose-based weight boundaries for Part B (24-week treatment period). MEASUREMENTS AND MAIN RESULTS: The primary endpoint of Part A was pharmacokinetics and the primary endpoint for Part B was safety and tolerability. Secondary endpoints for Part B were absolute change in sweat chloride concentration from baseline at Week 24 and pharmacokinetics. Analysis of pharmacokinetic data from Part A confirmed the appropriateness of Part B dosing. In Part B, 44 children (95.7%) had adverse events which for most were either mild (52.2% of children) or moderate (39.1% of children) in severity. The most common adverse events were cough, infective pulmonary exacerbation of cystic fibrosis, pyrexia, and vomiting. At Week 24, mean absolute change from baseline in sweat chloride concentration was ‒29.1 mmol/L (95% confidence interval, ‒34.8 to ‒23.4). Growth parameters (body mass index, weight, length, and associated z-scores) were normal at baseline and remained normal during the 24-week treatment period. Improving trends in some biomarkers of pancreatic function and intestinal inflammation such as fecal elastase-1, serum immunoreactive trypsinogen, and fecal calprotectin were observed. CONCLUSIONS: Lumacaftor/ivacaftor was generally safe and well tolerated in children aged 1 to <2 years with the F/F genotype with a pharmacokinetic profile consistent with studies in older children. Efficacy results, including robust reductions in sweat chloride concentration, suggest the potential for CF disease modification with lumacaftor/ivacaftor treatment. These results support the use of lumacaftor/ivacaftor in this population. Clinical trial registration available at www. CLINICALTRIALS: gov, ID: NCT03601637.

3.
Med Sci Sports Exerc ; 54(5): 741-750, 2022 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-35148537

RESUMO

PURPOSE: The electronic health record, data science advances, and dynamic environmental and infectious threats to child health highlight the need for harmonized and interoperable approaches to pediatric cardiopulmonary exercise testing (CPET). Accordingly, we developed a terminology harmonization in exercise medicine and exercise science domain analysis model (THEMES DAM) to structure CPET data elements. METHODS: THEMES DAM identified 114 data elements, including participant information, calibration, equipment, protocols, laboratory personnel, encouragement strategies, and analysis procedures. We used the THEMES DAM, vetted by the international data standards organization HL7, to construct a current-state survey of pediatric CPET centers in the United States. Forty-eight of 101 centers responded to a questionnaire covering seven major topic areas (38 items). RESULTS: Centers predominantly performed between 100 and 500 tests annually. Cardiac disease represented 55% of referrals. Almost all centers calibrated gas concentrations and flow daily, but 42% never calibrated their treadmill or cycle ergometers. All centers measured V̇O2peakbut calculated differently. Centers used a variety of protocols (e.g., for treadmill: 61%, Bruce; 43%, modified Bruce; 59%, other); 44% calculated CPET slopes from submaximal portions of CPET (e.g., V̇O2-HR). All centers verbally encouraged participants, but only 40% used a standardized approach. The interpretation of CPET was done by physicians (60%), exercise physiologists (25%), exercise technicians (10%), nurses (1%), or others (4%). Ninety-one percent would agree to collaborate in multicenter research, 89% to establish dynamic reference values, and 83% to better interpret CPET. CONCLUSIONS: The survey data and the implementation of THEMES DAM could accelerate interoperability across multiple centers. This would facilitate a nimble approach to create pediatric reference values responsive to the constantly changing health environment and stimulate novel approaches to CPET research and clinical application.


Assuntos
Teste de Esforço , Consumo de Oxigênio , Criança , Ergometria , Exercício Físico , Teste de Esforço/métodos , Humanos , Valores de Referência
5.
Pediatr Pulmonol ; 56(12): 3758-3767, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34469079

RESUMO

INTRODUCTION: Newborn screening (NBS) for cystic fibrosis (CF) was implemented in all US states and DC by 2010. This hypothesis-generating study was designed to form the basis of additional analyses and to plan quality improvement initiatives. The aims were to describe the outcomes of infants with CF born during the first 9 years of universal NBS. METHODS: We included participants in the CF Foundation Patient Registry born 2010-2018 with age of recorded CF diagnosis 0-365 days old. We compared the age of center-reported diagnosis, age at first CF event (defined as earliest sweat test, clinic visit, or hospitalization), demographics, and outcomes between three cohorts born between 2010-2012, 2013-2015, and 2016-2018. RESULTS: In 6354 infants, the median age at first CF event decreased from the first to the third cohort. Weight-for-age (WFA) was < 10th percentile in about 40% of infants at the first CF Center visit. Median WFA z-score at 1-2 years was more than 0 but height-for-age (HFA) z-score was less than 0 through age 5-6 years. The second cohort had a higher HFA z-score than the first cohort at age 5-6 years. Pseudomonas aeruginosa infection was less common in later cohorts. About 1/3 of infants were hospitalized in the first year of life with no changes over time. CONCLUSION: Over 9 years of CF NBS, median age at first CF event decreased. CF NBS had positive health impacts, but early life nutritional deficits and a high rate of infant hospitalizations persist.


