Associations in asthma between quantitative computed tomography and bronchial biopsy-derived airway remodelling.

Airway remodelling in asthma remains poorly understood. This study aimed to determine the association of airway remodelling measured on bronchial biopsies with 1) lung function impairment and 2) thoracic quantitative computed tomography (QCT)-derived morphometry and densitometry measures of proximal airway remodelling and air trapping.Subjects were recruited from a single centre. Bronchial biopsy remodelling features that were the strongest predictors of lung function impairment and QCT-derived proximal airway morphometry and air trapping markers were determined by stepwise multiple regression. The best predictor of air trapping was validated in an independent replication group.Airway smooth muscle % was the only predictor of post-bronchodilator forced expiratory volume in 1 s (FEV1) % pred, while both airway smooth muscle % and vascularity were predictors of FEV1/forced vital capacity. Epithelial thickness and airway smooth muscle % were predictors of mean segmental bronchial luminal area (R2=0.12; p=0.02 and R2=0.12; p=0.015), whereas epithelial thickness was the only predictor of wall area % (R2=0.13; p=0.018). Vascularity was the only significant predictor of air trapping (R2=0.24; p=0.001), which was validated in the replication group (R2=0.19; p=0.031).In asthma, airway smooth muscle content and vascularity were both associated with airflow obstruction. QCT-derived proximal airway morphometry was most strongly associated with epithelial thickness and airway smooth muscle content, whereas air trapping was related to vascularity.

Characterization of acinar airspace involvement in asthmatic patients by using inert gas washout and hyperpolarized (3)helium magnetic resonance.

BACKGROUND: The multiple-breath inert gas washout parameter acinar ventilation heterogeneity (Sacin) is thought to be a marker of acinar airway involvement but has not been validated by using quantitative imaging techniques in asthmatic patients. OBJECTIVE: We aimed to use hyperpolarized (3)He diffusion magnetic resonance at multiple diffusion timescales and quantitative computed tomographic (CT) densitometry to determine the nature of acinar airway involvement in asthmatic patients. METHODS: Thirty-seven patients with asthma and 17 age-matched healthy control subjects underwent spirometry, body plethysmography, multiple-breath inert gas washout (with the tracer gas sulfur hexafluoride), and hyperpolarized (3)He diffusion magnetic resonance. A subset of asthmatic patients (n = 27) underwent quantitative CT densitometry. RESULTS: Ninety-four percent (16/17) of patients with an increased Sacin had Global Initiative for Asthma treatment step 4 to 5 asthma, and 13 of 17 had refractory disease. The apparent diffusion coefficient (ADC) of (3)He at 1 second was significantly higher in patients with Sacin-high asthma compared with that in healthy control subjects (0.024 vs 0.017, P < .05). Sacin correlated strongly with ADCs at 1 second (R = 0.65, P < .001) but weakly with ADCs at 13 ms (R = 0.38, P < .05). ADCs at both 13 ms and 1 second correlated strongly with the mean lung density expiratory/inspiratory ratio, a CT marker of expiratory air trapping (R = 0.77, P < .0001 for ADCs at 13 ms; R = 0.72, P < .001 for ADCs at 1 second). CONCLUSION: Sacin is associated with alterations in long-range diffusion within the acinar airways and gas trapping. The precise anatomic nature and mechanistic role in patients with severe asthma requires further evaluation.

Relationship between lung function and quantitative computed tomographic parameters of airway remodeling, air trapping, and emphysema in patients with asthma and chronic obstructive pulmonary disease: A single-center study.

