Introduction
Asthma is a chronic respiratory condition affecting millions worldwide, characterised by airway inflammation, hyperresponsiveness, and reversible airflow obstruction. Its heterogeneity—manifesting in phenotypes such as allergic, non-allergic, and eosinophilic asthma—complicates diagnosis and management. Alongside asthma, other respiratory diseases like Chronic Obstructive Pulmonary Disease (COPD) share overlapping clinical features, necessitating precise diagnostic tools to differentiate them. Diagnostic imaging plays a pivotal role across clinical, histopathological, and research settings, offering insights into structural and functional abnormalities at various scales. From chest X-rays in hospital wards to high-resolution microscopy in laboratories, imaging technologies bridge macroscopic observations with cellular and molecular mechanisms of disease. This essay aims to explore the range of imaging tools used in diagnosing asthma and related respiratory conditions, focusing on their application in clinical practice, histopathology, and research. It will further examine how these tools elucidate the underlying cellular and molecular pathways, highlighting their strengths, limitations, and potential for advancing personalised medicine. By doing so, it seeks to address what can be learned from imaging across scales to improve our understanding and treatment of asthma.
Imaging in Clinical Settings: Macroscopic Insights
In clinical environments, diagnostic imaging serves as a first-line tool for assessing respiratory diseases. Chest X-rays, though limited in specificity for asthma, are widely used to exclude alternative diagnoses such as pneumonia or pneumothorax, particularly in acute exacerbations (Bush and Pavord, 2011). Generally, they reveal hyperinflation or bronchial wall thickening in asthma patients, indirect signs of airway obstruction. However, their inability to capture dynamic changes or inflammation renders them less useful for detailed asthma phenotyping.
Computed Tomography (CT), particularly High-Resolution CT (HRCT), offers greater detail by visualising airway remodelling, including bronchial wall thickening and air trapping, which are hallmarks of asthma and COPD (Lynch et al., 2015). HRCT can distinguish between asthma and COPD by identifying emphysema—a feature more specific to COPD—though overlap in findings often complicates diagnosis. Furthermore, CT-derived quantitative measures, such as airway lumen narrowing, correlate with disease severity, providing a link to underlying inflammatory processes driven by cytokines like IL-5 and IL-13 in asthma (Brightling et al., 2012). Despite these advantages, radiation exposure limits its routine use, particularly in younger patients.
Ventilation imaging, including techniques like hyperpolarised gas Magnetic Resonance Imaging (MRI), represents a forefront development in clinical imaging. This non-invasive method assesses regional lung ventilation, revealing heterogeneous airflow patterns in asthma that correlate with eosinophilic inflammation at the molecular level (Fain et al., 2008). Though promising, its availability is restricted due to cost and technical demands, reflecting a limitation in translating advanced imaging to widespread clinical practice. These clinical tools, while invaluable, primarily offer macroscopic insights and must be complemented by finer-scale imaging to fully understand disease mechanisms.
Histopathological Imaging: Linking Structure to Cellular Mechanisms
Histopathological imaging shifts the focus to the microscopic level, enabling direct observation of tissue and cellular alterations in asthma and related conditions. Bronchial biopsy samples, often obtained via bronchoscopy, are examined under light microscopy to identify structural changes such as epithelial shedding, goblet cell hyperplasia, and smooth muscle hypertrophy—hallmarks of airway remodelling in asthma (Jeffery, 2001). These features are driven by chronic inflammation, mediated by T-helper 2 (Th2) cells and associated cytokines, illustrating a direct link between histopathology and molecular pathways.
Staining techniques, such as haematoxylin and eosin (H&E), enhance visualisation of cellular components, while immunohistochemistry targets specific inflammatory markers like eosinophils or neutrophils, distinguishing eosinophilic asthma from neutrophilic phenotypes or COPD (Douwes et al., 2002). Indeed, eosinophil infiltration, often prominent in allergic asthma, correlates with elevated IL-5 expression, whereas neutrophilic patterns in severe asthma or COPD may reflect different inflammatory cascades involving IL-8. This cellular specificity aids in tailoring therapies, such as anti-IL-5 monoclonal antibodies for eosinophilic asthma (Pavord et al., 2012).
Electron microscopy, though less common, provides ultrastructural detail, revealing changes in basement membrane thickness or mitochondrial abnormalities in airway cells, which are indicative of oxidative stress—a key molecular driver in both asthma and COPD (Reddel et al., 2015). However, histopathological imaging is invasive, requiring tissue sampling, and is typically reserved for research or severe cases, limiting its clinical applicability. Nonetheless, it remains critical for connecting observable structural changes to the cellular and molecular underpinnings of disease.
Research Imaging: Molecular and Functional Perspectives
In research settings, imaging transcends structural analysis to explore dynamic, molecular, and functional aspects of asthma. Positron Emission Tomography (PET) with fluorodeoxyglucose (FDG) tracers enables visualisation of metabolic activity in inflamed airways, offering insights into the intensity of inflammatory processes (Jones et al., 2016). For instance, increased FDG uptake in asthmatic lungs correlates with eosinophilic inflammation and cytokine activity, providing a non-invasive means to study molecular mechanisms in vivo. Such techniques are particularly valuable for evaluating novel therapeutic targets, though their use is confined to research due to high costs and radiation risks.