Assuntos
Fibrose Cística , Criança , Pré-Escolar , Estudos de Coortes , Fibrose Cística/diagnóstico , Fibrose Cística/epidemiologia , Humanos , Lactente , Recém-Nascido , Triagem Neonatal , Sistema de Registros , Estudos Retrospectivos , Estados Unidos/epidemiologia
8.
Lancet Respir Med ; 9(9): 977-988, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-33965000

RESUMO

BACKGROUND: A previous phase 3 study showed that lumacaftor-ivacaftor was generally safe and well tolerated over 24 weeks of treatment in children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation. In this study, we aimed to assess the long-term safety of lumacaftor-ivacaftor in a rollover study of children who participated in this previous phase 3 study. METHODS: In this multicentre, phase 3, open-label, extension study (study 116; VX16-809-116), we assessed safety of lumacaftor-ivacaftor in children included in a previous multicentre, phase 3, open-label study (study 115; VX15-809-115). The study was done at 20 cystic fibrosis care centres in the USA and Canada. Children aged 2-5 years with cystic fibrosis homozygous for the F508del-CFTR mutation who completed 24 weeks of lumacaftor-ivacaftor treatment in study 115 received weight-based and age-based doses of oral lumacaftor-ivacaftor: children weighing less than 14 kg and aged younger than 6 years at study 116 screening received lumacaftor 100 mg-ivacaftor 125 mg every 12 h; children weighing 14 kg or more and aged younger than 6 years at screening received lumacaftor 150 mg-ivacaftor 188 mg every 12 h; and children aged 6 years or older received lumacaftor 200 mg-ivacaftor 250 mg every 12 h. Children received treatment for up to 96 weeks, equivalent to up to 120 weeks of treatment in total from the start of study 115 to completion of study 116. The primary endpoint was the safety and tolerability of the study drug in all participants who had received lumacaftor-ivacaftor for 24 weeks in study 115 and had received at least one dose in study 116. Secondary endpoints included change from baseline in study 115 at week 96 of study 116 in sweat chloride concentration, growth parameters, markers of pancreatic function, and lung clearance index (LCI) parameters in all children who received at least one dose of lumacaftor-ivacaftor in study 116. This study is registered with ClinicalTrials.gov, NCT03125395. FINDINGS: This extension study ran from May 12, 2017, to July 17, 2019. Of 60 participants enrolled and who received lumacaftor-ivacaftor in study 115, 57 (95%) were included in study 116 and continued to receive the study drug. A total of 47 (82%) of 57 participants completed 96 weeks of treatment. Most participants (56 [98%] of 57) had at least one adverse event during study 116, most of which were mild (19 [33%] participants) or moderate (29 [51%] participants) in severity. The most common adverse events were cough (47 [82%] participants), nasal congestion (25 [44%] participants), pyrexia (23 [40%] participants), rhinorrhoea (18 [32%] participants), and vomiting (17 [30%] participants). A total of 15 (26%) participants had at least one serious adverse event; most were consistent with underlying cystic fibrosis or common childhood illnesses. Respiratory adverse events occurred in five (9%) participants, none of which were serious or led to treatment discontinuation. Elevated aminotransferase concentrations, most of which were mild or moderate in severity, occurred in ten (18%) participants. Three (5%) participants discontinued treatment due to adverse events (two due to increased aminotransferase concentrations [one of whom had concurrent pancreatitis], considered as possibly related to study drug; and one due to gastritis and metabolic acidosis, considered unlikely to be related to study drug). No clinically significant abnormalities or changes were seen in electrocardiograms, vital signs, pulse oximetry, ophthalmological examinations, or spirometry assessments. Improvements in secondary endpoints observed in study 115 were generally maintained up to week 96 of study 116, including improvements in sweat chloride concentration (mean absolute change from study 115 baseline at week 96 of study 116 -29·6 mmol/L [95% CI -33·7 to -25·5]), an increase in growth parameters and pancreatic function, and stable lung function relative to baseline, as measured by the LCI. INTERPRETATION: Lumacaftor-ivacaftor was generally safe and well tolerated, and treatment effects were generally maintained for the duration of the extension study. These findings support the use of lumacaftor-ivacaftor for up to 120 weeks in young children with cystic fibrosis aged 2 years and older homozygous for the F508del-CFTR mutation. FUNDING: Vertex Pharmaceuticals Incorporated.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Aminofenóis/efeitos adversos , Aminopiridinas/efeitos adversos , Benzodioxóis/efeitos adversos , Criança , Pré-Escolar , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Humanos , Mutação , Quinolonas
9.
Sci Transl Med ; 13(587)2021 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-33790027