BACKGROUND: There is a paucity of studies comparing asthma and chronic obstructive pulmonary disease (COPD) based on thoracic quantitative computed tomographic (QCT) parameters. OBJECTIVES: We sought to compare QCT parameters of airway remodeling, air trapping, and emphysema between asthmatic patients and patients with COPD and explore their relationship with airflow limitation. METHODS: Asthmatic patients (n = 171), patients with COPD (n = 81), and healthy subjects (n = 49) recruited from a single center underwent QCT and clinical characterization. RESULTS: Proximal airway percentage wall area (%WA) was significantly increased in asthmatic patients (62.5% [SD, 2.2]) and patients with COPD (62.7% [SD, 2.3]) compared with that in healthy control subjects (60.3% [SD, 2.2], P < .001). Air trapping measured based on mean lung density expiratory/inspiratory ratio was significantly increased in patients with COPD (mean, 0.922 [SD, 0.037]) and asthmatic patients (mean, 0.852 [SD, 0.061]) compared with that in healthy subjects (mean, 0.816 [SD, 0.066], P < .001). Emphysema assessed based on lung density measured by using Hounsfield units below which 15% of the voxels lie (Perc15) was a feature of COPD only (patients with COPD: mean, -964 [SD, 19.62] vs asthmatic patients: mean, -937 [SD, 22.7] and healthy subjects: mean, -937 [SD, 17.1], P < .001). Multiple regression analyses showed that the strongest predictor of lung function impairment in asthmatic patients was %WA, whereas in the COPD and asthma subgrouped with postbronchodilator FEV1 percent predicted value of less than 80%, it was air trapping. Factor analysis of QCT parameters in asthmatic patients and patients with COPD combined determined 3 components, with %WA, air trapping, and Perc15 values being the highest loading factors. Cluster analysis identified 3 clusters with mild, moderate, or severe lung function impairment with corresponding decreased lung density (Perc15 values) and increased air trapping. CONCLUSIONS: In asthmatic patients and patients with COPD, lung function impairment is strongly associated with air trapping, with a contribution from proximal airway narrowing in asthmatic patients.

Comparison of CT-based Lobar Ventilation with 3He MR Imaging Ventilation Measurements.

PURPOSE: To compare lobar lung ventilation computed from expiratory and inspiratory computed tomographic (CT) data with direct measurements of ventilation at hyperpolarized helium 3 ((3)He) magnetic resonance (MR) imaging by using same-breath hydrogen 1 ((1)H) MR imaging examinations to coregister the multimodality images. MATERIALS AND METHODS: The study was approved by the national research ethics committee, and written patient consent was obtained. Thirty patients with asthma underwent breath-hold CT at total lung capacity and functional residual capacity. (3)He and (1)H MR images were acquired during the same breath hold at a lung volume of functional residual capacity plus 1 L. Lobar segmentations delineated by major fissures on both CT scans were used to calculate the percentage of ventilation per lobe from the change in inspiratory and expiratory lobar volumes. CT-based ventilation was compared with (3)He MR imaging ventilation by using diffeomorphic image registration of (1)H MR imaging to CT, which enabled indirect registration of (3)He MR imaging to CT. Statistical analysis was performed by using the Wilcoxon signed-rank test, Pearson correlation coefficient, and Bland-Altman analysis. RESULTS: The mean ± standard deviation absolute difference between the CT and (3)He MR imaging percentage of ventilation volume in all lobes was 4.0% (right upper and right middle lobes, 5.4% ± 3.3; right lower lobe, 3.7% ± 3.9; left upper lobe, 2.8% ± 2.7; left lower lobe, 3.9% ± 2.6; Wilcoxon signed-rank test, P < .05). The Pearson correlation coefficient between the two techniques in all lobes was 0.65 (P < .001). Greater percentage of ventilation was seen in the upper lobes with (3)He MR imaging and in the lower lobes with CT. This was confirmed with Bland-Altman analysis, with 95% limits of agreement for right upper and middle lobes, -2.4, 12.7; right lower lobe, -11.7, 4.6; left upper lobe, -4.9, 8.7; and left lower lobe, -9.8, 2.8. CONCLUSION: The percentage of regional ventilation per lobe calculated at CT was comparable to a direct measurement of lung ventilation at hyperpolarized (3)He MR imaging. This work provides evidence for the validity of the CT model, and same-breath (1)H MR imaging enables regional interpretation of (3)He ventilation MR imaging on the underlying lung anatomy at thin-section CT.

Quantitative computed tomography-derived clusters: redefining airway remodeling in asthmatic patients.

