In vivo imaging of inflammation in chronic obstructive pulmonary disease for endotyping of disease: the progression from structural to functional imaging of the lung

Abstract

Novel disease modifying therapies are much needed in airways disease, particularly COPD. The heterogenous nature of COPD has provided challenges in identifying which populations will respond to specific therapies, as well as in determining which patients will go on to develop progressive or clinically relevant disease. Precision medicine and risk-stratification approaches are therefore required to identify those who require early intervention and those who will respond to specific therapies, both in the clinical setting as well as in therapeutic trials.

CT imaging of airways disease has provided invaluable information for many years, with more modern, automated analysis approaches able to detect small changes in structure which reflect ongoing disease processes rather than the end-product of disease. Continued development of CT analysis methods may also permit a better understanding of the early changes in airways disease to provide improved risk-stratification. However, detection of active inflammatory processes at the molecular level will require novel approaches to imaging in airways disease. Molecular imaging using SPECT technology provides a means to achieve this. Furthermore, integration of quantitative CT analysis into molecular imaging approaches may provide patient-specific data which can assist interpretation of molecular imaging results.

Firstly, an analysis of CT imaging in an observational, longitudinal study investigating changes in early COPD is presented, which focuses on continuing the development of novel analysis techniques in the detection of early COPD. This analysis aimed to identify biomarkers which determine risk of disease progression, and CT-detected changes in the pulmonary vasculature were investigated as there is a growing body of evidence to suggest that changes in the pulmonary vasculature occur very early in the disease process. There were correlations between markers for small vessel fraction (BV5/TPVV) or density (BV5/TLV) and other physiological markers of early COPD. Patients who developed small airways disease at any point in the study, defined by oscillometry or spirometry markers, showed significantly higher BV5/TPVV or BV5/TLV, though this was complicated by the confounding effects of lung volume. A longitudinal analysis also revealed that small vessel measures at baseline were associated with progression of FEV1 decline and markers of small airways disease, and that this association differed depending on the degree of progression of early disease at the time of the scan.

Whilst these structural changes appear to be a dynamic process indicative of active inflammation, CT does not image inflammation directly. A SPECT-CT molecular imaging platform using automated analysis approaches was developed for this purpose. As a first step towards the development of precision medicine approaches, attempts were made to quantify inflammatory cytokine activity in COPD. 99mTc-anti-TNF-α was infused prior to SPECT imaging to detect TNF-α activity as proof-of-concept in COPD. There were differences between the COPD and healthy control groups, with a significant increase in normalised SPECT activity between the two SPECT scan time-points in the COPD group (64.88% +/- (SD) 31.04, p=0.029, paired t-test) but not in the healthy group (35.38% +/- 34.33, p=NS). Two key confounding factors were also identified when analysing results at a single scan time-point (vessel density and emphysema, determined by quantitative CT measures) and experimental techniques were developed to adjust for this.

Whilst structural imaging continues to provide insight into the disease process and heterogeneity in the COPD population, progression towards functional molecular imaging approaches could provide much-needed novel precision medicine approaches. The studies described here provide advances towards imaging-based risk-stratification in early disease and non-invasive precision medicine approaches, imaging inflammation directly at the site of disease activity.

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Identifiers

ORCID for Benjamin Matthew Kelvey Welham: orcid.org/0000-0001-9683-252X

ORCID for Tom Wilkinson: orcid.org/0000-0003-1771-3851

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