RESUMO

The concentration of chloride in sweat remains the most robust biomarker for confirmatory diagnosis of cystic fibrosis (CF), a common life-shortening genetic disorder. Early diagnosis via quantitative assessment of sweat chloride allows prompt initiation of care and is critically important to extend life expectancy and improve quality of life. The collection and analysis of sweat using conventional wrist-strapped devices and iontophoresis can be cumbersome, particularly for infants with fragile skin, who often have insufficient sweat production. Here, we introduce a soft, epidermal microfluidic device ("sweat sticker") designed for the simple and rapid collection and analysis of sweat. Intimate, conformal coupling with the skin supports nearly perfect efficiency in sweat collection without leakage. Real-time image analysis of chloride reagents allows for quantitative assessment of chloride concentrations using a smartphone camera, without requiring extraction of sweat or external analysis. Clinical validation studies involving patients with CF and healthy subjects, across a spectrum of age groups, support clinical equivalence compared to existing device platforms in terms of accuracy and demonstrate meaningful reductions in rates of leakage. The wearable microfluidic technologies and smartphone-based analytics reported here establish the foundation for diagnosis of CF outside of clinical settings.


Assuntos
Fibrose Cística , Suor , Cloretos , Fibrose Cística/diagnóstico , Fibrose Cística/terapia , Humanos , Lactente , Qualidade de Vida , Smartphone
10.
Am J Respir Crit Care Med ; 203(12): 1522-1532, 2021 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-33734030

RESUMO

Rationale: Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) was shown to be efficacious and safe in patients ≥12 years of age with cystic fibrosis and at least one F508del-CFTR (cystic fibrosis transmembrane conductance regulator) allele, but it has not been evaluated in children <12 years of age. Objectives: To assess the safety, pharmacokinetics, and efficacy of ELX/TEZ/IVA in children 6 through 11 years of age with F508del-minimal function or F508del-F508del genotypes. Methods: In this 24-week open-label phase 3 study, children (N = 66) weighing <30 kg received 50% of the ELX/TEZ/IVA adult daily dose (ELX 100 mg once daily, TEZ 50 mg once daily, and IVA 75 mg every 12 h) whereas children weighing ⩾30 kg received the full adult daily dose (ELX 200 mg once daily, TEZ 100 mg once daily, and IVA 150 mg every 12 h). Measurements and Main Results: The primary endpoint was safety and tolerability. The safety and pharmacokinetic profiles of ELX/TEZ/IVA were generally consistent with those observed in older patients. The most commonly reported adverse events included cough, headache, and pyrexia; in most of the children who had adverse events, these were mild or moderate in severity. Through Week 24, ELX/TEZ/IVA treatment improved the percentage of predicted FEV1 (10.2 percentage points; 95% confidence interval [CI], 7.9 to 12.6), Cystic Fibrosis Questionnaire-Revised respiratory domain score (7.0 points; 95% CI, 4.7 to 9.2), lung clearance index2.5 (-1.71 units; 95% CI, -2.11 to -1.30), and sweat chloride (-60.9 mmol/L; 95% CI, -63.7 to -58.2); body mass index-for-age z-score increased over the 24-week treatment period when compared with the pretreatment baseline. Conclusions: Our results show ELX/TEZ/IVA is safe and efficacious in children 6 through 11 years of age with at least one F508del-CFTR allele, supporting its use in this patient population. Clinical trial registered with www.clinicaltrials.gov (NCT03691779).


