RESUMEN
Cystic fibrosis is a genetic disease with multisystem involvement and associated morbidity and mortality that are most directly related to progressive lung disease. The hallmark findings of cystic fibrosis in the lungs are chronic inflammation and infection, leading to progressive loss of pulmonary function and often requiring lung transplant. Predominant lung findings include mucous plugging, bronchiectasis, and air trapping, often with associated atelectasis, consolidation, and emphysema; these findings form the basis of several clinical scoring systems that are used for imaging assessment. Recently, there have been major breakthroughs in the pharmacologic management of cystic fibrosis, including highly effective modulator therapies that directly target the underlying cystic fibrosis transmembrane conductance regulator molecular defect, often leading to remarkable improvements in lung function and quality of life with corresponding significant improvements in imaging markers. The authors review current guidelines regarding cystic fibrosis with respect to disease monitoring, identifying complications, and managing advanced lung disease. In addition, they discuss the evolving role of imaging, including current trends, emerging technologies, and proposed updates to imaging guidelines endorsed by international expert committees on cystic fibrosis, which favor increased use of cross-sectional imaging to enable earlier detection of structural changes in early disease and more sensitive detection of acute changes in advanced disease. It is important for radiologists to be familiar with these trends and updates so that they can most effectively assist clinicians in guiding the management of patients with cystic fibrosis in all stages of disease. ©RSNA, 2024.
Asunto(s)
Fibrosis Quística , Fibrosis Quística/diagnóstico por imagen , Humanos , Radiografía Torácica/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: VX-809, a cystic fibrosis transmembrane conductance regulator (CFTR) modulator, has been shown to increase the cell surface density of functional F508del-CFTR in vitro. METHODS: A randomised, double-blind, placebo-controlled study evaluated the safety, tolerability and pharmacodynamics of VX-809 in adult patients with cystic fibrosis (n=89) who were homozygous for the F508del-CFTR mutation. Subjects were randomised to one of four VX-809 28 day dose groups (25, 50, 100 and 200 mg) or matching placebo. RESULTS: The type and incidence of adverse events were similar among VX-809- and placebo-treated subjects. Respiratory events were the most commonly reported and led to discontinuation by one subject in each active treatment arm. Pharmacokinetic data supported a once-daily oral dosing regimen. Pharmacodynamic data suggested that VX-809 improved CFTR function in at least one organ (sweat gland). VX-809 reduced elevated sweat chloride values in a dose-dependent manner (p=0.0013) that was statistically significant in the 100 and 200 mg dose groups. There was no statistically significant improvement in CFTR function in the nasal epithelium as measured by nasal potential difference, nor were there statistically significant changes in lung function or patient-reported outcomes. No maturation of immature F508del-CFTR was detected in the subgroup that provided rectal biopsy specimens. CONCLUSIONS: In this study, VX-809 had a similar adverse event profile to placebo for 28 days in F508del-CFTR homozygous patients, and demonstrated biological activity with positive impact on CFTR function in the sweat gland. Additional data are needed to determine how improvements detected in CFTR function secondary to VX-809 in the sweat gland relate to those measurable in the respiratory tract and to long-term measures of clinical benefit. CLINICAL TRIAL NUMBER: NCT00865904.
