RESUMO
Clinical trials for the treatment of cystic fibrosis (CF) lung disease are important to test and optimise new therapeutic interventions. To evaluate the effect of these interventions, sensitive and accurate outcome measures are needed. The most commonly used endpoints are spirometric variables such as the forced expiratory volume in 1 s and respiratory tract exacerbations. Unfortunately, these endpoints are relatively insensitive for monitoring progression of CF lung disease, and thus require a large number of patients when used in clinical studies. In addition, these endpoints are not suitable to study CF lung disease in young children. Chest computed tomography (CT) holds great promise for use as a sensitive surrogate endpoint in CF. A large body of evidence has been produced to validate the use of chest CT as a primary endpoint to study CF lung disease. However, before chest CT can be used in clinical trials, it has to be recognised as a validated surrogate endpoint by regulatory agencies. The aim of this review is to summarise what is currently known about the use of chest CT as surrogate endpoint in clinical trials in CF.
Assuntos
Ensaios Clínicos como Assunto/métodos , Fibrose Cística/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Fibrose Cística/fisiopatologia , Fibrose Cística/terapia , Progressão da Doença , Humanos , Processamento de Imagem Assistida por Computador , Qualidade de Vida , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Espirometria , Resultado do TratamentoRESUMO
RATIONALE: Up to one-third of patients with cystic fibrosis (CF) awaiting lung transplantation (LTX) die while waiting. Inclusion of computed tomography (CT) scores may improve survival prediction models such as the lung allocation score (LAS). OBJECTIVES: This study investigated the association between CT and survival in patients with CF screened for LTX. METHODS: Clinical data and chest CTs of 411 patients with CF screened for LTX between 1990 and 2005 were collected from 17 centers. CTs were scored with the Severe Advanced Lung Disease (SALD) four-category scoring system, including the components infection/inflammation (INF), air trapping/hypoperfusion (AT), normal/hyperperfusion (NOR), and bulla/cysts (BUL). The volume of each component was computed using semiautomated software. Survival analysis included Kaplan-Meier curves and Cox regression models. MEASUREMENTS AND MAIN RESULTS: Three hundred and sixty-six (186 males) of 411 patients entered the waiting list (median age, 23 yr; range, 5-58 yr). Subsequently, 67 of 366 (18%) died while waiting, 263 of 366 (72%) underwent LTX, and 36 of 366 (10%) were awaiting LTX at the census date. INF and LAS were significantly associated with waiting list mortality in univariate analyses. The multivariate Cox model including INF and LAS grouped in tertiles, and comparing tertiles 2 and 3 with tertile 1, showed waiting list mortality hazard ratios of 1.62 (95% confidence interval [95% CI], 0.78-3.36; P = 0.19) and 2.65 (95% CI, 1.35-5.20; P = 0.005) for INF, and 1.42 (95% CI, 0.63-3.24; P = 0.40), and 2.32 (95% CI, 1.17-4.60; P = 0.016) for LAS, respectively. These results indicated that INF and LAS had significant, independent predictive value for survival. CONCLUSIONS: CT score INF correlates with survival, and adds to the predictive value of LAS.
