Integrated Cardiopulmonary MRI Assessment of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a heterogeneous condition that can affect the lung parenchyma, pulmonary vasculature, and cardiac chambers. Accurate diagnosis often requires multiple complex assessments of the cardiac and pulmonary systems. MRI is able to comprehensively assess cardiac structure and function, as well as lung parenchymal, pulmonary vascular, and functional lung changes. Therefore, MRI has the potential to provide an integrated functional and structural assessment of the cardiopulmonary system in a single exam. Cardiac MRI is used in the assessment of PH in most large PH centers, whereas lung MRI is an emerging technique in patients with PH. This article reviews the current literature on cardiopulmonary MRI in PH, including cine MRI, black-blood imaging, late gadolinium enhancement, T1 mapping, myocardial strain analysis, contrast-enhanced perfusion imaging and contrast-enhanced MR angiography, and hyperpolarized gas functional lung imaging. This article also highlights recent developments in this field and areas of interest for future research including cardiac MRI-based diagnostic models, machine learning in cardiac MRI, oxygen-enhanced 1 H imaging, contrast-free 1 H perfusion and ventilation imaging, contrast-free angiography and UTE imaging. EVIDENCE LEVEL: 5 TECHNICAL EFFICACY: Stage 3.

Pharmacokinetic modelling for the simultaneous assessment of perfusion and 18F-flutemetamol uptake in cerebral amyloid angiopathy using a reduced PET-MR acquisition time: Proof of concept.

PURPOSE: Cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease associated with perivascular ß-amyloid deposition. CAA is also associated with strokes due to lobar intracerebral haemorrhage (ICH). 18F-flutemetamol amyloid ligand PET may improve the early detection of CAA. We performed pharmacokinetic modelling using both full (0-30, 90-120 min) and reduced (30 min) 18F-flutemetamol PET-MR acquisitions, to investigate regional cerebral perfusion and amyloid deposition in ICH patients. METHODS: Dynamic18F-flutemetamol PET-MR was performed in a pilot cohort of sixteen ICH participants; eight lobar ICH cases with probable CAA and eight deep ICH patients. A model-based input function (mIF) method was developed for compartmental modelling. mIF 1-tissue (1-TC) and 2-tissue (2-TC) compartmental modelling, reference tissue models and standardized uptake value ratios were assessed in the setting of probable CAA detection. RESULTS: The mIF 1-TC model detected perfusion deficits and 18F-flutemetamol uptake in cases with probable CAA versus deep ICH patients, in both full and reduced PET acquisition time (all P < 0.05). In the reduced PET acquisition, mIF 1-TC modelling reached the highest sensitivity and specificity in detecting perfusion deficits (0.87, 0.77) and 18F-flutemetamol uptake (0.83, 0.71) in cases with probable CAA. Overall, 52 and 48 out of the 64 brain areas with 18F-flutemetamol-determined amyloid deposition showed reduced perfusion for 1-TC and 2-TC models, respectively. CONCLUSION: Pharmacokinetic (1-TC) modelling using a 30 min PET-MR time frame detected impaired haemodynamics and increased amyloid load in probable CAA. Perfusion deficits and amyloid burden co-existed within cases with CAA, demonstrating a distinct imaging pattern which may have merit in elucidating the pathophysiological process of CAA.

Current state of the art MRI for the longitudinal assessment of cystic fibrosis.