Asunto(s)
Aminopiridinas/administración & dosificación , Benzodioxoles/administración & dosificación , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , ADN/genética , Mutación , Adolescente , Adulto , Aminopiridinas/farmacocinética , Benzodioxoles/farmacocinética , Fibrosis Quística/genética , Fibrosis Quística/metabolismo , Regulador de Conductancia de Transmembrana de Fibrosis Quística/efectos de los fármacos , Regulador de Conductancia de Transmembrana de Fibrosis Quística/metabolismo , Análisis Mutacional de ADN , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Homocigoto , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Glándulas Sudoríparas/metabolismo , Resultado del Tratamiento , Adulto JovenRESUMEN
The care for individuals with cystic fibrosis (CF) with at least one F508del mutation will greatly change as a result of the unparalleled clinical benefits observed with the new triple-combination CFTR (CF transmembrane regulator)-modulator therapy elexacaftor/tezacaftor/ivacaftor (ETI). Incorporating ETI into the standard of care creates new motivation and opportunity to consider reductions in overall treatment burden and evaluate whether other chronic medications can now be safely discontinued without loss of clinical benefit. SIMPLIFY is a master protocol poised to test the impact of discontinuing versus continuing two commonly used chronic therapies in people with CF who are at least 12 years of age or older and stable on ETI therapy. The protocol is composed of two concurrent randomized controlled trials designed to evaluate the independent short-term effects of discontinuing hypertonic saline or dornase alfa, enabling individuals on both therapies to participate in one or both trials. The primary objective for each trial is to determine whether discontinuing treatment is noninferior to continuing treatment after establishment of ETI, as measured by the 6-week absolute change in the percent-predicted forced expiratory volume in 1 second. Developing this study required a balance between ideal study-design principles and feasibility. SIMPLIFY will be the largest multicenter, randomized, controlled medication-withdrawal study in CF. This study is uniquely positioned to provide timely evidence on whether the daily treatment burden can be reduced among individuals on CFTR-modulator therapy. Clinical trial registered with www.clinicaltrials.gov (NCT04378153).
Asunto(s)
Fibrosis Quística , Quinolonas , Aminofenoles/uso terapéutico , Benzodioxoles/uso terapéutico , Fibrosis Quística/tratamiento farmacológico , Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , HumanosAsunto(s)
Carcinoma de Células Escamosas/patología , Hemangiosarcoma/diagnóstico , Neoplasias Pulmonares/diagnóstico , Nódulos Pulmonares Múltiples/diagnóstico , Neoplasias Primarias Secundarias/diagnóstico , Neoplasias de la Glándula Submandibular/patología , Anciano , Hemangiosarcoma/diagnóstico por imagen , Hemangiosarcoma/patología , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Neoplasias Pulmonares/diagnóstico por imagen , Neoplasias Pulmonares/patología , Masculino , Nódulos Pulmonares Múltiples/diagnóstico por imagen , Nódulos Pulmonares Múltiples/patología , Neoplasias Primarias Secundarias/diagnóstico por imagen , Neoplasias Primarias Secundarias/patología , Tomografía Computarizada por Rayos XRESUMEN
RATIONALE: Few noninvasive biomarkers for pulmonary inflammation are currently available that can assess the lung-specific response to antiinflammatory treatments. Positron emission tomography with [(18)F]fluorodeoxyglucose (FDG-PET) is a promising new method that can be used to quantify pulmonary neutrophilic inflammation. OBJECTIVES: To evaluate the ability of FDG-PET to measure the pulmonary antiinflammatory effects of hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) and recombinant human activated protein C (rhAPC) in a human model of experimentally-induced lung inflammation. METHODS: Eighteen healthy volunteers were randomized to receive placebo, lovastatin, or rhAPC before intrabronchial segmental endotoxin challenge. FDG-PET imaging was performed before and after endotoxin instillation. The rate of [(18)F]FDG uptake was calculated as the influx constant K(i) by Patlak graphical analysis. Bronchoalveolar lavage (BAL) was performed to determine leukocyte concentrations for correlation with the PET imaging results. MEASUREMENTS AND MAIN RESULTS: There was a statistically significant decrease in K(i) in the lovastatin-treated group that was not seen in the placebo-treated group, suggesting attenuation of inflammation by lovastatin treatment despite a small decrease in BAL total leukocyte and neutrophil counts that was not statistically significant. No significant decrease in K(i) was observed in the rhAPC-treated group, correlating with a lack of change in BAL parameters and indicating no significant antiinflammatory effect with rhAPC. CONCLUSIONS: FDG-PET imaging is a sensitive method for quantifying the lung-specific response to antiinflammatory therapies and may serve as an attractive platform for assessing the efficacy of novel antiinflammatory therapies at early phases in the drug development process. Clinical trial registered with www.clinicaltrials.gov (NCT00741013).
