As a heterogeneous condition, chronic obstructive pulmonary disease (COPD) is best understood when distinctions are made regarding the different phenotypes that affect disease prognosis and help to establish personalized therapeutic strategies. COPD diagnosis continues to be reliant on spirometry; however, advancements in diagnostic imaging, including quantitative CT scans of tissue density, are helping to distinguish between airway-predominant bronchitis COPD and the tissue-disrupting disease associated with emphysema to predict lung function decline.

“In terms of how CT scan can delineate phenotypes, the most concrete example in current practice is using emphysema patterns to identify patients who may benefit from lung volume reduction surgery or endobronchial valves,” said Peter P. Olivieri III, MD, chair of the Division of Pulmonary and Critical Care and director of the Interventional Pulmonary Program at University of Maryland Baltimore Washington Medical Center in Glen Burnie. “This was historically determined based on visual assessment of CT, but quantitative analysis of emphysema severity and location, as well as interlobar fissure integrity, is now used, along with assessment of hyperinflation and gas trapping on pulmonary function tests, to determine [treatment] candidacy,” said Olivieri.

“Additional quantitative CT-based analyses have been investigated, including those focusing on airway, including those that correlate with airflow obstruction, symptoms, and exacerbations. These hold promise but have not yet been incorporated into COPD guidelines or routine practice.” While the use of imaging to guide management in COPD is largely in the research sphere currently, pulmonologists and radiologists are recognizing characteristics that can determine appropriate care planning and surgical interventions.

Moving Beyond Spirometry

Recent studies have examined the utility of CT imaging in addition to spirometry for phenotyping as well as for improving diagnosis, selection of intervention, and overall improvement of pathophysiologic understanding. Imaging is proving to be especially significant among those who have been living with COPD longer, said Nathaniel Marchetti, DO, professor of thoracic medicine and surgery in the Lewis Katz School of Medicine at Temple University in Philadelphia. 

“For patients with more advanced disease and COPD, a CAT scan should always be done because you’re looking for different things that might triage or steer patients toward other therapy,” said Marchetti. As an example, those patients with the emphysema phenotype in which the disease is worse in either the upper or lower lobes whose lungs are hyperinflated might be directed toward lung volume reduction therapies, whether it’s surgical or endobronchial, said Marchetti.

From a radiologic standpoint, incorporating imaging into decision-making post-spirometry allows for correlation of pathophysiologic airway assessment with actual structural data regarding the lungs. “You’re getting very specific structural information as to what is contributing to the patient’s spirometric results,” said Yogesh Gupta, DO, diagnostic radiologist at Temple Health in Philadelphia. “You’re able to see what specific portion of the lung is being affected — whether it’s more of the airway or the lung parenchyma. Combining the spirometric data with the imaging data is a very powerful tool.”

Phenotype Particulars and Characteristics

From the airway perspective with emphysema, Gupta said imaging might reveal bronchial wall thickening that points to inflammation. “When you compare the wall of one who doesn’t have any emphysema vs the patient who does, there is a noticeable difference in wall thickness,” he said. “Over time, smoking-related particulates and inflammation that occurs as a result of smoking-related particulates destroy the small airways. It’s the airway inflammation and airway destruction resulting in that emphysema. There are quantitative tools today that are able to determine this when it can be somewhat subjective if we as radiologists are trying to determine if there is bronchial wall thickening. The vast majority of patients we see who have COPD will have bronchial wall thickening or bronchitis.”

Imaging evidence of airway disease is also seen indirectly through small nodules found within the lung parenchyma that cluster along the smaller airways. “These clusters are indicative of small airways that are branches of the larger airway that are essentially abnormal,” said Gupta. High-resolution CT will be composed of both inspiratory and expiratory scans, allowing for the benefit of comparison to determine abnormalities involving smaller airways. However, if the views look relatively similar and there’s not much difference, that could mean there’s extreme air trapping, said Gupta. This could indicate that small airways throughout the lungs have become destroyed or that there is no actual small airway abnormality if the patient is relatively homogeneous.

“For patients who have predominant airway disease, when they exhale, there’s going to be a mosaicism,” said Marchetti. “There will be areas of gas trapping. If they don’t have emphysema on inspiratory scans, that tells you they’ve got a lot of air trapping in that area related to small airways disease rather than emphysema. Or you’ll have chronic bronchitis, an airway-predominant phenotype, where the airway is narrowed because of wall thickening, edema, and mucus plugging or debris-plugging the airways.”

Emphysema Phenotypes and Distinctions

Related to the emphysema-based phenotype, Gupta said two major distinctions include the centrilobular and paraseptal subtypes. Centrilobular emphysema is essentially a lucency within the lung represented by a darker region that can indicate an excess of air, damage to normal lung tissue, or destruction of airspace that’s generally within the lung parenchyma. Located generally within the center of the secondary pulmonary lobule, centrilobular is more commonly encountered. Paraseptal emphysema, located along the periphery of the lung or along the pleural lining, is not as well understood and is more connected to smoking, according to Gupta. “When emphysema is smoking-related, it tends to be most pronounced in the upper lobes,” he said.

