Quantitative lung CT analysis for the study and diagnosis of Chronic Obstructive Pulmonary Disease

The importance of medical imaging in the research of Chronic Obstructive Pulmonary Dis- ease (COPD) has risen over the last decades. COPD affects the pulmonary system through two competing mechanisms; emphysema and small airways disease. The relative contribu- tion of each component varies widely across patients whilst they can also evolve regionally in the lung. Patients can also be susceptible to exacerbations, which can dramatically ac- celerate lung function decline. Diagnosis of COPD is based on lung function tests, which measure airflow limitation. There is a growing consensus that this is inadequate in view of the complexities of COPD. Computed Tomography (CT) facilitates direct quantification of the pathological changes that lead to airflow limitation and can add to our understanding of the disease progression of COPD. There is a need to better capture lung pathophysiology whilst understanding regional aspects of disease progression. This has motivated the work presented in this thesis. Two novel methods are proposed to quantify the severity of COPD from CT by analysing the global distribution of features sampled locally in the lung. They can be exploited in the classification of lung CT images or to uncover potential trajectories of disease progression. A novel lobe segmentation algorithm is presented that is based on a probabilistic segmen- tation of the fissures whilst also constructing a groupwise fissure prior. In combination with the local sampling methods, a pipeline of analysis was developed that permits a re- gional analysis of lung disease. This was applied to study exacerbation susceptible COPD. Lastly, the applicability of performing disease progression modelling to study COPD has been shown. Two main subgroups of COPD were found, which are consistent with current clinical knowledge of COPD subtypes. This research may facilitate precise phenotypic characterisation of COPD from CT, which will increase our understanding of its natural history and associated heterogeneities. This will be instrumental in the precision medicine of COPD

COPD phenotypes and machine learning cluster analysis : A systematic review and future research agenda

Funding This research did not receive any specific grant from funding agencies in the public, commercial, or ot-for-profit sectors.Peer reviewedPostprin

Pulmonary CT and MRI phenotypes that help explain chronic pulmonary obstruction disease pathophysiology and outcomes

Pulmonary x-ray computed tomographic (CT) and magnetic resonance imaging (MRI) research and development has been motivated, in part, by the quest to subphenotype common chronic lung diseases such as chronic obstructive pulmonary disease (COPD). For thoracic CT and MRI, the main COPD research tools, disease biomarkers are being validated that go beyond anatomy and structure to include pulmonary functional measurements such as regional ventilation, perfusion, and inflammation. In addition, there has also been a drive to improve spatial and contrast resolution while at the same time reducing or eliminating radiation exposure. Therefore, this review focuses on our evolving understanding of patient-relevant and clinically important COPD endpoints and how current and emerging MRI and CT tools and measurements may be exploited for their identification, quantification, and utilization. Since reviews of the imaging physics of pulmonary CT and MRI and reviews of other COPD imaging methods were previously published and well-summarized, we focus on the current clinical challenges in COPD and the potential of newly emerging MR and CT imaging measurements to address them. Here we summarize MRI and CT imaging methods and their clinical translation for generating reproducible and sensitive measurements of COPD related to pulmonary ventilation and perfusion as well as parenchyma morphology. The key clinical problems in COPD provide an important framework in which pulmonary imaging needs to rapidly move in order to address the staggering burden, costs, as well as the mortality and morbidity associated with COPD

Hyperpolarized 3He Magnetic Resonance Imaging Phenotypes of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the world. Identifying clinically relevant COPD phenotypes has the potential to reduce the global burden of COPD by helping to alleviate symptoms, slow disease progression and prevent exacerbation by stratifying patient cohorts and forming targeted treatment plans. In this regard, quantitative pulmonary imaging with hyperpolarized 3He magnetic resonance imaging (MRI) and thoracic computed tomography (CT) have emerged as ways to identify and measure biomarkers of lung structure and function. 3He MRI may be used as a tool to probe both functional and structural properties of the lung whereby static-ventilation maps allow the direct visualization of ventilated lung regions and 3He apparent diffusion coefficient maps show the lung microstructure at alveolar scales. At the same time, thoracic CT provides quantitative measurements of lung density and airway wall and lumen dimensions. Together, MRI and CT may be used to characterize the relative contributions of airways disease and emphysema on overall lung function, providing a way to phenotype underlying disease processes in a way that conventional measurements of airflow, taken at the mouth, cannot. Importantly, structure-function measurements obtained from 3He MRI and CT can be extracted from the whole-lung or from individual lung lobes, providing direct information on specific lung regions. In this thesis, my goal was to identify pulmonary imaging phenotypes to provide a better understanding of COPD pathophysiology in ex-smokers with and without airflow limitation. This thesis showed: 1) ex-smokers without airflow limitation had imaging evidence of subclinical lung and vascular disease, 2) pulmonary abnormalities in ex- smokers without airflow limitation were spatially related to airways disease and very mild emphysema, and, 3) in ex-smokers with COPD, there were distinct apical-basal lung phenotypes associated with disease severity. Collectively, these findings provide strong evidence that quantitative pulmonary imaging phenotypes may be used to characterize the underlying pathophysiology of very mild or early COPD and in patients with severe disease