Asunto(s)
Fluorodesoxiglucosa F18 , Neumonía/diagnóstico por imagen , Radiofármacos , Adulto , Anticolesterolemiantes/uso terapéutico , Líquido del Lavado Bronquioalveolar , Método Doble Ciego , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lovastatina/uso terapéutico , Masculino , Activación Neutrófila , Neumonía/tratamiento farmacológico , Neumonía/inmunología , Tomografía de Emisión de Positrones/métodos , Proteína C/uso terapéutico , Proteínas Recombinantes/uso terapéutico , Adulto JovenRESUMEN
OBJECTIVE: Provide recommendations to the cystic fibrosis (CF) community to facilitate timely referral for lung transplantation for individuals with CF. METHODS: The CF Foundation organized a multidisciplinary committee to develop CF Lung Transplant Referral Consensus Guidelines. Three workgroups were formed: timing for transplant referral; modifiable barriers to transplant; and transition to transplant care. A focus group of lung transplant recipients with CF and spouses of CF recipients informed guideline development. RESULTS: The committee formulated 21 recommendation statements based on literature review, committee member practices, focus group insights, and in response to public comment. Critical approaches to optimizing access to lung transplant include early discussion of this treatment option, assessment for modifiable barriers to transplant, and open communication between the CF and lung transplant centers. CONCLUSIONS: These guidelines will help CF providers counsel their patients and may reduce the number of individuals with CF who die without consideration for lung transplant.
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Fibrosis Quística , Toma de Decisiones Conjunta , Trasplante de Pulmón , Selección de Paciente , Derivación y Consulta/organización & administración , Fibrosis Quística/diagnóstico , Fibrosis Quística/cirugía , Humanos , Trasplante de Pulmón/ética , Trasplante de Pulmón/métodos , Trasplante de Pulmón/psicología , Guías de Práctica Clínica como AsuntoRESUMEN
Recent studies indicate that a focal, limited, inflammatory response can be safely elicited after direct bronchial instillation of small doses of endotoxin into a single lung segment. Because the radiotracer [18F]fluorodeoxyglucose ([18F]FDG) is taken up at accelerated rates within inflamed tissues, we hypothesized that we could detect and quantify this regional inflammatory response with positron emission tomography (PET). We imaged 18 normal volunteers in a dose-escalation study with 3 endotoxin dosing groups (n = 6 in each group): 1 ng/kg, 2 ng/kg, and 4 ng/kg. Endotoxin was instilled by bronchoscopy into a segment of the right middle lobe, with imaging performed approximately 24 h later, followed by bronchoalveolar lavage (BAL). A "subtraction imaging analysis" was performed in the highest dose cohort to identify the area of inflammation, using the preendotoxin scan as a baseline. BAL neutrophil counts were significantly higher in the highest dose group compared with the other two groups (1,413 +/- 625 vs. 511 +/- 396 and 395 +/- 400 cells/mm3; P < 0.05). Autoradiography performed on cells harvested by BAL showed specific [3H]deoxyglucose ([3H]DG) uptake limited to neutrophils. In vitro [3H]DG uptake in BAL neutrophils in the 4 ng/kg dose group (but not in the 2 ng/kg group) was statistically greater than in peripheral blood neutrophils obtained before endotoxin instillation. The rate of [18F]FDG uptake was greatest in the 4 ng/kg group, with a consistent, statistically significant increase in the rate of uptake after endotoxin instillation compared with baseline. We conclude that the inflammatory response to low-dose endotoxin in a single lung segment can be visualized and quantified by imaging with FDG-PET.