Assuntos
Fibrose Cística/diagnóstico por imagem , Transplante de Pulmão , Tomografia Computadorizada por Raios X , Listas de Espera/mortalidade , Adolescente , Adulto , Criança , Pré-Escolar , Estudos de Coortes , Fibrose Cística/mortalidade , Fibrose Cística/cirurgia , Técnicas de Apoio para a Decisão , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Prognóstico , Modelos de Riscos Proporcionais , Índice de Gravidade de Doença , Adulto JovemRESUMO
PURPOSE: To estimate the effect of the number of computed tomography (CT) sections on trapped air (TA) assessment in patients with cystic fibrosis (CF) by using an established scoring system and a new quantitative scoring system and to compare CT and pulmonary function test (PFT) estimates of TA in a cross-sectional and longitudinal study. MATERIALS AND METHODS: In this institutional review board-approved pilot study, 20 subjects aged 6-20 years (12 female and eight male; median age, 12.6 years) contributed two expiratory CT studies (three-section baseline CT, volumetric follow-up CT) and two PFT studies over 2 years after parental informed consent was obtained. From follow-up CT studies, seven sets were composed: Set 1 was volumetric. Sets 2, 3, 4, and 5, had spacing of 2.4, 4.8, 9.6, and 20.4 mm, respectively, between sections. Sets 6 and 7 contained five and three sections, respectively. Longitudinal follow-up was performed with three sections. All images were deidentified and randomized, and TA was scored with the Brody II system and a new quantitative system. Statistical analysis included the Wilcoxon signed rank test, calculation of Spearman and intraclass correlation coefficients, and use of three-section and linear mixed models. RESULTS: For the Brody II system, the intraclass correlation coefficient for set 1 versus those for sets 2 through 7 was 0.75 versus 0.87; however, mean scores from sets 6 and 7 were significantly lower than the mean score from set 1 (P = .01 and P < .001, respectively). For the quantitative system, the number of sections did not affect TA assessment (intraclass correlation coefficient range, 0.82-0.88; P > .13 for all). CT and PFT estimates were not correlated (r(s) = 20.19 to 0.09, P = .43-.93). No change in TA over time was found for CT or PFT (P > .16 for all). CONCLUSION: The number of sections affected Brody II estimates, suggesting that three-section protocols lead to underestimation of TA assessment in patients with CF when using the Brody II system; CT and PFT estimates of TA showed no correlation and no significant change over time.
Assuntos
Ar , Fibrose Cística/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Criança , Estudos Transversais , Fibrose Cística/fisiopatologia , Expiração , Feminino , Seguimentos , Humanos , Modelos Lineares , Estudos Longitudinais , Masculino , Testes de Função Respiratória , Estudos Retrospectivos , Estatísticas não ParamétricasRESUMO
OBJECTIVES: To determine the diagnostic accuracy of high-resolution computed tomography (HRCT) for the detection of nontuberculous mycobacterium infection (NTM) in adult cystic fibrosis (CF) patients. METHODS: Twenty-seven CF patients with sputum-culture-proven NTM (NTM+) underwent HRCT. An age, gender and spirometrically matched group of 27 CF patients without NTM (NTM-) was included as controls. Images were randomly and blindly analysed by two readers in consensus and scored using a modified Bhalla scoring system. RESULTS: Significant differences were seen between NTM (+) and NTM (-) patients in the severity of the bronchiectasis subscore [45 % (1.8/4) vs. 35 % (1.4/4), P = 0.029], collapse/consolidation subscore [33 % (1.3/3 vs. 15 % (0.6/3)], tree-in-bud/centrilobular nodules subscore [43 % (1.7/3) vs. 25 % (1.0/3), P = 0.002] and the total CT score [56 % (18.4/33) vs. 46 % (15.2/33), P = 0.002]. Binary logistic regression revealed BMI, peribronchial thickening, collapse/consolidation and tree-in-bud/centrilobular nodules to be predictors of NTM status (R(2 )= 0.43). Receiver-operator curve analysis of the regression model showed an area under the curve of 0.89, P < 0.0001. CONCLUSION: In adults with CF, seven or more bronchopulmonary segments showing tree-in-bud/centrilobular nodules on HRCT is highly suggestive of NTM colonisation. KEY POINTS: Lung function declines rapidly in cystic fibrosis patients with nontuberculous mycobacterium infection. High-resolution computed tomography can help identify nontuberculous mycobacterium in CF patients. Extensive collapse/consolidation and tree-in-bud/centrilobular nodules are predictive of NTM infection. Multiple bronchopulmonary segments showing tree-in-bud/centrilobular nodules strongly suggest nontuberculous mycobacterium infection.