Pulmonary MRI can now provide high-resolution images that are sensitive to early disease and specific to inflammation in cystic fibrosis (CF) lung disease. With specificity and function limited via computed tomography (CT), there are significant advantages to MRI. Many of the modern MRI techniques can be performed throughout life, and can be employed to understand changes over time, in addition to quantification of treatment response. Proton density and T1 /T2 contrast images can be obtained within a single breath-hold, providing depiction of structural abnormalities and active inflammation. Modern radial and/or spiral ultrashort echo-time (UTE) techniques rival CT in resolution for depiction and quantification of structure, for both airway and parenchymal abnormalities. Contrast perfusion MRI techniques are now utilized routinely to visualize changes in pulmonary and bronchial circulation that routinely occur in CF lung disease, and noncontrast techniques are moving closer to clinical translation. Functional information can be obtained from noncontrast proton images alone, using techniques such as Fourier decomposition. Hyperpolarized-gas MRI, increasingly using 129 Xe, is now becoming more widespread and has been demonstrated to have high sensitivity to early airway obstruction in CF via ventilation MRI. The sensitivity of 129 Xe MRI promises future use in personalized medicine, management of early CF lung disease, and in future clinical trials. By combining structural and functional techniques, with or without hyperpolarized gases, regional structure-function relationships can be obtained, giving insight into the pathophysiology of disease and improved clinical management. This article reviews the modern MRI techniques that can routinely be employed for CF lung disease in nearly any large medical center. Level of Evidence: 4 Technical Efficacy Stage: 5 J. Magn. Reson. Imaging 2019.

Value of MRI in medicine: More than just another test?

There is increasing scrutiny from healthcare organizations towards the utility and associated costs of imaging. MRI has traditionally been used as a high-end modality, and although shown extremely important for many types of clinical scenarios, it has been suggested as too expensive by some. This editorial will try and explain how value should be addressed and gives some insights and practical examples of how value of MRI can be increased. It requires a global effort to increase accessibility, value for money, and impact on patient management. We hope this editorial sheds some light and gives some indications of where the field may wish to address some of its research to proactively demonstrate the value of MRI. Level of Evidence: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2019;49:e14-e25.

MRI for solitary pulmonary nodule and mass assessment: Current state of the art.

Since the clinical introduction of magnetic resonance imaging (MRI), the chest has been one of its most challenging applications, and many physicists and radiologists have tried since the 1980s to use MR for assessment of different lung diseases as well as mediastinal and pleural diseases. Since then, however, technical advances in sequencing, scanners, and coils, adaptation of parallel imaging techniques, utilization of contrast media, and development of postprocessing tools have been reported by many basic and clinical researchers. As a result, state-of-the-art thoracic MRI is now substituted for traditional imaging techniques and/or plays a complementary role in the management of patients with various chest diseases, and especially in the detection of pulmonary nodules and in thoracic oncology. In addition, MRI has continued to be developed to help overcome the limitations of computed tomography (CT) and nuclear medicine examinations. It can currently provide not only morphological, but also functional, physiological, pathophysiological, and molecular information at 1.5T with a gradual shift from 1.5T to 3T MR systems. In this review, we focus on these recent advances in MRI for pulmonary nodule detection and pulmonary nodule and mass evaluation by using noncontrast-enhanced and contrast-enhanced techniques as well as new molecular imaging methods such as chemical exchange saturation transfer imaging for a comparison with other modalities such as single or multidetector row CT, 18F-fluoro-2-deoxyglucose positron emission tomography (FDG-PET), and/or PET/CT. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1437-1458.

Screening for lung cancer: Does MRI have a role?