Asunto(s)
Endotoxinas/efectos adversos , Fluorodesoxiglucosa F18/farmacocinética , Neumonía/diagnóstico por imagen , Neumonía/etiología , Tomografía de Emisión de Positrones , Radiofármacos/farmacocinética , Autorradiografía/métodos , Lavado Broncoalveolar , Recuento de Células , Relación Dosis-Respuesta a Droga , Femenino , Humanos , Pulmón/microbiología , Pulmón/patología , Masculino , Neutrófilos/química , Neutrófilos/patología , Neumonía/patologíaRESUMEN
STUDY OBJECTIVES: To determine risk factors associated with an accelerated decline in lung function in cystic fibrosis (CF), and whether longitudinal changes in FEV(1) would be a better predictor of the need for referral for lung transplantation than any single value for FEV(1.) DESIGN: The rate of decline in pulmonary function was determined by standard linear regression from each patient's calendar year's best percentage of predicted FEV(1) (%FEV(1)) over at least 4 years, and patients were classified into three cohorts based on their rate of decline. Differences between groups in age, weight-for-age z score, gender, genotype, pancreatic status, diabetes, and the presence of various lung microbial isolates were analyzed. A subset of 30 patients referred for lung transplantation were further analyzed, and a prediction model for lung transplantation referral was created using the patient's rate of decline in lung function, the mean waiting time for donor organs, and the average level of lung function of patients prior to lung transplantation. PATIENTS: One hundred fifty-three patients with CF followed up at the Washington University Adult Cystic Fibrosis Center. RESULTS: Younger age, malnutrition, and concurrent infection with both Pseudomonas aeruginosa and Staphylococcus aureus were significant (p < 0.05) risk factors for rapidly declining lung function. Among patients with rapidly declining lung function, referral for lung transplantation would have occurred 8.4 months earlier than actual referral age (p < 0.05) if the prediction model had been used, possibly resulting in additional patient salvage in several cases. CONCLUSIONS: Rate of decline in lung function should be routinely evaluated in patients with CF, and a prediction model utilizing the rate of decline in %FEV(1), and the median regional waiting period for donor lungs for patients with CF may assist in the timing of referral for lung transplantation and more rapidly declining lung function.
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Fibrosis Quística/fisiopatología , Fibrosis Quística/cirugía , Trasplante de Pulmón , Pulmón/fisiopatología , Adulto , Factores de Edad , Peso Corporal , Complicaciones de la Diabetes , Femenino , Volumen Espiratorio Forzado , Genotipo , Humanos , Pulmón/microbiología , Masculino , Modelos Teóricos , Páncreas/fisiopatología , Derivación y Consulta , Análisis de Regresión , Factores de Riesgo , Terapia Recuperativa , Factores Sexuales , Factores de TiempoRESUMEN
A 38-year-old immunocompetent man with occupational exposure to Aspergillus presented with dyspnea, pleuritic chest pain, and hemoptysis. Chest roentgenograms and computed tomography scans demonstrated multiple pulmonary nodules bilaterally. An initial set of bronchial washing cultures grew Aspergillus fumigatus, serologic testing showed an elevated anti-Aspergillus titer, and immunodiffusion testing was positive for antibody against A. fumigatus and A. niger. There was no microbiologic or serologic evidence of infection by other pathogens, and no clinical or laboratory evidence of autoimmune disease. An open lung biopsy was diagnostic of pulmonary hyalinizing granuloma. This novel association with Aspergillus infection not only expands the spectrum of pathogens linked to pulmonary hyalinizing granuloma but also documents a new pattern of lung disease that can be caused by Aspergillus.
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Aspergilosis/patología , Aspergillus , Granuloma/patología , Enfermedades Pulmonares Fúngicas/patología , Adulto , Aspergilosis/complicaciones , Aspergillus/inmunología , Aspergillus/aislamiento & purificación , Aspergillus/patogenicidad , Granuloma/complicaciones , Granuloma/metabolismo , Humanos , Hialina/metabolismo , Enfermedades Pulmonares Fúngicas/complicaciones , Enfermedades Pulmonares Fúngicas/metabolismo , Masculino , Radiografía TorácicaRESUMEN
BACKGROUND: Cystic fibrosis (CF) is a common life-shortening genetic disease in which women have been described to have worse outcomes than males, particularly in response to respiratory infections with Pseudomonas aeruginosa. However, as advancements in therapies have improved life expectancy, this gender disparity has been challenged. The objective of this study is to examine whether a gender-based survival difference still exists in this population and determine the impact of common CF respiratory infections on outcomes in males versus females with CF. METHODS: We conducted a retrospective cohort analysis of 32,766 patients from the United States Cystic Fibrosis Foundation Patient Registry over a 13-year period. Kaplan-Meier and Cox proportional hazards models were used to compare overall mortality and pathogen based survival rates in males and females. RESULTS: Females demonstrated a decreased median life expectancy (36.0 years; 95% confidence interval [CI] 35.0-37.3) compared with men (38.7 years; 95% CI 37.8-39.6; p<0.001). Female gender proved to be a significant risk factor for death (hazard ratio 2.22, 95% CI 1.79-2.77), despite accounting for variables known to influence CF mortality. Women were also found to become colonized earlier with several bacteria and to have worse outcomes with common CF pathogens. CONCLUSIONS: CF women continue to have a shortened life expectancy relative to men despite accounting for key CF-related comorbidities. Women also become colonized with certain common CF pathogens earlier than men and show a decreased life expectancy in the setting of respiratory infections. Explanations for this gender disparity are only beginning to be unraveled and further investigation into mechanisms is needed to help develop therapies that may narrow this gender gap.