BACKGROUND: Asthma heterogeneity is multidimensional and requires additional tools to unravel its complexity. Computed tomography (CT)-assessed proximal airway remodeling and air trapping in asthmatic patients might provide new insights into underlying disease mechanisms. OBJECTIVES: The aim of this study was to explore novel, quantitative, CT-determined asthma phenotypes. METHODS: Sixty-five asthmatic patients and 30 healthy subjects underwent detailed clinical, physiologic characterization and quantitative CT analysis. Factor and cluster analysis techniques were used to determine 3 novel, quantitative, CT-based asthma phenotypes. RESULTS: Patients with severe and mild-to-moderate asthma demonstrated smaller mean right upper lobe apical segmental bronchus (RB1) lumen volume (LV) in comparison with healthy control subjects (272.3 mm(3) [SD, 112.6 mm(3)], 259.0 mm(3) [SD, 53.3 mm(3)], 366.4 mm(3) [SD, 195.3 mm(3)], respectively; P = .007) but no difference in RB1 wall volume (WV). Air trapping measured based on mean lung density expiratory/inspiratory ratio was greater in patients with severe and mild-to-moderate asthma compared with that seen in healthy control subjects (0.861 [SD, 0.05)], 0.866 [SD, 0.07], and 0.830 [SD, 0.06], respectively; P = .04). The fractal dimension of the segmented airway tree was less in asthmatic patients compared with that seen in control subjects (P = .007). Three novel, quantitative, CT-based asthma clusters were identified, all of which demonstrated air trapping. Cluster 1 demonstrates increased RB1 WV and RB1 LV but decreased RB1 percentage WV. On the contrary, cluster 3 subjects have the smallest RB1 WV and LV values but the highest RB1 percentage WV values. There is a lack of proximal airway remodeling in cluster 2 subjects. CONCLUSIONS: Quantitative CT analysis provides a new perspective in asthma phenotyping, which might prove useful in patient selection for novel therapies.

Computed tomography scans in severe asthma: utility and clinical implications.

PURPOSE OF REVIEW: Asthma is a global burden, affecting 5% of the general adult population, of whom approximately 5-10% suffer from severe asthma. Severe asthma is a complex heterogeneous disease entity, with high morbidity and mortality. Increasingly novel techniques in computed tomography (CT) are being used to understand the pathophysiology of severe asthma. The utility and clinical implications of these CT techniques are the focus of this review. RECENT FINDINGS: Novel qualitative and quantitative CT imaging techniques have enabled us to study the large airway architecture in detail, assess the small airway structure, and perform functional analysis of regional ventilation. SUMMARY: Despite advances in CT imaging techniques, there is an urgent need for both proof-of-concept studies and large cross-sectional and longitudinal clinical trials in severe asthma to validate and clinically correlate imaging derived measures. This will extend our current understanding of the pathophysiology of severe asthma, and unravel the structure-function relationship, with the potential to discover novel severe asthma phenotypes and predict mortality, morbidity, and response to existing and novel pharmacological and nonpharmacological therapies.

An experience sampling study of learning, affect, and the demands control support model.

The demands control support model (R. A. Karasek & T. Theorell, 1990) indicates that job control and social support enable workers to engage in problem solving. In turn, problem solving is thought to influence learning and well-being (e.g., anxious affect, activated pleasant affect). Two samples (N = 78, N = 106) provided data up to 4 times per day for up to 5 working days. The extent to which job control was used for problem solving was assessed by measuring the extent to which participants changed aspects of their work activities to solve problems. The extent to which social support was used to solve problems was assessed by measuring the extent to which participants discussed problems to solve problems. Learning mediated the relationship between changing aspects of work activities to solve problems and activated pleasant affect. Learning also mediated the relationship between discussing problems to solve problems and activated pleasant affect. The findings indicated that how individuals use control and support to respond to problem-solving demands is associated with organizational and individual phenomena, such as learning and affective well-being.

Fevipiprant, a prostaglandin D2 receptor 2 antagonist, in patients with persistent eosinophilic asthma: a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial.