The fluctuation behavior of heart and respiratory system signals as a quantitative tool for studying long-term environmental exposures and chronic diseases

Background: Several studies over the last decades have suggested that a wide range of disease states, as well as the aging process itself, are marked by progressive impairment of the involved physiological processes to adapt, resulting in a loss of complexity in the dynamics of physiological functions. Therefore, measuring complexity from physiological system signals holds enormous promise for providing a new understanding of the mechanisms underlying physiological systems and how they change with diseases and aging. Furthermore, since physiological systems are continuously exposed to environmental factors, measuring how physiological complexity changes during exposure to environmental elements might also provide new insights into their effects. Indeed, this approach may be able to unveil subtle but important changes in the regulatory mechanisms of physiological systems not detectable by traditional analysis methods. Objectives: The overall objective of this PhD thesis was to quantify the complexity of the dynamics of heart and respiratory system signals, in order to investigate how this complexity changes with long-term environmental exposures and chronic diseases, using data from large epidemiological and clinical studies, in order to control for most potential confounders of the fluctuation behavior of systems signals (e.g., demographic, environmental, clinical, and lifestyle factors). We specifically aimed (1) at assessing the influence, first, of long-term smoking cessation, and second, of long-term exposure to traffic-related particulate matter of less than 10 micrometers in diameter (TPM10), on the regulation of the autonomic cardiovascular system and heart rate dynamics in an aging general population, using data from the SAPALDIA cohort study; (2) to assess whether the subgrouping of patients with recurrent obstructive airway diseases, including mild-to-moderate asthma, severe asthma, and COPD, according to their pattern of lung function fluctuation, allows for the identification of phenotypes with specific treatable traits, using data from the BIOAIR study. Methods: In the SAPALDIA cohort, a population-based Swiss cohort, 1608 participants ≥ 50 years of age underwent ambulatory 24-hr electrocardiogram monitoring and reported on lifestyle and medical history. In each participant, heart rate variability and heart rate dynamics were characterized by means of various quantitative analyses of the inter-beat interval time series generated from 24-hour electrocardiogram recordings. Each parameter obtained was then used as the outcome variable in multivariable linear regression models in order to evaluate the association with (1) smoking status and time elapsed since smoking cessation; (2) long-term exposure to TPM10. The models were adjusted for known confounding factors. In the BIOAIR study, we conducted a time series clustering analysis based on the fluctuation of twice-daily FEV1 measurements recorded over a one year period in a mixed group of 134 adults with mild-to-moderate asthma, severe asthma, or COPD from the longitudinal Pan-European BIOAIR study. Results: In the SAPALDIA cohort, our findings indicate that smoking triggers adverse changes in the regulation of the cardiovascular system, even at low levels of exposure since current light smokers exhibited significant changes as compared to lifelong non-smokers. Moreover, there was evidence for a dose-response effect. Furthermore, full recovery was achieved in former smokers (i.e., normalization to the level of lifelong non-smokers). However, while light smokers fully recovered within the 15 first years of cessation, heavy former smokers might need up to 15-25 years to fully recover. Regarding long-term exposure to TPM10, we did not observe an overall association with heart rate variability/heart rate dynamics in the entire study population. However, significant changes in the heart rate dynamics were found in subjects without cardiovascular morbidity and significant changes, both in the heart rate dynamics and in the heart rate variability, were found in non-obese subjects without cardiovascular morbidity. Furthermore, subjects with homozygous GSTM1 gene deletion appeared to be more susceptible to the effects of TPM10. In the BIOAIR study, we identified five phenotypes, of those three distinct phenotypes of severe asthma, in which the progressive functional alteration of the lung corresponded to a gradually increasing clinical severity and translated into specific risks of exacerbation and treatment response features. Conclusions: This thesis hopes to demonstrate the importance of multidimensional approaches to gain understanding in the complex functioning of the human physiological system and of disease processes. Characterization of the complexity in the fluctuation behavior of system signals holds enormous promise for providing new understandings of the regulatory mechanisms of physiological systems and how they change with diseases. However, it is important to combine this kind of approach with classical epidemiological approaches in order to disentangle the various contributions of the intrinsic physiological dynamics, aging, diseases and comorbidities, lifestyle, and environment. In the SAPALDIA cohort study, we were able to disentangle the influence of specific environmental exposures, such as particulate matter air pollution and smoking exposure, on the heart rate variability and heart rate dynamics, and thus to unveil long-term alterations in former heavy smokers, as well as adverse effects of low level, but long-term, exposure to TPM10 in healthy subjects and in subjects with homozygous GSTM1 gene deletion. In the BIOAIR study, we provide evidence that airway dynamics contain substantial information, which enables the identification of clinically meaningful phenotypes, in which the functional alteration of the lung translates into specific treatable traits

