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In smokers without known interstitial lung disease (ILD), worsening pulmonary parenchymal abnormalities on chest CT were still associated with more severe acute respiratory disease (ARD) events, a secondary analysis of the COPDGene Study revealed.

Progression of such interstitial lung abnormalities (ILAs) -- summed together in an artificial intelligence-based quantitative interstitial abnormality (QIA) index -- was associated with greater risks of a severe ARD event between the smokers' baseline visit and roughly 5-year follow-up visit in the trial (OR 1.29 for each annual percentage increase, 95% CI 1.06-1.56) and later on as well (OR 1.26 for each annual percentage increase, 95% CI 1.05-1.52).

Associations remained after adjusting for factors like coronary artery disease, congestive heart failure, diabetes, hypertension, and high cholesterol, reported Bina Choi, MD, of Brigham and Women's Hospital and Harvard Medical School in Boston, and coauthors in .

QIAs are associated with decreased lung function and a higher risk of respiratory symptoms and death, despite not meeting diagnostic criteria for advanced pulmonary disease.

"QIA includes features like reticulation and ground-glass opacities as well as subtle density changes with important clinical implications," said Choi in a press release. "In some patients, QIA may be a precursor to advanced diseases such as pulmonary fibrosis or emphysema."

Additionally, the researchers found that people in the highest quartile of QIA progression (≥1.2% annually) experienced more frequent ARD events (IRR 1.46, 95% CI 1.14-1.86) and severe ARD events (IRR 1.79, 95% CI 1.18-2.73) when compared with peers in the lowest quartile (≤-1.7%) during the intercurrent period between the baseline and 5-year visits.

"The association of QIA progression with acute events in the intercurrent period suggests that some QIAs represent areas of active disease and inflammation, and the association with events in the subsequent period suggests QIAs may additionally represent irreversible changes that continue to cause symptoms and exacerbations after radiographic progression," Choi's group wrote.

Indeed, ARD events are known to occur even in people with a smoking history without chronic obstructive pulmonary disease (COPD) who show no spirometric obstruction or emphysema on imaging.

"While many acute respiratory disease events are likely related to airway disease and COPD, some may instead be associated with QIA especially in people without obstruction or emphysema," said Choi.

For the present study, QIA was calculated automatically -- based on a model trained on ground-glass opacities, nodularity, linear scarring, centrilobular nodules, reticulation, honeycombing, and subpleural lines -- and expressed as a percentage of lung volume affected.

Choi and colleagues said that risk factors for QIA progression include female sex, advanced age, and presence of MUC5B polymorphism.

Brent Little, MD, of Mayo Clinic Florida in Jacksonville, expressed concerns regarding the automated QIA index, as a had 45.6% of people flagged this way for QIA when 6.9% actually had ILAs according to visual inspection of CT scans. "The low specificity of the algorithm and high percentage of participants judged to have QIA point to overestimation, perhaps in part caused by reversible parenchymal features such as dependent atelectasis."

Little did note, writing in an , that the association between QIA and events, in contrast with the lack of association seen between QIA and emphysema, could point to the use of QIA as a biomarker.

"Could QIA serve as an imaging biomarker in the same way that coronary calcium scores correlate well with risk of future major adverse cardiovascular events?" he posed. "QIA could be viewed as a composite of multiple alveolar, small airway, and interstitial disease processes of varying chronicity that, taken together, might represent an important index of lung health."

A total of 3,972 participants from the COPDGene Study were included in this secondary analysis. Patients were excluded if they had a history of lung diseases other than COPD or asthma, or if their baseline CT indicated ILD or bronchiectasis.

Of the included patients, 53.4% were women, the average age was 60.7 years, and the average BMI at baseline was 29.1. The study population was 23.9% Black and 76.1% white. Over 43% were current smokers at baseline, with an average history of 42.4 pack-years.

CT scans were performed alongside serum laboratory measurements, spirometry, scans, and questionnaires at the initial visit and at a follow-up visit about 5 years later. A follow-up program provided participants with questionnaires every 3 to 6 months in between the two visits, as well as after the follow-up visit, to assess ARDS and its associated events.

At baseline, average lung occupied by QIA was 6% and that occupied by emphysema was 7%.

As for other CT-based airway metrics of airway disease, the average wall thickness for a hypothetical airway of 10-mm internal lumen perimeter on CT was 2.3 mm, and the quantitative density measurement of air trapping on localized parametric response mapping of paired inspiratory and expiratory CT scans was 15.6%.

ARD episodes were those involving increased cough or dyspnea lasting 48 hours and requiring antibiotics or corticosteroids. Severe ARD events were ones that ultimately required either hospitalization or an emergency room visit.

Between baseline and 5-year follow-up, 35.1% of patients experienced one or more ARD events, with those who experienced them having an average of 4.4 events. Severe ARD events were reported in 15.8% of patients, at an average of 2.8 events per person. After the follow-up visit, 22.2% of patients had one or more severe ARD events and experienced an average of 2.7 events.

In regard to emphysema, each annual percentage increase between initial and follow-up visits was associated with an 11% greater chance of having one or more intercurrent ARD events (OR 1.11, 95% CI 1.03-1.20, P=0.005). However, this association did not hold up following the second visit, nor was an association found between emphysema progression and severe ARD events, either intercurrently or subsequently.

Limitations to the study included its observational design, reliance on questionnaires for ARD event data, and lack of certain clinical details such as ARD event timing, Choi's group acknowledged.

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