Lung diseases are highly prevalent and their early diagnosis is essential for successful treatment. Noninvasive imaging techniques are an important component of the diagnostic process for lung diseases and can also provide important information in terms of prognosis, as well as assessing disease progression and monitoring treatment response. Currently, chest X-ray, computed tomography (CT) and magnetic resonance imaging (MRI) are the most commonly used imaging modalities after patient examination. While X-rays and CT provide anatomical and structural information of the lungs, they are limited in their ability to differentiate between lung diseases with overlapping pathophysiology such as fibrosis, inflammation and infection, or to enable diagnosis at a very early disease stage. Infectious lung diseases present additional challenges, since bacterial infections tend to be diagnosed only after they have become systemic or have caused significant anatomical tissue damage, at which stage they are challenging to treat owing to the high bacterial burden.
The mainstay of imaging in fibrotic lung disease such as interstitial lung disease (ILD) and cystic fibrosis is high resolution CT (HRCT). Thin-slices multi-detector computed tomography (MDCT) plays a key role in the differential diagnosis of ILD, which is characterised by inflammation of the interstitial spaces in addition to fibrotic changes, and can assess disease progression; however, subtle changes in the volume and character of abnormalities can be difficult to assess. Furthermore, this technique is limited in its ability to define areas of active inflammation and detecting early-stage disease.1 CT imaging can differentiate some forms of ILD, but this approach is not specific for inflammation.2
Inflammatory lung disease such as COPD represent a huge health and economic burden. While CT can be used to recognise the key morphological features of emphysema, bronchial wall thickening and gas trapping, it has not proved useful in the investigation and management of COPD and it is not routinely recommended.3 Disease severity in COPD is measured by pulmonary function tests. However, since pulmonary function tests do not directly measure the cause of lung dysfunction, changes may not be detected for at least a year.4 As a result, drug development is lengthy and expensive, since long periods of observation are needed to detect a drug effect.
Once of the major limitations of CT imaging techniques in patients with inflammatory conditions such as COPD is its inability to identify abnormalities of the small airways; the bronchioles are typically less than 2 mm in internal diameter. However, a new functional imaging technique known as parametric response mapping (PRM) has provided a potentially useful imaging biomarker to identify small airway imaging in COPD. This is a voxel-based image-analysis technique measures that lung density during inhalation and exhalation. It provides a colour map, which represents normal lung tissue, small airway disease, or emphysema, and identifies small airway loss, narrowing and obstruction.5
Molecular imaging can overcome some of the limitations of CT scanning in fibrotic and inflammatory lung disease. Molecular probes are small molecules, peptides or antibodies that recognise a specific biological process and are tagged with a radiolabelled or fluorescent tracer to enable visualisation. They can be used with most imaging technologies such as positron emission tomography (PET) and single-photon mission computed tomography (SPECT), which have high sensitivity and resolution, and can provide information at the molecular level. Imaging with 18F-fluorodeoxyglucose (18F-FDG) with positron emission tomography (PET) is an established method of measuring lung inflammation.2 However, since 18F-FDG, uptake indicates metabolic activity and increased glucose uptake by activated macrophages and inflammatory cells, it cannot distinguish between inflammation, fibrosis infection or malignancy.6 More specific markers, such as 2-(3-[18F]fluoropropyl)-2-methyl-malonic acid are currently being investigated in pulmonary fibrosis in animal models.7
In recent years, more specific targeted nuclear imaging has been investigated in inflammatory lung disease. A recent preclinical proof-of-concept study showed that molecular imaging of integrin αvβ3 and somatostatin receptor 2 using SPECT/CT is a potentially effective imaging tool for ILD.8 This is an important step towards precision medicine in ILD.
SPECT imaging has been used to provide images of the distribution of ventilation and perfusion within the lungs, together with ventilation and perfusion scintigraphy, using radioaerosols such as 99mTc-labeled diethylene triamine pentaacetic acid (DTPA) and 99mTc-labeled clusters of carbon particles (Technegas) or inert radioactive gases (133Xe and 81mKr) but the latter is of limited use due to its high cost and short half-life. This technique appears to be a sensitive method for detecting changes in COPD.9 The use of Technegas has also reduced acquisition time and radiation dosage, allowing the use of SPECT in paediatric patients with chronic pulmonary disorders.10
Molecular imaging is also particularly useful in the non-invasive diagnosis of bacterial infections at an early stage. A new radiotracer, 2-18F-fluorodeoxysorbitol (18F-FDS), has recently been shown to identify and track bacterial infection in lungs better than current imaging methods.11 This technique could potentially be used in patients to identify infection sites and determine the bacterial infection class, so that patients could avoid taking antibiotics that are known to have no effect against specific bacteria. Recent research has also shown that 68Ga-based imaging agents are more specific than 18F-FDG for bacterial infection, and offer the potential for use in combined PET/CT.12 Other pathogen-specific tracers currently being evaluated include radiolabelled tracers based on antibiotics and bacterial metabolic activities such as 99mTc- labelled UBI29–41, 99mTc-vancomycin, m-18F-fluoro-para-amino benzoic acid (PABA), methyl-11C-D-methionine, 18F-maltohexaose and 18F-maltotriose.13 These approaches could accelerate the diagnosis of bacterial lung infection and facilitate the evaluation of antibiotic treatment efficacy. Importantly, these methods appear to be safe and have caused no major adverse effects. However, further research will be needed to investigate the risks associated with repeated use.
