Changes in physiological, functional and structural markers of cystic fibrosis lung disease with treatment of a pulmonary exacerbation.

BACKGROUND: Clinical trials in cystic fibrosis (CF) have been hindered by the paucity of well characterised and clinically relevant outcome measures. AIM: To evaluate a range of conventional and novel biomarkers of CF lung disease in a multicentre setting as a contributing study in selecting outcome assays for a clinical trial of CFTR gene therapy. METHODS: A multicentre observational study of adult and paediatric patients with CF (>10 years) treated for a physician-defined exacerbation of CF pulmonary symptoms. Measurements were performed at commencement and immediately after a course of intravenous antibiotics. Disease activity was assessed using 46 assays across five key domains: symptoms, lung physiology, structural changes on CT, pulmonary and systemic inflammatory markers. RESULTS: Statistically significant improvements were seen in forced expiratory volume in 1 s (p<0.001, n=32), lung clearance index (p<0.01, n=32), symptoms (p<0.0001, n=37), CT scores for airway wall thickness (p<0.01, n=31), air trapping (p<0.01, n=30) and large mucus plugs (p=0.0001, n=31), serum C-reactive protein (p<0.0001, n=34), serum interleukin-6 (p<0.0001, n=33) and serum calprotectin (p<0.0001, n=31). DISCUSSION: We identify the key biomarkers of inflammation, imaging and physiology that alter alongside symptomatic improvement following treatment of an acute CF exacerbation. These data, in parallel with our study of biomarkers in patients with stable CF, provide important guidance in choosing optimal biomarkers for novel therapies. Further, they highlight that such acute therapy predominantly improves large airway parameters and systemic inflammation, but has less effect on airway inflammation.

Biopsy-proved idiopathic pulmonary fibrosis: spectrum of nondiagnostic thin-section CT diagnoses.

PURPOSE: To document the spectrum of misleading thin-section computed tomographic (CT) diagnoses in patients with biopsy-proved idiopathic pulmonary fibrosis (IPF). MATERIALS AND METHODS: This study had institutional review board approval, and patient consent was not required. Three observers, blinded to any clinical information and the purpose of the study, recorded thin-section CT differential diagnoses and assigned a percentage likelihood to each for a group of 123 patients (79 men, 44 women; age range, 27-82 years) with various chronic interstitial lung diseases, including a core group of 55 biopsy-proved cases of IPF. Patients with IPF in the core group, in whom IPF was diagnosed as low-grade probability (<30%) by at least two observers, were considered to have atypical IPF cases, and the alternative diagnoses were analyzed further. RESULTS: Thirty-four (62%) of 55 biopsy-proved IPF cases were regarded as alternative diagnoses. In these atypical IPF cases, the first-choice diagnoses, expressed with high degree of probability, were nonspecific interstitial pneumonia (NSIP; 18 [53%] of 34), chronic hypersensitivity pneumonitis (HP; four [12%] of 34), sarcoidosis (three [9%] of 34), and organizing pneumonia (one [3%] of 34); in eight (23%) of 34 cases, no single diagnosis was favored by more than one observer. Frequent differential diagnoses, although not always the first-choice diagnosis, were NSIP (n = 29), chronic HP (n = 23), and sarcoidosis (n = 9). CONCLUSION: In the correct clinical setting, a diagnosis of IPF is not excluded by thin-section CT appearances more suggestive of NSIP, chronic HP, or sarcoidosis. (c) RSNA, 2010.

United kingdom cystic fibrosis gene therapy consortium multidose trial: the proposed use of computed tomography.

Interest in the role of computed tomography (CT) as a monitoring tool in cystic fibrosis (CF) research has gained momentum in the past 5 years. This is a consequence of the rapid development of therapeutic options for CF lung disease and hence the need for sensitive outcome measures that can be applied to clinical intervention trials. The following article summarizes the proposed use of CT in a forthcoming multidose gene therapy trial. Issues surrounding dose, timing of scans, scoring, and quantification of CT morphologic features are discussed. The literature which supports the use of CT as a surrogate outcome measure is also summarized.

Interstitial lung disease: effects of thin-section CT on clinical decision making.