Assuntos
Agonistas dos Canais de Cloreto/uso terapêutico , Regulador de Condutância Transmembrana em Fibrose Cística/efeitos dos fármacos , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Indóis/uso terapêutico , Pirazóis/uso terapêutico , Quinolonas/uso terapêutico , Alelos , Criança , Agonistas dos Canais de Cloreto/farmacocinética , Combinação de Medicamentos , Feminino , Variação Genética , Genótipo , Humanos , Indóis/farmacocinética , Masculino , Pirazóis/farmacocinética , Quinolonas/farmacocinética
11.
Pediatr Pulmonol ; 56(6): 1496-1503, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33470563

RESUMO

BACKGROUND: Cystic fibrosis transmembrane conductance regulator (CFTR) modulators are disease-modifying medications for cystic fibrosis (CF) and are shown to be efficacious for only specific CFTR mutations. CFTR mutation frequency varies by ancestry, which is different from but related to demographic racial and ethnic group. Eligibility for CFTR modulator therapy has not been previously reported by race and ethnicity. METHODS: We conducted a cross-sectional study of patients in the 2018 CF Foundation Patient Registry. We analyzed the percentage of patients in each US Census defined racial and ethnic group eligible for CFTR modulators based on CFTR mutations approved by the US FDA and then based on both mutations and FDA approval by age. We compared lung function based on CFTR modulator eligibility and prescription. FINDINGS: Based on CFTR mutations alone, 92.4% of non-Hispanic White patients, 69.7% of Black/African American patients, 75.6% of Hispanic patients, and 80.5% of other race patients eligible for CFTR modulators. For each CFTR modulator, Black/African American patients were least likely to have eligible mutations, and non-Hispanic White patients were most likely. There was no difference in the disparity between racial and/or ethnic groups with the addition of current FDA approval by age. The lowest pulmonary function in the cohort was seen in non-Hispanic White, Black/African American, and Hispanic patients not eligible for CFTR modulators. INTERPRETATION: Patients with CF from minority groups are less likely to be eligible for CFTR modulators. Because people with CF who are racial and ethnic minorities have increased disease severity and earlier mortality, this will further contribute to health disparities.


Assuntos
Fibrose Cística , Estudos Transversais , Fibrose Cística/tratamento farmacológico , Fibrose Cística/genética , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Genótipo , Humanos , Grupos Minoritários , Mutação
12.
Pediatr Pulmonol ; 56(5): 921-927, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33369260

RESUMO

INTRODUCTION: The 2017-2018 National Survey of Children's Health estimates that 30 million (42%) US children have experienced at least one adverse childhood experience (ACE), including abuse, neglect, and household dysfunction. ACEs negatively impact long-term health, and there has been no study of ACEs in cystic fibrosis (CF). We assessed willingness to disclose ACEs experienced by children with CF by surveying their parents and adults with CF. METHODS: We anonymously surveyed parents of children with CF and adults with CF at the Northwestern University/Lurie Children's CF Center to determine their willingness to disclose ACEs. RESULTS: The survey was completed by 46/157 (29%) parents and 36/105 (34%) adults with CF. Few parents (22%) and adults (17%) were willing to discuss most or all specific ACEs, more were willing to disclose the number of ACEs experienced in a category (57% parents, 47% adults), and the majority were willing to participate in anonymous research about ACEs (76% parents, 67% adults). Most parents (63%) and adults (50%) would prefer to have ACEs screened separately from their CF appointment, and most parents (63%) and adults (56%) wanted to learn more about ACEs from a member of their care team. CONCLUSIONS: Participants preferred to disclose the number of categorical ACEs rather than specific ACEs and most were open to participating in anonymous ACEs research. More research is needed before implementing screening. Educating patients, parents, and providers about ACEs and appropriate interventions when ACES are identified is needed for both research and clinical applications of ACEs screening.


Assuntos
Experiências Adversas da Infância , Fibrose Cística , Adulto , Criança , Maus-Tratos Infantis , Humanos , Pais , Inquéritos e Questionários
13.
Pediatr Pulmonol ; 2020 Nov 19.
Artigo em Inglês | MEDLINE | ID: mdl-33210843

RESUMO

During the year 2019, numerous research studies and other reports were published that are interesting and instructive to professionals who care for people with cystic fibrosis (CF) and their families.  This report is the third of 3 CF year in review articles and focuses on the multisystem manifestations of CF care. Previous articles have addressed cystic fibrosis transmembrane regulator modulators and reports on CF pulmonary disease and airway infections. It is an exciting time to be involved in care and research that aims to improve care for people with CF and their families.

14.
Pediatr Pulmonol ; 2020 Sep 24.
Artigo em Inglês | MEDLINE | ID: mdl-32970381

RESUMO

During the year 2019, research and case reports or series in the field of cystic fibrosis (CF) were in abundance. To adequately address the large body of CF research published during 2019, the CF year in review will be divided into three sections. This report is the second section, focusing specifically on new research related to pulmonary disease and infections. Additional sections will concentrate on CF transmembrane conductance regulator modulators and the multisystem effects of CF. It is an exciting time to be providing care for patients and their families with CF with all the exciting new discoveries that will be shared in these reviews.

