Recent Advances in Optical Coherence Tomography for the Diagnoses of Lung Disorders

Randy Hou; Tho Le; Septimiu D Murgu; Zhongping Chen; Matt Brenner


Expert Rev Resp Med. 2011;5(5):711-724. 

In This Article

Diagnostic Applications

The gold standard for thoracic imaging has been CT which currently allows high image resolution (~0.5 mm) to be readily available.[18] However, even the most advanced CT scanner does not resolve the small airways reliably, which, in fact, may approach the size of individual voxels. In a recent study, OCT was able to obtain airway wall dimensions of medium to large airways that correlated well with CT and obtain very clear images of small airways[18] and, therefore, may be appropriate to diagnose and study airway wall changes including remodeling in asthma and chronic obstructive pulmonary disease (COPD).

Obstructive Lung Diseases

Despite the prevalence of obstructive lung diseases such as asthma, COPD and bronchiectasis, little is known about airway remodeling and how it affects the elastic properties of the airway. In a controlled study, healthy subjects and subjects with a known history of asthma, COPD or bronchiectasis were evaluated with OCT. In asthma patients, the airway lumen was narrower and showed greater distention at a given airway pressure compared with control. Bronchiectasis patients showed a similar pattern, with a greater range of airway lumen area measurements, which may to some degree contribute to the propensity of bronchiectatic airways to collapsibility. It was postulated that these findings may be a result of chronic inflammation causing decreased effect of the radial distending force of the lung parenchyma on the airway, resulting in a narrower airway lumen at baseline which distends more easily with application of intraluminal airway pressure. There was no statistically significant difference in the OCT diameter measurements of the airways in COPD compared with controls. However, there was a strong trend towards greater compliance. This greater compliance can explain airway narrowing in COPD by decreasing the force necessary for the airway smooth muscle to exert on the airway to cause narrowing.[19] This study used measurements of airway compliance derived from simultaneous measurements of airway pressure with cross-sectional airway area obtained using anatomical OCT.

In the study described above, OCT was more sensitive than CT at detecting lung function changes in the smaller airways. Using measured luminal area and wall area as measured by OCT and CT, when compared with a patient's predicted forced expiratory volume in one second, it was found that while there was no correlation at the third-generation level, there was a negative correlation at the fifth-generation airway.[18] This suggests that a primary site of obstruction in COPD is in the peripheral airway and raises the possibility that OCT may become a tool in evaluating small airway changes associated with COPD.[18,20] The implications of this study are that OCT provides a way to evaluate regional airway properties not previously available, and this information may provide new insight into the mechanisms of obstructive lung diseases, which may in turn help guide treatment, provide an in vivo tool to longitudinally follow changes in airway to assess treatment efficacy and to study disease progression over time.

Lung Cancer

Thus far, routine screening for lung cancer is still controversial.[21] Therefore, there is still a need of newer techniques that can potentially assist in the early detection of lung cancer. In a pilot study enrolling five patients, a forward-scanning OCT probe was employed via a flexible bronchoscope and OCT images of endobronchial lesions, as well as normal mucosa were obtained, and these areas were biopsied as well.[22] These subjects were chosen because they had imaging studies that suggested the presence of an endobronchial lesion. Each patient had a single endobronchial mass that was visualized with WLB. The bronchoscopies were performed under moderate sedation, lasted an average of 29 min, and there were no related complications. Four of the five endobronchial lesions revealed various forms of lung cancer by histopathology, and none of the biopsies of normal mucosa revealed cancer. When comparing the OCT images of the malignant and benign regions of airway, there were clear differences. The malignant OCT images had lost some of the contrast and layering seen in benign images. This pilot study showed that OCT can be safely employed through a flexible bronchoscope with minimal additional risk or burden to the patient, and produce images that clearly show a difference between malignant and normal tissue in vivo, and in real time. The main limitation of OCT in this study was that other nonmalignant pathologic changes were not compared with malignant pathology. Therefore, while OCT could distinguish malignant from normal tissue, it remains to be seen if OCT can distinguish malignant from nonmalignant pathologic changes (such as granulation, strictures or other inflammatory pathology). In addition, the OCT probe had a rigid tip that could not be passed through the working channel of the bronchoscope, and therefore had to be attached to the bronchoscope's exterior. This made navigation of the bronchoscope more difficult.[22]

In a separate study, both in vivo and ex vivo analysis of bronchial mucosa were performed using a radial OCT probe in seven patients.[23] Both benign and malignant airway mucosa were examined. Again, when comparing normal to abnormal mucosa, there was a loss of the distinct layering structure in the abnormal tissue.[23] In a study comprised of 15 patients already diagnosed with lung cancer awaiting curative surgery, OCT was employed through a flexible bronchoscope and airway mucosa of excised lung lobes were imaged immediately following the lobectomy surgeries.[6] Images with a depth of penetration of 2–3 mm and a spatial resolution of 10 µm were achieved. There was a strong correlation between OCT and histology. In addition, inflammatory infiltrates, squamous metaplasia and tumor was able to be identified on the OCT images, when analyzed with the corresponding histologic images.[6] Therefore, with both forward-scanning and radial OCT probes, a distinct difference can be seen in the OCT images of benign and malignant mucosa from normal mucosa. However, its utility to differentiate various airway pathologies (benign from malignant) remains to be established. These studies suggest that OCT has potential to be a powerful diagnostic tool for airway malignancies. In the future, it may be possible to utilize OCT in conjunction with other pulmonary imaging modalities such as EBUS and autoflourescence bronchoscopy to provide biopsy guidance and increased diagnostic yield.