BACKGROUND: Eosinophilic airway inflammation is often present in asthma, and reduction of such inflammation results in improved clinical outcomes. We hypothesised that fevipiprant (QAW039), an antagonist of prostaglandin D2 receptor 2, might reduce eosinophilic airway inflammation in patients with moderate-to-severe eosinophilic asthma. METHODS: We performed a single-centre, randomised, double-blind, parallel-group, placebo-controlled trial at Glenfield Hospital (Leicester, UK). We recruited patients with persistent, moderate-to-severe asthma and an elevated sputum eosinophil count (≥2%). After a 2-week single-blind placebo run-in period, patients were randomly assigned (1:1) by the trial pharmacist, using previously generated treatment allocation cards, to receive fevipiprant (225 mg twice per day orally) or placebo, stratified by the use of oral corticosteroid treatment and bronchoscopy. The 12-week treatment period was followed by a 6-week single-blind placebo washout period. The primary outcome was the change in sputum eosinophil percentage from baseline to 12 weeks after treatment, analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT01545726, and with EudraCT, number 2011-004966-13. FINDINGS: Between Feb 10, 2012, and Jan 30, 2013, 61 patients were randomly assigned to receive fevipiprant (n=30) or placebo (n=31). Three patients in the fevipiprant group and four patients in the placebo group withdrew because of asthma exacerbations. Two patients in the fevipiprant group were incorrectly given placebo (one at the mid-treatment visit and one throughout the course of the study). They were both included in the fevipiprant group for the primary analysis, but the patient who was incorrectly given placebo throughout was included in the placebo group for the safety analyses. Between baseline and 12 weeks after treatment, sputum eosinophil percentage decreased from a geometric mean of 5·4% (95% CI 3·1-9·6) to 1·1% (0·7-1·9) in the fevipiprant group and from 4·6% (2·5-8·7) to 3·9% (CI 2·3-6·7) in the placebo group. Compared with baseline, mean sputum eosinophil percentage was reduced by 4·5 times in the fevipiprant group and by 1·3 times in the placebo group (difference between groups 3·5 times, 95% CI 1·7-7·0; p=0·0014). Fevipiprant had a favourable safety profile, with no deaths or serious adverse events reported. No patient withdrawals were judged by the investigator to be related to the study drug. INTERPRETATION: Fevipiprant reduces eosinophilic airway inflammation and is well tolerated in patients with persistent moderate-to-severe asthma and raised sputum eosinophil counts despite inhaled corticosteroid treatment. FUNDING: Novartis Pharmaceuticals, AirPROM project, and the UK National Institute for Health Research.

Novel imaging approaches in adult asthma and their clinical potential.

Currently, imaging in asthma is confined to chest radiography and CT. The emergence of new imaging techniques and tremendous improvement of existing imaging methods, primarily due to technological advancement, has completely changed its research and clinical prospects. In research, imaging in asthma is now being employed to provide quantitative assessment of morphology, function and pathogenic processes at the molecular level. The unique ability of imaging for non-invasive, repeated, quantitative, and in vivo assessment of structure and function in asthma could lead to identification of 'imaging biomarkers' with potential as outcome measures in future clinical trials. Emerging imaging techniques and their utility in the research and clinical setting is discussed in this review.

Dynamic flow characteristics in normal and asthmatic lungs.

Complex flow patterns exist within the asymmetric branching airway network in the lungs. These flow patterns are known to become increasingly heterogeneous during disease as a result of various mechanisms such as bronchoconstriction or alterations in lung tissue compliance. Here, we present a coupled model of tissue deformation and network airflow enabling predictions of dynamic flow properties, including temporal flow rate, pressure distribution, and the occurrence of reverse flows. We created two patient-specific airway geometries, one for a healthy subject and one for a severe asthmatic subject, derived using a combination of high-resolution CT data and a volume-filling branching algorithm. In addition, we created virtually constricted airway geometry by reducing the airway radii of the healthy subject model. The flow model was applied to these three different geometries to solve the pressure and flow distribution over a breathing cycle. The differences in wave phase of the flows in parallel airways induced by asymmetric airway geometry and bidirectional interaction between intra-acinar and airway network pressures were small in central airways but were more evident in peripheral airways. The asthmatic model showed elevated ventilation heterogeneity and significant flow disturbance. The reverse flows in the asthmatic model not only altered the local flow characteristics but also affected total lung resistance. The clinical significance of temporal flow disturbance on lung ventilation in normal airway model is obscure. However, increased flow disturbance and ventilation heterogeneity observed in the asthmatic model suggests that reverse flow may be an important factor for asthmatic lung function.