While the inauguration of national low dose computed tomographic (LDCT) lung cancer screening programs has started in the USA, other countries remain undecided, awaiting the results of ongoing trials. The continuous technical development achieved by stronger gradients, parallel imaging and shorter echo time has made lung magnetic resonance imaging (MRI) an interesting alternative to CT. For the detection of solid lesions with lung MRI, experimental and clinical studies have shown a threshold size of 3-4mm for nodules, with detection rates of 60-90% for lesions of 5-8mm and close to 100% for lesions of 8mm or larger. From experimental work, the sensitivity for infiltrative, non-solid lesions would be expected to be similarly high as that for solid lesions, but the published data for the MRI detection of lepidic growth type adenocarcinoma is sparse. Moreover, biological features such as a longer T2 time of lung cancer tissue, tissue compliance and a more rapid uptake of contrast material compared to granulomatous diseases, in principle should allow for the multi-parametric characterization of lung pathology. Experience with the clinical use of lung MRI is growing. There are now standardized protocols which are easy to implement on current scanner hardware configurations. The image quality has become more robust and currently ongoing studies will help to further contribute experience with multi-center, multi-vendor and multi-platform implementation of this technology. All of the required prerequisites have now been achieved to allow for a dedicated prospective large scale MRI based lung cancer screening trial to investigate the outcomes from using MRI rather than CT for lung cancer screening. This is driven by the hypothesis that MRI would reach a similarly high sensitivity for the detection of early lung cancer with fewer false positive exams (better specificity) than LDCT. The purpose of this review article is to discuss the potential role of lung MRI for the early detection of lung cancer from a technical point of view and to discuss a few of the possible scenarios for lung cancer screening implementation using this imaging modality. There is little doubt that MRI could play a significant role in lung cancer screening, but how and when will depend on the threshold needed for positive screens (e.g. lesion volume and required diagnostic accuracy), cost-effectiveness and improved patient outcomes from a reduction in the need to follow up benign nodules. Potential applications range from lung MRI as the first choice screening modality to the role of an ad hoc on site test for the detailed evaluation of a subgroup of positive screening results.

Use of Coronary Computed Tomographic Angiography to Guide Management of Patients With Coronary Disease.

BACKGROUND: In a prospective, multicenter, randomized controlled trial, 4,146 patients were randomized to receive standard care or standard care plus coronary computed tomography angiography (CCTA). OBJECTIVES: The purpose of this study was to explore the consequences of CCTA-assisted diagnosis on invasive coronary angiography, preventive treatments, and clinical outcomes. METHODS: In post hoc analyses, we assessed changes in invasive coronary angiography, preventive treatments, and clinical outcomes using national electronic health records. RESULTS: Despite similar overall rates (409 vs. 401; p = 0.451), invasive angiography was less likely to demonstrate normal coronary arteries (20 vs. 56; hazard ratios [HRs]: 0.39 [95% confidence interval (CI): 0.23 to 0.68]; p < 0.001) but more likely to show obstructive coronary artery disease (283 vs. 230; HR: 1.29 [95% CI: 1.08 to 1.55]; p = 0.005) in those allocated to CCTA. More preventive therapies (283 vs. 74; HR: 4.03 [95% CI: 3.12 to 5.20]; p < 0.001) were initiated after CCTA, with each drug commencing at a median of 48 to 52 days after clinic attendance. From the median time for preventive therapy initiation (50 days), fatal and nonfatal myocardial infarction was halved in patients allocated to CCTA compared with those assigned to standard care (17 vs. 34; HR: 0.50 [95% CI: 0.28 to 0.88]; p = 0.020). Cumulative 6-month costs were slightly higher with CCTA: difference $462 (95% CI: $303 to $621). CONCLUSIONS: In patients with suspected angina due to coronary heart disease, CCTA leads to more appropriate use of invasive angiography and alterations in preventive therapies that were associated with a halving of fatal and non-fatal myocardial infarction. (Scottish COmputed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

Observer variability in the assessment of CT coronary angiography and coronary artery calcium score: substudy of the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial.