Multi-Level Integrated Analysis of Chronic Obstructive Pulmonary Disease (COPD) heterogeneity

[eng] Non-Communicable Diseases (NCDs), including cancer, cardiovascular (heart diseases or stroke), respiratory (COPD or asthma) and metabolic diseases (diabetes) are chronic conditions that represent a major global health problem of the 21st century. All of them, however, are the end-result of a complex set of gene-environment interactions that develop over years and often lead to several NCDs co-existing in the same individual (multi-morbidity). Multi-level integrated analysis has the potential to uncover the heterogeneity of NCDs by conceptualizing them as emergent properties of a complex, non-linear, dynamic and multilevel biological system, or network of biological and environmental interactions. Chronic Obstructive Pulmonary Disease (COPD) is a NCD of increasing prevalence worldwide that is projected to be by 2020 the third leading cause of death worldwide. It is currently viewed as a broad diagnostic term that encompass a continuum of subtypes each characterized by distinct functional or pathobiological mechanisms (endotypes) and is characterized by persistent respiratory symptoms and airflow limitation. The underlying hypothesis of this PhD Thesis is that multi-level integrated analysis can help us understand highly heterogeneous respiratory diseases such as COPD. Specifically, the following two aspects of COPD heterogeneity will be addressed: 1) Exacerbations of COPD (ECOPD): ECOPD are episodes of worsening of the symptoms whose pathogenesis and biology are not entirely understood. They are heterogeneous events of non-specific diagnosis. Biomarkers analysis and networks medicine were used to uncover novel pathobiological information from the comparison of the multi-level (i.e., clinical, physiological, biological, imaging and microbiological) correlation networks determined during ECOPD and clinical recover. We concluded that ECOPD are characterised by disruption of network homeokinesis that exists during convalescence and can be identified objectively by using a panel of three biomarkers (dyspnoea, circulating neutrophils and CRP levels) frequently determined in clinical practice. 2) Early low lung function and health in later life: In 2015 Lange P. et al. showed that low peak lung function in early adulthood is associated with the diagnosis of COPD later in life. We assessed in three general population cohorts the prevalence of low peak lung function and its association with other clinical or biological parameters - specifically respiratory, cardiovascular, and metabolic abnormalities – as well as incidence of comorbid diseases during follow-up. We concluded that low peak lung function in early adulthood is common in the general population and could identify a group of individuals at risk of early (cardiovascular, metabolic and systemic) comorbidities and premature death

Emphysema presence, severity, and distribution has little impact on the clinical presentation of a cohort of patients with mild to moderate COPD

Phenotypic characterization of patients with COPD may have potential prognostic and therapeutic implications. Available information on the relationship between emphysema and the clinical presentation in patients with COPD is limited to advanced stages of the disease. The objective of this study was to describe emphysema presence, severity, and distribution and its impact on clinical presentation of patients with mild to moderate COPD. METHODS: One hundred fifteen patients with COPD underwent clinical and chest CT scan evaluation for the presence, severity, and distribution of emphysema. Patients with and without emphysema and with different forms of emphysema distribution (upper/lower/core/peel) were compared. The impact of emphysema severity and distribution on clinical presentation was determined. RESULTS: Fifty percent of the patients had mild homogeneously distributed emphysema (1.84; 0.76%-4.77%). Upper and core zones had the more severe degree of emphysema. Patients with emphysema were older, more frequently men, and had lower FEV(1)%, higher total lung capacity percentage, and lower diffusing capacity of the lung for carbon monoxide. No differences were found between the clinical or physiologic parameters of the different emphysema distributions. CONCLUSIONS: In patients with mild to moderate COPD, although the presence of emphysema has an impact on physiologic presentation, its severity and distribution seem to have little impact on clinical presentation

Chronic obstructive pulmonary disease with mild airflow limitation: current knowledge and proposal for future research - a consensus document from six scientific societies