Assuntos
Fibrose Cística/diagnóstico por imagem , Infecções por Mycobacterium não Tuberculosas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Distribuição de Qui-Quadrado , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Curva ROC , Índice de Gravidade de Doença , Espirometria , Escarro/microbiologiaRESUMO
PURPOSE: To assess whether chest computed tomography (CT) scores from ultra-low-dose end-expiratory scans alone could suffice for assessment of all cystic fibrosis (CF)-related structural lung abnormalities. MATERIALS AND METHODS: In this institutional review board-approved study, 20 patients with CF aged 6-20 years (eight males, 12 females) underwent low-dose end-inspiratory CT and ultra-low-dose end-expiratory CT. Informed consent was obtained. Scans were randomized and scored by using the Brody-II CT scoring system to assess bronchiectasis, airway wall thickening, mucus plugging, and opacities. Scoring was performed by two observers who were blinded to patient identity and clinical information. Mean scores were used for all analyses. Statistical analysis included assessment of intra- and interobserver variability, calculation of intraclass correlation coefficients (ICCs), and Bland-Altman plots. RESULTS: Median age was 12.6 years (range, 6.3-20.3 years), median forced expiratory volume in 1 second was 100% (range, 46%-127%) of the predicted value, and median forced vital capacity was 99% (range, 61%-123%) of the predicted value. Very good agreement was observed between end-inspiratory and end-expiratory CT scores for Brody-II total score (ICC = 0.96), bronchiectasis (ICC = 0.98), airway wall thickening (ICC = 0.94), mucus plugging (ICC = 0.96), and opacities (ICC = 0.90). Intra- and interobserver agreement were good to very good (ICC range, 0.70-0.98). Bland-Altman plots showed that differences in scores were independent of score magnitude. CONCLUSION: In this pilot study, CT scores from end-expiratory and end-inspiratory CT match closely, suggesting that ultra-low-dose end-expiratory CT alone may be sufficient for monitoring CF-related lung disease. This would help reduce radiation dose for a single investigation by up to 75%.
Assuntos
Fibrose Cística/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Criança , Feminino , Humanos , Medidas de Volume Pulmonar , Masculino , Projetos Piloto , Doses de Radiação , Adulto JovemRESUMO
BACKGROUND: To evaluate the relationship between lung parenchymal abnormalities on chest CT and health-related quality of life in adult cystic fibrosis (CF). METHODS: The chest CT scans of 101 consecutive CF adults (mean age 27.8±7.9, 64 males) were prospectively scored by two blinded radiologists in consensus using a modified Bhalla score. Health-related quality of life was assessed using the revised Quittner Cystic Fibrosis Questionnaire (CFQ-R). Multiple regressions were performed with each of the CFQ-R domains and all clinical and imaging findings to assess independent correlations. RESULTS: There were 18 inpatients and 83 outpatients. For the cohort of inpatients, CT abnormalities were significantly (P<0.005 for all) associated with Respiratory Symptoms (Air Trapping), and also with Social Functioning (Consolidation) and Role Functioning (Consolidation). For outpatients, CT abnormalities were significantly (P<0.005 for all) associated with Respiratory Symptoms (Consolidation) and also with Physical Functioning (Consolidation), Vitality (Consolidation, Severity of Bronchiectasis), Eating Problems (airway wall thickening), Treatment Burden (Total CT Score), Body Image (Severity of Bronchiectasis) and Role Functioning (Tree-in-bud nodules). Consolidation was the commonest independent CT predictor for both inpatients (predictor for 2 domains) and outpatients (predictor in 3 domains). Several chest CT abnormalities excluded traditional measures such as FEV1 and BMI from the majority of CFQ-R domains. CONCLUSIONS: Chest CT abnormalities are significantly associated with quality of life measures in adult CF, independent of clinical or spirometric measurements.
RESUMO
PURPOSE: To investigate changes in trapped air volume and distribution over time and compare computed tomography (CT) with pulmonary function tests for determining trapped air. METHODS: Thirty children contributed two CTs and pulmonary function tests over 2 years. Localized changes in trapped air on CT were assessed using image analysis software, by deforming the CT at timepoint 2 to match timepoint 1, and measuring the volume of stable (TAstable), disappeared (TAdisappeared) and new (TAnew) trapped air as a proportion of total lung volume. We used the difference between total lung capacity measured by plethysmography and helium dilution, residual volume to total lung capacity ratio, forced expiratory flow at 75% of vital capacity, and maximum mid-expiratory flow as pulmonary function test markers of trapped air. Statistical analysis included Wilcoxon's signed rank test and Spearman correlation coefficients. RESULTS: Median (range) age at baseline was 11.9 (5-17) years. Median (range) of trapped air was 9.5 (2-33)% at timepoint 1 and 9.0 (0-25)% at timepoint 2 (p=0.49). Median (range) TAstable, TAdisappeared and TAnew were respectively 3.0 (0-12)%, 5.0 (1-22)% and 7.0 (0-20)%. Trapped air on CT correlated statistically significantly with all pulmonary function measures (p<0.01), other than residual volume to total lung capacity ratio (p=0.37). CONCLUSION: Trapped air on CT did not significantly progress over 2 years, may have a substantial stable component, and is significantly correlated with pulmonary function markers.
