TABLE 2

Examples of new or emerging techniques for studying COPD and idiopathic pulmonary fibrosis (IPF)

Technique	Description	Uses and advances made with the technique	Current limitations
Micro-CT imaging	High-resolution CT imaging	Higher-resolution versus standard CT imaging [61] Can reveal structural changes associated with small airway disease [61] Reveals massive loss in number and area of terminal bronchioles in patients with centrilobular emphysematous COPD [6] When partnered with parametric response mapping as an imaging biomarker, micro-CT could identify terminal bronchiole pathology in COPD [62]	Performed on ex vivo samples, or explants, rather than on the patient [6, 61, 62]
PET	Molecular imaging; most commonly measuring ¹⁸F-FDG uptake	Has been explored as a noninvasive biomarker for pulmonary inflammation [63] Ability to quantify inflammation is under investigation [63]	Validation of imaging approaches required; changes in lung air, blood and water volumes depending on disease severity can cause variations in signals [63]
Gas diffusion MRI	Noble gases such as ³He and ¹²⁹Xe used to visualise lung structure	Could be used to monitor disease progression and response to therapy [59] Can detect microstructural changes in the lung, even in asymptomatic smokers [59] Quantitative microstructure data obtainable by measuring gas diffusion in alveoli; the technique can differentiate between patients with COPD and healthy individuals [64] Alveolar sizes can be visualised to form a picture of alveolar loss in COPD [64] Provides sensitive and reproducible data on gas exchange impairment in IPF, correlating with spirometry data [65]	Adaption of existing scanners is required [66]
SPECT	Radiotracers used to image the lung, where both airways and blood flow can be imaged	Both the airways and blood flow can be imaged, allowing the detection of comorbidities such as pulmonary embolism [67, 68] Can detect abnormalities in apparently healthy smokers [69]	Only semi-quantitative [69] Not as high resolution as other imaging methods [68] Takes a long time to acquire an image (e.g. 45 min) [68]
IOS	Noninvasive measurement of respiratory mechanics in response to pressure oscillations	A reliable tool for investigating proximal and peripheral airways resistance in patients with COPD [70] Peripheral airway resistance and compliance using IOS closely linked to COPD severity and exacerbations [58] Could be used as a screening tool for early-stage COPD [58] Useful for patients who cannot perform spirometry manoeuvres [71]	The minimal clinically important difference in IOS parameters needs to be established
OCT	A high-resolution optical imaging method	Resolution down to micrometre scale [72] Can be used to accurately measure distal airways [73] Could detect early changes to the distal airways and appears to be more sensitive than CT [72, 73]	Ultrafine bronchoscopy (with sedation) required to reach the distal airways [73]
Multiple-breath nitrogen washout	Noninvasive measurement of residual nitrogen in the airways to detect any abnormalities in gas distribution in the lung	Does not require maximal effort and can be used in a paediatric setting [74] Provides information on abnormalities in the small airways, including terminal bronchioles [75] Can detect abnormalities in early disease [76]	Limited standardisation, which impacts the availability of widely applicable reference values [75]
Breathomics	Exhaled breath analysis to detect changes in volatile organic compounds	Could be used to diagnose COPD and differentiate COPD from asthma [77] May be able to predict disease progression [77] Could help distinguish COPD phenotypes [77]	Results can be confounded by parameters such as medication use, comorbidities, smoking and study site [77]

CT: computed tomography; PET: positron emission tomography; ¹⁸F-FDG: ¹⁸F-2-fluoro-2-deoxy-d-glucose; MRI: magnetic resonance imaging; SPECT: single-photon emission computed tomography; IOS: impulse oscillometry; OCT: optical coherence tomography.