Chronic obstructive pulmonary disease (COPD) is a leading cause of mortality and morbidity worldwide, with high and growing prevalence. Its underdiagnosis and hence under-treatment is a general feature across all countries. This is particularly true for the mild or early stages of the disease, when symptoms do not yet interfere with daily living activities and both patients and doctors are likely to underestimate the presence of the disease. A diagnosis of COPD requires spirometry in subjects with a history of exposure to known risk factors and symptoms. Postbronchodilator forced expiratory volume in 1 second (FEV1)/forced vital capacity <0.7 or less than the lower limit of normal confirms the presence of airflow limitation, the severity of which can be measured by FEV1% predicted: stage 1 defines COPD with mild airflow limitation, which means postbronchodilator FEV1 6580% predicted. In recent years, an elegant series of studies has shown that "exclusive reliance on spirometry, in patients with mild airflow limitation, may result in underestimation of clinically important physiologic impairment". In fact, exercise tolerance, diffusing capacity, and gas exchange can be impaired in subjects at a mild stage of airflow limitation. Furthermore, growing evidence indicates that smokers without overt abnormal spirometry have respiratory symptoms and undergo therapy. This is an essential issue in COPD. In fact, on one hand, airflow limitation, even mild, can unduly limit the patient's physical activity, with deleterious consequences on quality of life and even survival; on the other hand, particularly in younger subjects, mild airflow limitation might coincide with the early stage of the disease. Therefore, we thought that it was worthwhile to analyze further and discuss this stage of "mild COPD". To this end, representatives of scientific societies from five European countries have met and developed this document to stimulate the attention of the scientific community on COPD with "mild" airflow limitation. The aim of this document is to highlight some key features of this important concept and help the practicing physician to understand better what is behind "mild" COPD. Future research should address two major issues: first, whether mild airflow limitation represents an early stage of COPD and what the mechanisms underlying the evolution to more severe stages of the disease are; and second, not far removed from the first, whether regular treatment should be considered for COPD patients with mild airflow limitation, either to prevent progression of the disease or to encourage and improve physical activity or both

Chronic obstructive pulmonary disease and risk of lung cancer

Abstract Background: Lung cancer is a main cause of death in patients suffering from COPD and smokers with COPD have an increased risk of lung cancer compared to healthy smokers. COPD comprises a broad range of features, including emphysema, chronic bronchitis, asthmatic features, and acute exacerbations in COPD (AECOPD). We hypothesized that some of these features of COPD represent a higher risk of lung cancer and non-pulmonary cancer. Aims: 1. To explore if emphysema and airway wall thickness assessed quantitatively on CT increase the risk of lung cancer and non-pulmonary cancer. 2. To investigate if acute exacerbations in COPD are associated with the risk of lung cancer, and to see whether this association differs based on coexisting asthma. 3. To examine and compare two lung cancer screening scores in our population of patients with COPD. Materials and Methods: Participants included in the analyses of all three papers were from the GenKOLS study in Bergen, Norway, conducted between January 2003 and January 2005. Participants were 40-85 years of age and had a smoking history of at least 2.5 pack-years at baseline. GenKOLS was conducted as a case-control study. COPD was diagnosed when post-bronchodilator FEV1/FVC was <0.70 and FEV1<80% predicted. Baseline examinations included a detailed questionnaire on smoking habits, respiratory symptoms, and disease history, as well as pulmonary function tests. Approximately half of all the participants had a chest CT scan. Baseline data were linked to incident cancer data from the Cancer Registry of Norway throughout the year 2013. All subjects with a cancer diagnosis before inclusion were excluded from the analyses. In Paper III, the subjects were divided into high and low risk according to the National Lung Cancer Screening Trial (NLST) inclusion criteria, and the COPD-Lung Cancer Screening Score (COPD-LUCSS). Cox proportional hazards regression were used to examine the hazard ratios (HR) for the effect of the predictor variables on the risk of cancer. Results: 1. After adjustment for age, sex, pack-years, age of onset of smoking, smoking status at baseline, and FEV1, the baseline amount of emphysema remained a significant predictor of the incidence of non-pulmonary cancer and lung cancer. Airway wall thickness did not predict cancer independently. 2. AECOPD was significantly associated with lung cancer during ten years of follow-up only in COPD patients without asthma. The analysis was adjusted for sex, age, smoking variables, FEV1, and BMI. 3. The NLST selection criteria, and the COPD-LUCSS were both significantly associated with the risk of lung cancer. The area under the curve values showed that both models have poor discriminatory abilities in our cohort. There was no significant difference in the discriminatory ability between the scores. Conclusions: Some features of COPD were significantly associated with the risk of lung cancer, and even non-pulmonary cancer. Emphysema was significantly associated with lung cancer risk and risk of non-pulmonary cancer, whereas airway wall thickness was not. AECOPD was associated with an increased risk of lung cancer only in COPD patients without asthma. Some of these features of COPD might be of use in evaluating those who could benefit from lung cancer screening. Although both the NLST selection criteria and the COPD-LUCSS, were associated with an increased risk of lung cancer, both scores had poor discriminatory abilities in our cohort of COPD patients. More studies are needed to find better models to target those at higher risk of lung cancer.Doktorgradsavhandlin