Assuntos
Ar , Fibrose Cística/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Adolescente , Adulto , Criança , Pré-Escolar , Fibrose Cística/fisiopatologia , Feminino , Seguimentos , Humanos , Processamento de Imagem Assistida por Computador , Pulmão/fisiopatologia , Medidas de Volume Pulmonar , Masculino , Projetos Piloto , Reprodutibilidade dos Testes , Testes de Função Respiratória , Estudos Retrospectivos , Capacidade Vital , Adulto JovemRESUMO
BACKGROUND: Children with cystic fibrosis (CF) are often Pseudomonas aeruginosa (PsA) free and exhibit normal spirometry between the ages of 5 and 7. It is reported that computed tomography (CT) is more sensitive than FEV1 as an instrument in the identification of pulmonary disease. It is not known whether CF-CT scores in childhood may be used to highlight children at risk of developing severe disease. AIMS: 1 - To assess the number of respiratory exacerbations (RTEs) during a follow-up period of 6 years and their correlation with the CF-CT scores in young CF children. 2 - To assess whether PsA-negative CF children with high chest CF-CT scores are more likely to develop chronic PsA lung infection. METHODS: 68 chest CT performed in patients without chronic PsA infection were scored. All patients (median age 7.8 years) had at least 4 clinical, functional and microbiologic assessments/year in the subsequent 6 years. RTE was defined as hospitalization and IV antibiotic treatment for respiratory symptoms. RESULTS: 86.8% patients had <3 RTEs in the 6 year follow-up period. The number of RTEs in the 6 years subsequent to the CT scan was correlated to the bronchiectasis CT score (BCTS) (r = 0.612; p < 0.001) and to FEV1 at baseline (r = -0.495, p<0.001). A BCTS ≥ 17.5 identified patients with >3 RTEs during follow-up (sensitivity: 100%, specificity: 85%), while FEV1 did not. Only BCTS was significant in a logistic multivariate model (RR 1.15). BCTS was significantly lower and FEV1 higher in patients who did not develop chronic PsA infection by the end of the study. CONCLUSION: In CF children free from chronic PsA, both CT scores and FEV1 values demonstrate significant correlation with disease severity in the subsequent 6 years but CT score has higher predictive value in the identification of patients at risk.
Assuntos
Fibrose Cística/complicações , Fibrose Cística/diagnóstico por imagem , Pneumopatias/diagnóstico por imagem , Infecções por Pseudomonas/diagnóstico por imagem , Pseudomonas aeruginosa , Radiografia Torácica , Tomografia Computadorizada por Raios X , Criança , Pré-Escolar , Doença Crônica , Feminino , Volume Expiratório Forçado , Humanos , Pneumopatias/microbiologia , Pneumopatias/fisiopatologia , Masculino , Modelos Estatísticos , Infecções por Pseudomonas/fisiopatologia , Índice de Gravidade de Doença , EspirometriaRESUMO
This paper presents a mass preserving image registration algorithm for lung CT images. To account for the local change in lung tissue intensity during the breathing cycle, a tissue appearance model based on the principle of preservation of total lung mass is proposed. This model is incorporated into a standard image registration framework with a composition of a global affine and several free-form B-Spline transformations with increasing grid resolution. The proposed mass preserving registration method is compared to registration using the sum of squared intensity differences as a similarity function on four groups of data: 44 pairs of longitudinal inspiratory chest CT scans with small difference in lung volume; 44 pairs of longitudinal inspiratory chest CT scans with large difference in lung volume; 16 pairs of expiratory and inspiratory CT scans; and 5 pairs of images extracted at end exhale and end inhale phases of 4D-CT images. Registration errors, measured as the average distance between vessel tree centerlines in the matched images, are significantly lower for the proposed mass preserving image registration method in the second, third and fourth group, while there is no statistically significant difference between the two methods in the first group. Target registration error, assessed via a set of manually annotated landmarks in the last group, was significantly smaller for the proposed registration method.