Another approach to imaging infection is fluorescent imaging. A recent study used optical endomicroscopy to visualise a water-soluble optical imaging probe based on the antimicrobial peptide polymyxin, attached to a fluorophore. The probe binds to lipid A, a molecule expressed on Gram-negative bacterial membranes, and was able to specifically detect Gram-negative bacteria distal human airways and alveoli of human subjects within minutes, providing a potentially highly efficient technology in the diagnosis and treatment of these infections.14 Importantly, the platform was non-toxic and did not cause any major adverse effects. However, the authors recommended further study to assess the potential risks associated with repeated use of this technique.
Molecular imaging and nuclear medicine approaches offer useful tools for better understanding lung inflammation, infection and fibrosis. Although most studies to date have been small and do not allow us to draw firm conclusions about the clinical utility of these imaging approaches, these new approaches appear to be very promising. One of the biggest challenges in the future will be to optimise the combination of imaging modality and molecular probes in order to obtain an accurate and differential diagnosis. As new targeted tracers are developed, molecular imaging is likely to find increasing use in diagnosis, patient monitoring and drug development, which should hopefully lead to improved outcomes.
References
1.Hansell DM, Bankier AA, MacMahon H, et al. Fleischner Society: glossary of terms for thoracic imaging. Radiology. 2008;246:697–722.
2. Scherer PM, Chen DL. Imaging Pulmonary Inflammation. J Nucl Med. 2016;57:1764–70.
3. Ostridge K, Wilkinson TM. Present and future utility of computed tomography scanning in the assessment and management of COPD. Eur Respir J. 2016;48:216–28.
4. Weinstock T, McCannon, J. Pulmonary Function Testing. Available at: www.pulmonologyadvisor.com/home/decision-support-in-medicine/pulmonary-medicine/pulmonary-function-testing/ (accessed 26 March 2019).
5. Vasilescu DM, Martinez FJ, Marchetti N, et al. Non-Invasive Imaging Biomarker Identifies Small Airway Damage in Severe COPD. Am J Respir Crit Care Med. 2019; doi: 10.1164/rccm.201811-2083OC. [Epub ahead of print].
6. Kubota R, Kubota K, Yamada S, et al. Microautoradiographic study for the differentiation of intratumoral macrophages, granulation tissues and cancer cells by the dynamics of fluorine-18-fluorodeoxyglucose uptake. J Nucl Med. 1994;35:104–12.
7. Xiong Y, Nie D, Liu S, et al. Apoptotic PET Imaging of Rat Pulmonary Fibrosis With [(18)F]ML-8. Mol Imaging. 2018;17:1536012118795728.
8. Schniering J, Benesova M, Brunner M, et al. Visualisation of interstitial lung disease by molecular imaging of integrin alphavbeta3 and somatostatin receptor 2. Ann Rheum Dis. 2019;78:218–27.
9. Mortensen J, Berg RMG. Lung Scintigraphy in COPD. Semin Nucl Med. 2019;49:16–21.
10. Sanchez-Crespo A. Lung Ventilation/Perfusion Single Photon Emission Computed Tomography (SPECT) in Infants and Children with Nonembolic Chronic Pulmonary Disorders. Semin Nucl Med. 2019;49:37–46.
11. Li J, Zheng H, Fodah R, et al. Validation of 2-(18)F-Fluorodeoxysorbitol as a Potential Radiopharmaceutical for Imaging Bacterial Infection in the Lung. J Nucl Med. 2018;59:134–9.
12. Vorster M, Buscombe J, Saad Z, et al. Past and Future of Ga-citrate for Infection and Inflammation Imaging. Curr Pharm Des. 2018;24:787–94.
13. Welling MM, Hensbergen AW, Bunschoten A, et al. An update on radiotracer development for molecular imaging of bacterial infections. Clin Transl Imaging. 2019. https://doi.org/10.1007/s40336-019-00. Available at: https://link.springer.com/article/10.1007/s40336-019-00317-4 (accessed 8 April 2019).
14. Akram AR, Chankeshwara SV, Scholefield E, et al. In situ identification of Gram-negative bacteria in human lungs using a topical fluorescent peptide targeting lipid A. Sci Transl Med. 2018;10:pii:eaal0033.