Severe asthma: novel advances in the pathogenesis and therapy.

Asthma affects an estimated 300 million people worldwide and is severe in approximately 10% of sufferers. Asthma, especially severe asthma, is a heterogeneous disease that results from complex host-environment interactions. This review article outlines recent advances in both the understanding of pathogenesis and novel therapies. The pathogenesis of severe asthma can be broadly thought of in four domains: T(H)2 inflammation, non -T(H)2 inflammation, airway remodeling, and airway smooth muscle dysfunction. They can develop independently or partly as a consequence of each other. Interactions between these domains, their causation, and consequent impact upon disordered airway physiology and clinical expression are poorly understood. Recent advances in specific T(H)2- and non -T(H2)-targeted therapy, bronchial thermoplasty targeting airway remodeling and advances in therapies for airway smooth muscle dysfunction present new opportunities for treatment and inform our understanding of asthma pathogenesis. As our understanding of the pathogenesis increases, the need for individualized investigation, treatment, and management of asthma becomes more apparent.

A method for quantitative analysis of regional lung ventilation using deformable image registration of CT and hybrid hyperpolarized gas/1H MRI.

Hyperpolarized gas magnetic resonance imaging (MRI) generates highly detailed maps of lung ventilation and physiological function while CT provides corresponding anatomical and structural information. Fusion of such complementary images enables quantitative analysis of pulmonary structure-function. However, direct image registration of hyperpolarized gas MRI to CT is problematic, particularly in lungs whose boundaries are difficult to delineate due to ventilation heterogeneity. This study presents a novel indirect method of registering hyperpolarized gas MRI to CT utilizing (1)H-structural MR images that are acquired in the same breath-hold as the gas MRI. The feasibility of using this technique for regional quantification of ventilation of specific pulmonary structures is demonstrated for the lobes.The direct and indirect methods of hyperpolarized gas MRI to CT image registration were compared using lung images from 15 asthma patients. Both affine and diffeomorphic image transformations were implemented. Registration accuracy was evaluated using the target registration error (TRE) of anatomical landmarks identified on (1)H MRI and CT. The Wilcoxon signed-rank test was used to test statistical significance.For the affine transformation, the indirect method of image registration was significantly more accurate than the direct method (TRE = 14.7 ± 3.2 versus 19.6 ± 12.7 mm, p = 0.036). Using a deformable transformation, the indirect method was also more accurate than the direct method (TRE = 13.5 ± 3.3 versus 20.4 ± 12.8 mm, p = 0.006).Accurate image registration is critical for quantification of regional lung ventilation with hyperpolarized gas MRI within the anatomy delineated by CT. Automatic deformable image registration of hyperpolarized gas MRI to CT via same breath-hold (1)H MRI is more accurate than direct registration. Potential applications include improved multi-modality image fusion, functionally weighted radiotherapy planning, and quantification of lobar ventilation in obstructive airways disease.

An unusual cause of recurrent falls in an older gentleman.

The authors present the case of an 82-year-old gentleman who was admitted through Accident & Emergency with a history of increasingly recurrent falls. A thorough history and examination led to the provisional diagnosis of cervical cord compression. Subsequent investigations confirmed an erosive abnormality around the odontoid peg, with an adjacent soft tissue mass. The patient underwent a partial odontoidectomy and the histological examination of the pannus revealed a basophilic crystalline arthropathy, consistent with pseudogout.

Mycobacterium avium-intracellulare infection presenting as a testicular mass in an immunocompromised patient: a case report.

Isolated mycobacterial infections of the genital tract are extremely rare. Here we present a 63-year-old gentleman who developed an isolated non-tuberculous mycobacterial mass in the inferior pole of his right testis, secondary to immunocompromise related to multiple autoimmune and haematological conditions and their treatments.