“There can be some variance, where it might be lower lung predominant or diffusive and become severe enough,” said Gupta. Generally speaking, on differential diagnosis, the presence of severe lower lung zone-predominant emphysema also invites the possibility of a disorder known as alpha-1 antitrypsin deficiency, a genetic condition that results in the body’s failure to produce enough alpha-1 antitrypsin protein, a protective protein produced primarily by the liver that fights infections. When there’s a deficiency, the lungs can remain unprotected against neutrophil elastase enzymes, which can cause breakdown of structural proteins and contribute to the CT appearance rather than the damage being strictly smoking-related. “If you’ve done a CAT scan and they have low or low-predominant emphysema, patients should be checked for alpha-1 antitrypsin deficiency, particularly in younger patients, because that can alter treatment and you can give them replacement therapy,” said Marchetti. “For patients who have more airway-centric disease, you might see a lot of airway wall thickening.”

Gupta said there are various ancillary findings that pulmonologists might not specifically be looking for in the broad array of possibilities for patients with COPD being imaged for the first time. “Another type of change that can be seen in smokers is the development of fibrosis,” he said. “If we suspect fibrosis, it can impact how the patient is treated and inform spirometric results.” The appearance can be gray or white patches against darker, healthy lung tissue. Smokers can also develop cysts in their lungs, although that’s considered relatively rare. 

At Temple Lung Center, where director Gerard J. Criner, MD, an internationally recognized expert in lung diseases who served as the lead investigator in multicenter clinical trials including LIBERATE and EMPROVE, CT scans are also vital in helping to screen patients and potentially direct them toward clinical trials if other therapies are not available, said Marchetti. “We have multiple clinical trials that are open,” he said. “For example, we’ve been evaluating some experimental therapies for chronic bronchitis. The CAT scan allowed us to look at that phenotype and direct them toward clinical trials that might be open. There are other clinical trials open to look at emptying lung volume a little bit better.”

According to Olivieri, patients with one or more moderate-to-severe exacerbations in the past year could benefit from long-acting muscarinic antagonist (LAMA) or long-acting beta-agonist (LABA) inhaler regimens. Patients with a significant exacerbation history and a peripheral blood eosinophil count of ≥ 300 cells/μL could also benefit from initial triple therapy with LAMA/LABA/inhaled corticosteroid (ICS). “Patients with comorbid asthma might benefit from a more asthma-driven management, which involves a heavier emphasis on inhaled corticosteroids and biologics,” said Olivieri. “Patients who continue to have exacerbations on LAMA/LABA therapy are often managed with LAMA/LABA/ICS, especially if peripheral blood eosinophil count is ≥ 100 cells/μL. For those with continued exacerbations despite LAMA/LABA/ICS or with a blood eosinophil count of < 100 cells/μL, biologics, chronic azithromycin use, and roflumilast can be considered. Patients with significant emphysema and hyperinflation refractory to medical management may benefit from lung volume reduction, either via a surgical approach or with endobronchial valves.”

Planning Personalized Care by Phenotype

In most instances, phenotyping will direct providers toward treatments, said Marchetti. “If patients are more airway predominant, you might want to look for treatments that are more directed toward the airways, such as more aggressive bronchodilators with the benefit from biologic therapy, such as anti-interleukin-5 therapy,” he said. “The big buzz now in radiology and COPD literature is looking for mucus that’s plugging the airways. That may have a different treatment algorithm. You might look to see what their eosinophil count is and if they would benefit from biologic therapy. Or perhaps they should be receiving other chronic bronchitis-directed therapies as those become more widely available.”

If bolus disease or significant emphysema is seen, that might indicate surgical intervention, said Marchetti. “And if you see thickened airways, or airways that are dilated, or bronchiectasis, and you see severe mucus plugging of the small airways — that’s going to direct you toward the chronic bronchitis small-airways treatment algorithms,” he said.

For severity assessment, spirometry and symptoms remain the “gold schema,” said Marchetti. “But in patients who have severe emphysema, you can certainly tell based on the lung volumes. They’ll be severely gas-trapped, and there’s a lot of destruction of the lung tissue. That gives you a visual assessment of how bad the lung could be.”

Other comorbidities or unexpected findings that might be picked up on CT scan imaging might be pulmonary fibrosis on top of emphysema COPD, where patients are suddenly requiring more oxygen. “Or there may be a clue that the pulmonary artery is severely enlarged, and perhaps that patient is starting to develop pulmonary hypertension as a comorbidity of their disease,” said Marchetti. “That would also influence treatment options, whether it’s referral for transplant or to something else. And the radiologist might have a different point of view on it because they’re not treating the patient; they’re interpreting the diagnostic image, which is extremely important in the care of the patient.”

Olivieri, Marchetti, and Gupta report having no relevant financial disclosures.