Sepsis & Smoke Inhalation Airway Wall Injury

The ability of OCT to distinguish histologic properties of tracheal mucosa was demonstrated in excised rabbit tracheas. The OCT images were compared with histologic preparations of the same tissues and the results were found to be similar.[24] In later studies, a sepsis/pneumonia model was applied to rabbits, and the excised tracheas were again analyzed by both OCT and conventional histology. OCT was able to detect airway wall thickening consistent with tracheal edema, as well as epithelial denuding and mucosal sloughing.[25]

Airway injury from inhalation of smoke is a major source of morbidity and mortality in fire victims. The difficulty in treating victims of smoke inhalation is that there is currently no means by which to anticipate respiratory compromise with precision. There are several animal studies in which the airway was imaged with OCT following uniform exposure to smoke.[26–28] After just 15 min post-smoke exposure, there was evidence of increased thickness of the airway wall on OCT, with a maximum increase in airway wall thickness of 120% after 5 h.[26] In a subsequent study, it was also noted that the lower trachea experienced more swelling than the upper trachea. It was proposed that perhaps the lower trachea is inherently more sensitive to smoke, or that the position of the lower trachea/main bronchi creates more smoke particle deposition than the upper trachea.[27] In a follow-up study, a new, swept-source radial OCT probe was used to produce 3D images of the trachea during smoke exposure, which may provide further insight into the degree and pattern of smoke-related acute airway injury.[28] Using OCT, one could not only determine the extent of the injury but could also potentially be able to predict impending obstruction which could be used to guide treatment choices. In addition, it would provide a good tool to monitor for recovery, looking at changes both at the structural and cellular level.

Chronic Pulmonary Embolism & Pulmonary Hypertension

There are currently different sub-groups of patients with pulmonary hypertension, among which chronic thromboembolic pulmonary hypertension (CTEPH) and pulmonary arterial hypertension (PAH) are quite common. These two groups often present in similar fashion and have similar effects on the pulmonary circulation, but have different pathophysiology and require different treatment. In one study, normal patients, patients with CTEPH and patients with PAH underwent right heart catheterization and OCT of the pulmonary arteries.[29] The method of intravascular OCT was not explained in the cited reference. However, data from cardiovascular OCT reviews describe the technique in some detail. Blood absorbs light and will interfere with the capture of vessel wall anatomy. The conventional technique to solve this issue is by instilling either normal saline or lactated Ringer solution, which allows penetration of light, with or without proximal balloon occlusion of the vessel. Newer frequency domain OCT systems are able to capture images faster, thus allowing for the use of power injection of contrast medium and obviating the need for proximal balloon occlusion, and decreasing the risk of ischemic complications.[30]

The OCT images from these three groups were significantly different. Compared to the control group, the media and intima of the pulmonary arteries were much thicker in PAH patients. In CTEPH patients, the pulmonary arteries were either occluded presumably with thrombus, and/or contained flaps within the lumen.[29] This study provides evidence that OCT can potentially distinguish CTEPH from PAH. If OCT is further validated in larger studies for the purpose of diagnosing CTEPH, it holds potential as a confirmatory test for securing the diagnosis of CTEPH, especially if a strong diagnosis of CTEPH will change management significantly, such as in the case of a patient who is being considered for surgery. Therefore, on the initial diagnosis of pulmonary hypertension with right heart catheterization, OCT can potentially be performed at that time to assist with the diagnosis of CTEPH.

Pleural Disease

Current research in OCT imaging of the pleura is limited to animal studies. Such studies demonstrated that fine structures such as the visceral pleura and alveoli were able to be visualized with OCT at high resolution. In addition, empysema and metastatic cancer animal models showed that OCT was able to detect characteristic changes in the pleura and lung as a result of infection or malignancy, as well as areas of malignancy in the sub-pleural region 2–3 mm below the surface.[31] OCT was able to provide high-resolution detail about the pleura depending on the disease. Structural changes such as mucosal wall thickening, as seen in infection, could be seen. Pleural based nodules and lung tumors as small as 500 µm were also visualized using OCT. When comparing extensive disease such as induced empyema and metastatic disease in animals, distinguishable structures such as alveoli and visceral pleura are lost because of compression by tumor and filling of alveoli with purulent material.[31] While OCT can clearly distinguish normal from abnormal pleural and surface parenchymal disease, it is remains to be determined whether OCT is capable of differentiating between benign and malignant pathologies.