INTRODUCTION: Observer variability can influence the assessment of CT coronary angiography (CTCA) and the subsequent diagnosis of angina pectoris due to coronary heart disease. METHODS: We assessed 210 CTCAs from the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial for intraobserver and interobserver variability. Calcium score, coronary angiography and image quality were evaluated. Coronary artery disease was defined as none (<10%), mild (10-49%), moderate (50-70%) and severe (>70%) luminal stenosis and classified as no (<10%), non-obstructive (10-70%) or obstructive (>70%) coronary artery disease. Post-CTCA diagnosis of angina pectoris due to coronary heart disease was classified as yes, probable, unlikely or no. RESULTS: Patients had a mean body mass index of 29 (28, 30) kg/m(2), heart rate of 58 (57, 60)/min and 62% were men. Intraobserver and interobserver agreements for the presence or absence of coronary artery disease were excellent (95% agreement, κ 0.884 (0.817 to 0.951) and good (91%, 0.791 (0.703 to 0.879)). Intraobserver and interobserver agreement for the presence or absence of angina pectoris due to coronary heart disease were excellent (93%, 0.842 (0.918 to 0.755) and good (86%, 0.701 (0.799 to 0.603)), respectively. Observer variability of calcium score was excellent for calcium scores below 1000. More segments were categorised as uninterpretable with 64-multidetector compared to 320-multidetector CTCA (10.1% vs 2.6%, p<0.001) but there was no difference in observer variability. CONCLUSIONS: Multicentre multidetector CTCA has excellent agreement in patients under investigation for suspected angina due to coronary heart disease. TRIAL REGISTRATION NUMBER: NCT01149590.

Role of multidetector computed tomography in the diagnosis and management of patients attending the rapid access chest pain clinic, The Scottish computed tomography of the heart (SCOT-HEART) trial: study protocol for randomized controlled trial.

BACKGROUND: Rapid access chest pain clinics have facilitated the early diagnosis and treatment of patients with coronary heart disease and angina. Despite this important service provision, coronary heart disease continues to be under-diagnosed and many patients are left untreated and at risk. Recent advances in imaging technology have now led to the widespread use of noninvasive computed tomography, which can be used to measure coronary artery calcium scores and perform coronary angiography in one examination. However, this technology has not been robustly evaluated in its application to the clinic. METHODS/DESIGN: The SCOT-HEART study is an open parallel group prospective multicentre randomized controlled trial of 4,138 patients attending the rapid access chest pain clinic for evaluation of suspected cardiac chest pain. Following clinical consultation, participants will be approached and randomized 1:1 to receive standard care or standard care plus ≥64-multidetector computed tomography coronary angiography and coronary calcium score. Randomization will be conducted using a web-based system to ensure allocation concealment and will incorporate minimization. The primary endpoint of the study will be the proportion of patients diagnosed with angina pectoris secondary to coronary heart disease at 6 weeks. Secondary endpoints will include the assessment of subsequent symptoms, diagnosis, investigation and treatment. In addition, long-term health outcomes, safety endpoints, such as radiation dose, and health economic endpoints will be assessed. Assuming a clinic rate of 27.0% for the diagnosis of angina pectoris due to coronary heart disease, we will need to recruit 2,069 patients per group to detect an absolute increase of 4.0% in the rate of diagnosis at 80% power and a two-sided P value of 0.05. The SCOT-HEART study is currently recruiting participants and expects to report in 2014. DISCUSSION: This is the first study to look at the implementation of computed tomography in the patient care pathway that is outcome focused. This study will have major implications for the management of patients with cardiovascular disease. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01149590.

Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis.

BACKGROUND: The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown. METHODS AND RESULTS: Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r(2)=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r(2)=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r(2)=0.174, P<0.001). CONCLUSIONS: Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Assessment of hyperpolarized 3He lung MRI for regional evaluation of interventional therapy: a pilot study in pediatric cystic fibrosis.

PURPOSE: To determine whether regional changes in lung ventilation in a group of pediatric cystic fibrosis (CF) patients following a course of chest physiotherapy could be detected with (3)He MRI. MATERIALS AND METHODS: The reproducibility of lung ventilation volume measurements obtained with (3)He lung magnetic resonance imaging (MRI) was established in a group of five children with CF age 6-15 years. The same methodology was then used to evaluate whether standard chest physiotherapy (percussion and drainage) had any immediate effect on regional ventilated lung volumes in a further group of nine age-matched CF children (5-15 years). RESULTS: Global lung ventilation volumes remained the same within the limits of sensitivity derived from the reproducibility study; however, regional lung ventilation was observed to change in most patients after therapy. CONCLUSION: (3)He MRI can be successfully used in children with CF, and has the sensitivity to detect regional quantitative changes in lung ventilation following chest physiotherapy.