PURPOSE: To retrospectively quantify the change in the diagnosis and management of suspected interstitial lung disease when thin-section computed tomography (CT) is added to pretest probabilities. MATERIALS AND METHODS: The institutional review board does not require approval or patient informed consent for retrospective study of case records and CT studies. Six pulmonologists reviewed data sheets containing clinical information and results of pulmonary function tests and chest radiographs of 168 consecutive patients (86 women and 82 men; mean age, 59.8 years; age range, 22-86 years) suspected of having interstitial lung disease. Differential diagnoses and responses to specific questions regarding patient care were recorded before and after assimilation of thin-section CT findings. Both unweighted and weighted kappa analyses were used to determine agreement between pulmonologists before and after CT. RESULTS: First-choice diagnosis changed in 520 (51%) of 1008 cases, and agreement on first-choice diagnosis increased from 0.47 to 0.72 after thin-section CT. In addition, confidence in the first-choice diagnosis increased, and there was a reduction in the number of differential diagnoses offered by all pulmonologists (P < .005 and P < .001, respectively). Agreement on diagnostic probabilities for individual disorders increased substantially, particularly for diagnoses of idiopathic pulmonary fibrosis (weighted kappa = 0.58-0.89). With CT findings, pulmonologists changed their pre-CT responses regarding the use of bronchoalveolar lavage, transbronchial biopsy, and thoracoscopic biopsy in 242 (24.0%), 282 (28.0%), and 292 (29.0%) of 1008 cases, respectively. However, agreement for the use of these investigations was low both before and after CT. The request rate for thoracoscopic biopsy in patients in whom idiopathic fibrosis was diagnosed decreased from 48 of 179 (26.8%) to 26 of 233 (11.2%) after CT. CONCLUSION: Thin-section CT resulted in a change in first-choice diagnosis in half the cases. Diagnostic confidence improved, and CT findings increased agreement between pulmonologists on diagnostic probabilities across a range of interstitial lung diseases.

High-frequency color Doppler ultrasonography of the spermatic cord arteries: resistive index variation in a cohort of 51 healthy men.

OBJECTIVE: The purpose of this study was to determine the normal range of Doppler ultrasonographic measurements of spermatic cord arteries in a cohort of healthy men. METHODS: The spermatic cord arteries of 51 men were interrogated with color Doppler ultrasonography. The resistive index (RI) of each artery was measured for the entire cohort; peak systolic and end-diastolic velocity values were obtained in a smaller subgroup (n = 31). The artery with the lowest RI was labeled A; the other 2 arteries were identified as B and C. RESULTS: Three separate arteries were identified within the spermatic cord in all individuals. The median RI values for arteries A, B, and C were 0.70 (range, 0.48-0.82), 0.84 (0.67-0.90), and 0.84 (0.72-0.92), respectively. One-way analysis of variance showed a significant difference between the mean RIs of arteries A and B (P < .0001) and arteries A and artery C (P < .0001) but not between B and C (P = .49). Peak systolic and end-diastolic velocity values differed significantly between arteries A and B (P < .0001) and arteries A and C (P < .0001) but not between B and C (P = .31). No age effect was shown for the RI measurements of the cohort. CONCLUSIONS: Color Doppler ultrasonography enables the objective quantification of Doppler measurements of arteries within the spermatic cord. Knowledge of the normal range of Doppler measurements for spermatic cord arteries that supply the testes may be a useful adjunct to the assessment of the testes.

Functional impairment in emphysema: contribution of airway abnormalities and distribution of parenchymal disease.

OBJECTIVE: The aim of this study was to identify ancillary morphologic features on high-resolution CT that modify airflow obstruction and gas transfer levels in individuals with emphysema. MATERIALS AND METHODS: The extent of emphysema on high-resolution CT was quantified by density masking in 101 patients. CT scans were evaluated for airway abnormalities (bronchial wall thickness, extent of bronchiectasis, bronchial dilatation, and evidence of small airways disease) and disease heterogeneity (uniformity, core-rind distribution, craniocaudal distribution, and lung texture). Stepwise regression analysis was used to determine CT features that influenced forced expiratory volume in 1 sec (FEV1) and the single-breath diffusing capacity for carbon monoxide (Dlco) for a given extent of emphysema. RESULTS: The extent of emphysema using automated estimation was 28.4% +/- 12.3% (mean +/- SD). On univariate analysis the extent of emphysema correlated strongly with FEV1 (R = -0.63, p < 0.0005) and Dlco (R = -0.63, p < 0.0005) levels. Stepwise regression analysis revealed that bronchial wall thickness and the extent of emphysema were the strongest independent determinants of FEV1 (model R2 = 0.49; p = 0.002 and < 0.001, respectively); the extent of bronchiectasis and degree of bronchial dilation did not separately influence FEV1 levels. The only morphologic features linked to Dlco levels on multivariate analysis were increasingly extensive emphysema and a higher proportion of emphysema in the core region (model R2 = 0.45; p < 0.001 and 0.002, respectively). CONCLUSION: The important additional CT abnormalities in individuals with emphysema that influence FEV1 and Dlco levels irrespective of disease extent are bronchial wall thickness and core-rind heterogeneity, respectively. These observations have implications for the accurate functional assessment of patients considered for lung volume reduction surgery.