In a subsequent study, using a prototype SS-OCT system, high-resolution (10 µm) 3D OCT images were obtained with a multi-modal approach in conjunction with thoracoscopy.[32] A series of rabbits were inoculated with tumor cells in the pleural space. After an incubation period, a video-assisted thoracoscopic surgery was performed. The areas of tumor growth were visualized initially with white-light thoracoscopy. A rigid OCT probe was then inserted through a trocar at a separate incision site and OCT images of the same area were obtained during direct thoracoscopic visualization. The areas where this process was performed included the parietal and visceral pleura, as well as the pericardium. The rabbits were then euthanized, and histologic preparations of the areas of tumor were made. 3D reconstructions of the OCT images were obtained at high resolution, in the order of approximately 10 µm, and were comparable to the histologic preparations.[32] OCT may be particularly useful in guiding the location of thoracoscopic biopsy, if areas of tumor can be distinguished from nonmalignant irregularities. Future human studies will be needed to confirm the above findings.

One such example is identifying lesions with irregular blood vessels to biopsy using the combination of video pleuroscope and narrow band imaging performed during pleuroscopy. NBI enhances blood vessels by taking advantage of the absorption spectrum of hemoglobin. In one study, pleuroscopy was performed on 45 patients with pleural effusion of unknown etiology. Pleuroscopy with white light and NBI was performed. Blood vessels were then sub-classified based on physical characteristics and of those that were identified as irregular (type III) by NBI, 85% of them were found to be malignant. When compared with white light, it was found that the accuracy, sensitivity, and specificity was improved for detection of malignant lesions. The combination of OCT with other imaging modalities may also be helpful, but future human studies will be needed to address such questions.[33]

Obstructive Sleep Apnea

Potential use of OCT for imaging the upper airway (defined as the airway from the nares to the glottis) includes the ability to quantitatively evaluate the dynamics of the upper airway over a significant period of time, such as during an overnight polysomnogram. Through the technological advancement of aOCT, large hollow organs such as the upper airway are now able to be visualized in such a manner.[9] A series of studies by the same research group reveals the usefulness of OCT in the evaluation of obstructive sleep apnea (OSA). In one study employing FDODL (FDODL is a device that creates an optical delay in an interferometer, and allows the amount of delay to be scanned at a high speed) aOCT, the upper airway was visualized dynamically by passing an introducer sheath through the nares into the esophagus. The OCT probe was passed through this sheath and OCT analysis of the upper airway was performed, both at specific anatomical sites over a period of time, along with the 'pullback' method that allowed 3D reconstruction of the upper airway.[9]

In a validation study, aOCT imaging of the upper airway was compared with conventional CT imaging, and demonstrated that the cross-sectional area and luminal dimensions were comparable to values obtained via CT.[34] In one controlled study, OCT was used to image the upper airway of both subjects with OSA and BMI-, gender- and age-matched control subjects in the awake state. It was noted that the velopharynx was the portion of the upper airway in both groups with the smallest cross-sectional area, and that subjects with OSA had a smaller velopharyngeal area than the control subjects. OSA subjects also had longer uvulae. It appears from this study that the size, specifically of the velopharynx, and not the shape, of the upper airway determines risk for OSA.[35] In another study by the same group, a respiratory-gated aOCT system was used in OSA patients undergoing sleep studies. The system was able to assess upper airway changes associated with the use of continuous positive airway pressure at increasing pressures. An apnea event was also recorded on OCT, where the airway was shown to completely collapse for a period of 11 s, then recover patency after the patient experienced a post-apnea arousal.[36] Based on current research publications, OCT holds significant potential for clinical application in OSA, both in diagnosis, as well as titration of continuous positive airway pressure. It may even provide information that can guide surgical procedures to reverse OSA (such as targeting the velopharynx for patients with similar findings in the previous study), and improve the outcomes for uvulopalatopharyngeoplasty and other OSA-related operations by accurately delineating the sites of airway obstruction. Further research and analysis of upper airway OCT images will be needed to shape the way that OCT will be applied to the clinical management of OSA.[36–38]

Central Airway Obstruction

Anatomic or long range OCT has been used to study central airway diseases such as tracheobronchomalacia and tracheal stenosis. Conventional OCT provides high resolution images at a depth of 1–3 mm. With aOCT, the focus is on luminal size and shape using low coherence interferomometry by passing a fiber optic probe through the bronchoscope. It has the added advantage of creating a 3D image with rotation and retraction of the probe. This can be done in vivo providing good characterization of the airway in these diseases as well as providing real time data that may guide immediate treatment such as stent deployment for tracheal stenosis.[39]

One study performed used aOCT to measure airway dimensions on three subjects: one with subglottic tracheal stenosis; one with malignant left main bronchus obstruction; and another with severe tracheomalacia. aOCT was employed to quantify the degree of severity and can provide real time imaging to evaluate stenosis and the dynamic changes associated with malacia.[40]

These studies suggest that aOCT has many advantages in diseases such as tracheal stenosis and tracheobroncomalacia. It is comparable to CT in measuring the size and shape of stenotic lesions, but provides the added advantage of real time imaging at the time of stent deployment. This could allow the operator to decide what method of treatment to use at the time of imaging. In addition, aOCT can provide quantitative measurements of airway collapse in bronchomalacia and allow for longitudinal follow-up to follow-up treatment efficacy, as well as guide new treatments in the future.


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