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Bacterias/patogenicidad , Fibrosis Quística/mortalidad , Esperanza de Vida , Infecciones del Sistema Respiratorio/epidemiología , Factores Sexuales , Adolescente , Adulto , Edad de Inicio , Bacterias/aislamiento & purificación , Niño , Fibrosis Quística/diagnóstico , Fibrosis Quística/microbiología , Femenino , Humanos , Incidencia , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Modelos de Riesgos Proporcionales , Sistema de Registros , Infecciones del Sistema Respiratorio/complicaciones , Infecciones del Sistema Respiratorio/microbiología , Estudios Retrospectivos , Factores de Riesgo , Factores Socioeconómicos , Tasa de Supervivencia , Resultado del Tratamiento , Estados Unidos/epidemiología , Adulto JovenRESUMEN
BACKGROUND: Ataluren was developed to restore functional protein production in genetic disorders caused by nonsense mutations, which are the cause of cystic fibrosis in 10% of patients. This trial was designed to assess the efficacy and safety of ataluren in patients with nonsense-mutation cystic fibrosis. METHODS: This randomised, double-blind, placebo-controlled, phase 3 study enrolled patients from 36 sites in 11 countries in North America and Europe. Eligible patients with nonsense-mutation cystic fibrosis (aged ≥ 6 years; abnormal nasal potential difference; sweat chloride >40 mmol/L; forced expiratory volume in 1 s [FEV1] ≥ 40% and ≤ 90%) were randomly assigned by interactive response technology to receive oral ataluren (10 mg/kg in morning, 10 mg/kg midday, and 20 mg/kg in evening) or matching placebo for 48 weeks. Randomisation used a block size of four, stratified by age, chronic inhaled antibiotic use, and percent-predicted FEV1. The primary endpoint was relative change in percent-predicted FEV1 from baseline to week 48, analysed in all patients with a post-baseline spirometry measurement. This study is registered with ClinicalTrials.gov, number NCT00803205. FINDINGS: Between Sept 8, 2009, and Nov 30, 2010, 238 patients were randomly assigned, of whom 116 in each treatment group had a valid post-baseline spirometry measurement. Relative change from baseline in percent-predicted FEV1 did not differ significantly between ataluren and placebo at week 48 (-2.5% vs -5.5%; difference 3.0% [95% CI -0.8 to 6.3]; p=0.12). The number of pulmonary exacerbations did not differ significantly between treatment groups (rate ratio 0.77 [95% CI 0.57-1.05]; p=0.0992). However, post-hoc analysis of the subgroup of patients not using chronic inhaled tobramycin showed a 5.7% difference (95% CI 1.5-10.1) in relative change from baseline in percent-predicted FEV1 between the ataluren and placebo groups at week 48 (-0.7% [-4.0 to 2.1] vs -6.4% [-9.8 to -3.7]; nominal p=0.0082), and fewer pulmonary exacerbations in the ataluern group (1.42 events [0.9-1.9] vs 2.18 events [1.6-2.7]; rate ratio 0.60 [0.42-0.86]; nominal p=0.0061). Safety profiles were generally similar for ataluren and placebo, except for the occurrence of increased creatinine concentrations (ie, acute kidney injury), which occurred in 18 (15%) of 118 patients in the ataluren group compared with one (<1%) of 120 patients in the placebo group. No life-threatening adverse events or deaths were reported in either group. INTERPRETATION: Although ataluren did not improve lung function in the overall population of nonsense-mutation cystic fibrosis patients who received this treatment, it might be beneficial for patients not taking chronic inhaled tobramycin. FUNDING: PTC Therapeutics, Cystic Fibrosis Foundation, US Food and Drug Administration's Office of Orphan Products Development, and the National Institutes of Health.