Assessment of radiologist performance in the detection of lung nodules: dependence on the definition of "truth".

RATIONALE AND OBJECTIVES: Studies that evaluate the lung nodule detection performance of radiologists or computerized methods depend on an initial inventory of the nodules within the thoracic images (the "truth"). The purpose of this study was to analyze (1) variability in the "truth" defined by different combinations of experienced thoracic radiologists and (2) variability in the performance of other experienced thoracic radiologists based on these definitions of "truth" in the context of lung nodule detection in computed tomographic (CT) scans. MATERIALS AND METHODS: Twenty-five thoracic CT scans were reviewed by four thoracic radiologists, who independently marked lesions they considered to be nodules >or=3 mm in maximum diameter. Panel "truth" sets of nodules were then derived from the nodules marked by different combinations of two and three of these four radiologists. The nodule detection performance of the other radiologists was evaluated based on these panel "truth" sets. RESULTS: The number of "true" nodules in the different panel "truth" sets ranged from 15 to 89 (mean 49.8 +/- 25.6). The mean radiologist nodule detection sensitivities across radiologists and panel "truth" sets for different panel "truth" conditions ranged from 51.0 to 83.2%; mean false-positive rates ranged from 0.33 to 1.39 per case. CONCLUSIONS: Substantial variability exists across radiologists in the task of lung nodule identification in CT scans. The definition of "truth" on which lung nodule detection studies are based must be carefully considered, because even experienced thoracic radiologists may not perform well when measured against the "truth" established by other experienced thoracic radiologists.

Preablation assessment for the left atrium: comparison of ECG-gated cardiac CT with echocardiography.

RATIONALE AND OBJECTIVES: Evaluate the role of two-dimensional echocardiography and electrocardiographically (ECG)-gated contrast-enhanced multislice computed tomographic (MSCT) cardiac imaging to assess cardiac anatomy, specifically pulmonary venous anatomy and left atrial thrombus, in a selected group of patients before catheter-based atrial fibrillation ablation. MATERIALS AND METHODS: Left atrial anatomy and associated findings in 34 consecutive patients scheduled for electrophysiologic testing who underwent both echocardiography and ECG-gated 16-slice MSCT cardiac imaging were retrospectively compared. Results from two-dimensional transthoracic echocardiography (TTE), cardiac MSCT, electrophysiologic study (EPS), and transesophageal echocardiography (TEE) (when performed) were taken from the official medical record without prior knowledge of this study when interpretation was rendered for clinical use. Electronic record review included: presence of left atrial thrombus (defined as constant filling defect on at least two echocardiographic views or filling defect on computed tomography) and location, pulmonary venous anatomy, and other cardiac, mediastinal, or pulmonary abnormalities. RESULTS: Left atrial thrombus was identified by cardiac MSCT alone in five patients (15%). Pulmonary venous variants were identified with cardiac MSCT in two patients (6%). Both MSCT and echocardiography were normal in 17 subjects (79%). Echocardiography was better at identifying associated valvular abnormalities that were seen in 10 patients (29%). Cardiac MSCT angiography alone identified other cardiac and noncardiac abnormalities, including suspicious pulmonary malignancy, mediastinal adenopathy, and coronary stenosis in 15 patients (44%). CONCLUSIONS: Echocardiography and cardiac MSCT angiography often provide complimentary findings during the preprocedural evaluation for patients with atrial fibrillation requiring ablation. Cardiac MSCT may provide significant additional information about the left atrium, mediastinum, coronary circulation, and visualized lung fields. Based on this study, we would advise that patients considered for radiofrequency ablation for uncontrolled right atrial fibrillation have both echocardiography and ECG-gated contrast-enhanced cardiac MSCT performed as part of the preprocedure evaluation.