15.
Pediatr Pulmonol ; 55(12): 3236-3242, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32833326

RESUMO

During the year 2019, research and case reports/series in the field of cystic fibrosis (CF) were in abundance. To adequately address the large body of CF research published during 2019, the CF year in review will be divided into three sections. This report is the first section, focusing specifically on new research related to cystic fibrosis transmembrane conductance regulator modulator therapy. Additional sections will concentrate on pulmonary and infections research and the multisystem effects of CF. It is an exciting time to be providing care for patients and their families with CF with all the exciting new discoveries that will be shared in these reviews.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística/tratamento farmacológico , Humanos
16.
Pediatr Pulmonol ; 55(11): 3053-3056, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32797669

RESUMO

BACKGROUND: Diagnostic sweat testing is required for infants with positive newborn-screening (NBS) tests for cystic fibrosis (CF). Infants have "quantity not sufficient" (QNS) sweat volumes more often than older children. A comprehensive study of QNS sweat volumes in infants has not previously been reported. METHODS: We surveyed US CF Centers to obtain QNS rates in all infants who had sweat testing at under 14 days and under 3 months of age. We then calculated QNS rates reported to the Cystic Fibrosis Foundation Patient Registry (CFFPR) 2010-2018 in 10-day increments from 1 to 60 days of life. We compared QNS sweat test rates in preterm (<37-weeks gestational age) vs term infants. We assessed age at sweat test and proportion of infants who did not have a sweat test reported by 60 days of age. RESULTS: Thirty-nine of 144 (27%) of CF Centers reported a mean QNS rate of 10.5% (range, 0-100) in infants 14-days-old or younger. CFFPR data showed the highest QNS rates in the youngest infants and in those born before 37 weeks of gestation. The median age at sweat testing decreased over time, but more than 22% of infants did not have a sweat test reported by 60 days. CONCLUSION: Higher QNS rates are seen in the youngest infants with CF, but more than 80% of infants younger than 2 weeks of age have adequate sweat volumes. Sweat testing should not be delayed in infants with a positive CF NBS test.


Assuntos
Fibrose Cística/diagnóstico , Suor , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Triagem Neonatal
18.
J Cyst Fibros ; 19(4): 511-520, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32122785

RESUMO

Antimicrobials have undoubtedly improved the lives of people with CF, but important antimicrobial-related toxicities and the emergence of antimicrobial-resistant bacteria associated with their use must be considered. Antimicrobial stewardship (AMS) is advocated across the spectrum of healthcare to promote the appropriate use of antimicrobials to preserve their current effectiveness and to optimise treatment, and it is clear that AMS strategies are applicable to and can benefit both non-CF and CF populations. This perspective explores the definition and components of an AMS program, the current evidence for AMS, and the reasons why AMS is a challenging concept in the provision of CF care. We also discuss the elements of CF care which align with AMS programs and principles and propose research priorities for AMS in CF.


Assuntos
Antibacterianos/farmacologia , Gestão de Antimicrobianos , Fibrose Cística/tratamento farmacológico , Humanos
19.
Pediatr Pulmonol ; 54 Suppl 3: S74-S83, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31715087

RESUMO

Understanding variability in cystic fibrosis (CF) health outcomes requires an understanding of factors that go far beyond Cystic Fibrosis Transmembrane Receptor (CFTR) function caused by different gene mutations. Social and environmental factors that influence health have a significant influence on the trajectory of health in CF and in other chronic diseases. In this article, we review demographic factors associated with poorer health outcomes in CF, known and postulated biological mechanisms of these outcomes, and interventions that healthcare teams can implement that may reduce outcome disparities.


Assuntos
Fibrose Cística/epidemiologia , Fibrose Cística/etnologia , Fibrose Cística/genética , Fibrose Cística/mortalidade , Regulador de Condutância Transmembrana em Fibrose Cística/genética , Demografia , Humanos , Mutação , Estados Unidos/epidemiologia
20.
Pediatr Pulmonol ; 54(8): 1117-1128, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31106528

RESUMO

Cystic fibrosis research and case reports were robust in the year 2018. This report summarizes research and cases related to Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) modulator therapies, inflammation and infection, epidemiology and the physiologic, and imaging assessment of disease.


Assuntos
Regulador de Condutância Transmembrana em Fibrose Cística , Fibrose Cística , Fibrose Cística/tratamento farmacológico , Fibrose Cística/epidemiologia , Fibrose Cística/microbiologia , Fibrose Cística/fisiopatologia , Humanos , Infecções/diagnóstico , Infecções/epidemiologia
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