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Regulador de Conductancia de Transmembrana de Fibrosis Quística/genética , Fibrosis Quística/tratamiento farmacológico , Fibrosis Quística/genética , Oxadiazoles/uso terapéutico , Lesión Renal Aguda/inducido químicamente , Adolescente , Adulto , Antibacterianos/administración & dosificación , Niño , Cloruros/análisis , Codón sin Sentido , Fibrosis Quística/fisiopatología , Progresión de la Enfermedad , Método Doble Ciego , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Oxadiazoles/efectos adversos , Sudor/química , Tobramicina/administración & dosificación , Adulto JovenRESUMEN
Constrictive bronchiolitis obliterans is a fibrotic disease of small airways characterized by progressive obliteration of the airway lumen, with resulting obstructive pulmonary physiology. While previous work has demonstrated the collagenous nature of the constrictive fibrotic lesions, elastin expression in the disease has been poorly characterized. Elastin is a critical component of the pulmonary extracellular matrix, and is responsible for the reversible deformability characteristic of the alveoli, pulmonary blood vessels, and airways. Elastin is a long-lived protein with virtually no active protein production occurring after lung development is completed during early childhood. We report a novel case of cryptogenic bronchiolitis obliterans in which elastin gene expression is actively upregulated in affected airways, and accompanied by myofibroblast hyperplasia and disorganized elastic fiber deposition. In addition, deposition of new elastic fibers by myofibroblasts is noted in the alveoli surrounding the affected bronchioles.
Asunto(s)
Bronquiolitis Obliterante/metabolismo , Elastina/metabolismo , Regulación hacia Arriba/inmunología , Bronquiolitis Obliterante/fisiopatología , Elastina/genética , Expresión Génica , Humanos , Masculino , Persona de Mediana Edad , Estados UnidosRESUMEN
RATIONALE: Although infection contributes to morbidity in patients with cystic fibrosis (CF), the host inflammatory response is also an important cause of progressive pulmonary function deterioration. Quantifying the inflammatory burden in these patients is challenging and often requires invasive procedures. Positron emission tomographic imaging with [18F]fluorodeoxyglucose ([18FDG]) could be used as a noninvasive alternative to quantify lung inflammation. OBJECTIVE: To determine the relationships among lung [18F]FDG uptake, bronchoalveolar lavage (BAL) neutrophil concentrations, and pulmonary function in patients with CF. METHODS: Twenty patients and seven healthy volunteers were studied. A subset of seven patients also consented to undergo BAL. The uptake of [18F]FDG by the lungs was measured as the net influx rate constant Ki. Patients were stratified by rate of decline in pulmonary function into stable, intermediate, and rapidly declining groups. Ki was compared among groups and was correlated against neutrophil concentrations in BAL fluid. RESULTS: Ki was significantly elevated (p<0.05) among patients with CF as a whole compared with healthy control subjects (0.0015+/-0.0009 versus 0.0007+/-0.0002 ml blood/ml lung/min) but especially in patients with rapidly declining pulmonary function (0.0022+/-0.0011 ml blood/ml lung/min). Ki correlated positively with the number of neutrophils present in BAL fluid. CONCLUSION: Imaging with [18F]fluorodeoxyglucose and positron emission tomography can be used to assess inflammatory burden in patients with CF. Elevations in Ki may be able to identify patients with more aggressive disease and may be useful in monitoring changes in inflammatory burden in response to novel treatments.