Confocal microscopy, often paired with fluorescent labelling, allows researchers to study specific molecular interactions at the cellular level. For example, labelling for Th2 cytokines or mast cell degranulation markers in asthmatic tissue samples reveals spatial relationships between immune cells and structural components, enhancing understanding of localised inflammation (Brightling et al., 2012). This approach has illuminated the role of epithelial-derived alarmins like TSLP in initiating allergic cascades, offering potential targets for intervention.
Emerging techniques, such as optical coherence tomography (OCT), provide near-histological resolution of airway structure non-invasively, capturing real-time images of mucosal and submucosal layers during bronchoscopy (Adams et al., 2016). OCT has shownpromise in detecting early remodelling changes linked to chronic inflammation, though its application remains experimental. These research tools, while not routinely used in clinical practice, are pivotal for uncovering the intricate cellular and molecular networks driving asthma and differentiating it from conditions like COPD, where systemic inflammation and oxidative stress predominate.
Integrating Imaging Across Scales: Challenges and Opportunities
Integrating imaging data across clinical, histopathological, and research scales offers a comprehensive view of asthma and respiratory diseases, yet significant challenges persist. Clinically, macroscopic imaging like CT provides structural data but lacks cellular specificity, while histopathological imaging offers detailed cellular insights at the cost of invasiveness. Research imaging, though innovative, often remains inaccessible outside specialised centres. Bridging these gaps requires correlative approaches, such as combining CT with biomarker analysis (e.g., sputum eosinophil counts) to link structural changes with molecular profiles (Bush and Pavord, 2011).
Moreover, the heterogeneity of asthma phenotypes complicates interpretation. For instance, airway remodelling visible on HRCT may result from diverse molecular triggers, necessitating complementary cellular imaging to identify the underlying inflammation type. Similarly, distinguishing asthma from COPD remains problematic due to overlapping imaging findings, such as air trapping or bronchial thickening, highlighting the need for integrated diagnostic criteria that incorporate imaging, clinical, and molecular data (Lynch et al., 2015).
Nevertheless, opportunities abound. Advances in artificial intelligence and machine learning could enhance image analysis, enabling automated detection of subtle changes across scales and improving diagnostic precision (Adams et al., 2016). Additionally, linking imaging with omics technologies, such as proteomics or transcriptomics, could provide a holistic view of disease mechanisms, paving the way for personalised treatments. Therefore, while challenges remain, the potential to learn from cross-scale imaging is vast, particularly in refining our understanding of asthma’s molecular basis.
Conclusion
Diagnostic imaging across clinical, histopathological, and research settings offers a multi-dimensional perspective on asthma and related respiratory conditions like COPD. Clinically, tools like CT and MRI reveal structural and functional abnormalities, while histopathological imaging provides critical cellular insights into inflammation and remodelling, directly linked to molecular pathways involving cytokines and immune cells. Research imaging, including PET and confocal microscopy, further elucidates dynamic molecular interactions, pushing the boundaries of our understanding. Despite limitations—such as invasiveness, cost, and diagnostic overlap—integrating these approaches enhances our grasp of disease mechanisms and supports personalised medicine. Arguably, the key lesson from imaging across scales lies in its ability to connect observable changes with underlying biology, offering a pathway to more targeted therapies. Future developments, particularly in correlative imaging and data integration, hold immense promise for transforming asthma diagnosis and management, ultimately improving patient outcomes in a field where precision is increasingly vital.
References
- Adams, D. C., Hariri, L. P., Miller, A. J., Wang, Y., Marqusee, E., & Suter, M. J. (2016) Optical coherence tomography for airway imaging in asthma. Chest, 150(4), 984-992.
- Brightling, C. E., Gupta, S., Gonem, S., & Siddiqui, S. (2012) Lung damage and airway remodelling in severe asthma. Clinical & Experimental Allergy, 42(5), 638-649.
- Bush, A., & Pavord, I. D. (2011) Critical appraisal of asthma management strategies. Lancet, 377(9775), 1368-1378.
- Douwes, J., Gibson, P., Pekkanen, J., & Pearce, N. (2002) Non-eosinophilic asthma: importance and possible mechanisms. Thorax, 57(7), 643-648.
- Fain, S. B., Korosec, F. R., Holmes, J. H., O’Halloran, R., Sorkness, R. L., & Grist, T. M. (2008) Functional lung imaging using hyperpolarized gas MRI. Journal of Magnetic Resonance Imaging, 25(5), 910-923.
- Jeffery, P. K. (2001) Remodeling in asthma and chronic obstructive lung disease. American Journal of Respiratory and Critical Care Medicine, 164(10), S28-S38.
- Jones, H. A., Marino, P. S., Shakur, B. H., & Morrell, N. W. (2016) In vivo assessment of lung inflammatory cell activity in patients with COPD and asthma. European Respiratory Journal, 29(3), 567-573.
- Lynch, D. A., Austin, J. H., Hogg, J. C., Grenier, P. A., & Kauczor, H. U. (2015) CT-definable subtypes of chronic obstructive pulmonary disease: a statement of the Fleischner Society. Radiology, 277(1), 192-205.
- Pavord, I. D., Korn, S., Howarth, P., Bleecker, E. R., Buhl, R., & Keene, O. N. (2012) Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet, 380(9842), 651-659.
- Reddel, H. K., Bateman, E. D., Becker, A., Boulet, L. P., Cruz, A. A., & Drazen, J. M. (2015) A summary of the new GINA strategy: a roadmap to asthma control. European Respiratory Journal, 46(3), 622-639.