Assessment of lung disease in children with cystic fibrosis using hyperpolarized 3-Helium MRI: comparison with Shwachman score, Chrispin-Norman score and spirometry.

This study assesses the feasibility of hyperpolarized 3-Helium MRI in children with cystic fibrosis (CF) and correlates the findings with standard clinical parameters based on chest radiograph (CXR) and pulmonary function tests (PFT). An uncontrolled, observational study in eighteen children with cystic fibrosis aged 5 - 17 years (median 12.1 years), with different severity of disease was carried out. All subjects underwent routine clinical assessment including PFT and standard auxology; CXR was obtained and Shwachman and Chrispin-Norman scores calculated. Hyperpolarized 3-He magnetic resonance imaging (MRI) was carried out using a spin-exchange polarizer and a whole body 1.5 T scanner. Ventilation distribution images were obtained during a 21-second breath-hold and scored according to previously defined criteria. Spearman's non-parametric correlations test was performed to assess for statistical significance at the p<0.05 level. The children tolerated the procedure well. No desaturation events were observed during 3-He MRI. A significant, albeit moderate, correlation was found between MRI score and FEV1% predicted (r=-0.41; p=0.047) and FVC% predicted (r=-0.42; p=0.04), while there were trends of correlations between Shwachman score and MRI score (r=-0.38; p=0.06) and Shwachman score and FEV1% predicted (r=0.39; p=0.055). The feasibility of hyperpolarized 3-He MRI in children with CF was demonstrated. MRI appears to be able to demonstrate functional lung changes, although correlations with routine clinical tests are only moderate to poor. This non-ionising radiation technique could be useful for monitoring lung disease and assessing therapy in this patient population.

Assessment and compensation of susceptibility artifacts in gradient echo MRI of hyperpolarized 3He gas.

The effects of macroscopic background field gradients upon 2D gradient echo images of inhaled (3)He in the human lung were investigated at 1.5 T. Effective compensation of in-slice signal loss in (3)He gradient echo images was then demonstrated using a multiple acquisition interleaved single gradient echo sequence. This method restores signal dephasing through a combination of separate images acquired with different slice refocusing gradients. In vivo imaging of volunteers with the sequence shows substantial restoration of signal at the lung periphery and close to blood vessels. The technique presented may be useful when using (3)He MRI for volumetric measurements of lung ventilation and in studies using (3)He combined with intravenous contrast as a means of assessing lung ventilation/perfusion (V/Q).

Assessment of lung ventilation by MR imaging: current status and future perspectives.

The aim of this paper is to review the present status of novel MRI techniques as a new important instrument for functional ventilation imaging. The current status and future perspectives in research and clinical applications are summarized. Morphological lung imaging is based on chest radiography and computed tomography, whereas scintigraphy is used for ventilation imaging. During recent years, MRI has emerged as a new means for functional imaging of ventilation. Aerosolized contrast agents and oxygen are used in proton imaging, whereas non-proton imaging relies on fluorine compounds, such as sulfur hexafluoride and perfluorcarbons, or on hyperpolarized noble gases, such as helium-3 or xenon-129. All the gases are administered as inhaled "contrast agents" for imaging of the airways and airspaces. In general, straightforward images demonstrate the homogeneity of ventilation in a breath-hold and allow for determination of ventilated lung. The different properties of the different compounds enable the measurement of additional functional parameters. They comprise airspace size, regional oxygen partial pressure, and analysis of ventilation distribution, ventilation/perfusion ratios, and gas exchange, including oxygen uptake. Novel MRI techniques provide the potential for functional imaging of ventilation. The next steps include definition of the value and the potential of the different contrast mechanisms as well as determination of the significance of the functional information with regard to physiological research and patient management in chronic obstructive pulmonary disease and others.