Assuntos
Imageamento Tridimensional/métodos , Neoplasias Pulmonares/diagnóstico por imagem , Pulmão/diagnóstico por imagem , Reconhecimento Automatizado de Padrão/métodos , Intensificação de Imagem Radiográfica/métodos , Técnicas de Imagem de Sincronização Respiratória/métodos , Tomografia Computadorizada por Raios X/métodos , Algoritmos , Simulação por Computador , Humanos , Modelos Biológicos , Interpretação de Imagem Radiográfica Assistida por Computador/métodos , Reprodutibilidade dos Testes , Sensibilidade e EspecificidadeRESUMO
OBJECTIVE: Respiratory tract exacerbation rate (RTE-R) is a key clinical efficacy end point in cystic fibrosis (CF) trials. Chest CT scanning holds great potential as a surrogate end point. Evidence supporting the ability of CT scan scores to predict RTE-R is an important step in validating CT scanning as a surrogate end point. The objective of this study was to investigate the association between CT scan scores and RTE-R in a cohort of pediatric patients with CF. METHODS: A retrospective review of data from pediatric patients with CF included chest CT scans, spirometry, and 2 years follow-up. RTE-R was defined as the number of IV antibiotics courses per year. CT scans were scored with the Brody-II system, assessing bronchiectasis, airway wall thickening, mucus, and opacities. RESULTS: One hundred fifteen patients contributed 170 CT scans. Median age and FEV(1) at first CT scan were 12 years (range, 5-20 years) and 90% predicted (range, 23% predicted-132% predicted), respectively. Analyzing exacerbation counts using Poisson regression models, bronchiectasis score and FEV(1) both were found to be strong independent predictors of RTE-R in the subsequent 2 years. For the bronchiectasis score categorized in quartiles, RTE-R increased by factors of 1.8 (95% CI, 0.6-6.1; P = .31), 5.5 (95% CI, 1.9-15.4; P = .001), and 10.6 (95% CI, 3.8-29.4; P < .001), respectively, for each quartile compared with the quartile with the best (ie, lowest) scores. Similarly, time to first respiratory tract exacerbation was significantly associated with quartiles of both bronchiectasis score and FEV(1). CONCLUSIONS: The CT scan bronchiectasis score is strongly associated with RTE-R in pediatric patients with CF, providing an important piece of evidence in the validation of CT scans as an end point for CF clinical trials.
Assuntos
Bronquiectasia/etiologia , Fibrose Cística/complicações , Tomografia Computadorizada por Raios X , Adolescente , Bronquiectasia/diagnóstico , Bronquiectasia/epidemiologia , Criança , Pré-Escolar , Fibrose Cística/diagnóstico , Progressão da Doença , Feminino , Seguimentos , Humanos , Incidência , Masculino , Países Baixos/epidemiologia , Prognóstico , Recidiva , Testes de Função Respiratória , Estudos Retrospectivos , Adulto JovemRESUMO
INTRODUCTION: To date no studies have been published on nocturnal cough frequency in children with stable CF. Aim of the study was to assess nocturnal cough frequency in children with CF. In addition nocturnal cough frequency was correlated with parameters of disease severity. METHODS: During two nights cough was recorded with a digital audio recorder in 25 patients (mean age 13 years; range 6-19) with clinically stable CF. In addition oxygen saturation was measured. The day following the recording spirometry was carried out. CT scores were obtained from the most recent routine CT scan. Cough was expressed in cough seconds (csec) and in cough seconds per hour (csec/hr). RESULTS: Data shown are median values and interquartile range (IQR). First night: 8 csec (IQR 3-52); 0.9 csec/hr (IQR 0.3-6.1) Second night: 6 csec (IQR 2-32); 0.6 csec/hr (IQR 0.1-3.4). Csec in the 1st night did not correlate significantly with csec in the 2nd night. Only for the 2nd night a strong correlation was found between csec/hr and the FEV1%pred (r(s) = -0.75, P < 0.001) and FEF(75) %pred (r(s) = -0.71, P < 0.001). Bronchiectasis score correlated borderline with the mean csec/hr of both nights (r(s) = 0.39, P = 0.08). During both nights cough was significantly higher in the first hour of sleep (P < or = 0.04). CONCLUSION: Frequency of nocturnal coughing in children with CF was higher than that described for normal children. Nocturnal cough tended to be more severe in children with more advanced CF lung disease. Nocturnal cough was more severe in the first hour of sleep and varied from night-to-night.