Adult Interstitial Lung Abnormalities: The New Frontier of Pulmonary Fibrosis

Interstitial lung abnormalities (ILAs) are incidentally identified nondependent abnormalities (e.g., ground-glass opacity, reticular abnormalities, lung distortion, traction bronchiectasis, honeycombing, and nonemphysematous cysts) that involve ⩾5% of a lung zone in an individual in whom interstitial lung disease (ILD) is not suspected (1). Chest computed tomography (CT) scans are increasingly being performed for the purposes of lung cancer screening or the diagnostic evaluation of other lung diseases (e.g., chronic obstructive pulmonary disease, coronavirus disease [COVID-19]), and the identification of ILAs has therefore become more common (2). ILAs are regarded as an early stage of ILD; therefore, screening for ILAs could provide an opportunity for earlier diagnosis, risk-factor modification, and treatment (1, 3). Optimizing the approach to the management of ILAs is critical given its potential benefits, but it is uncertain because our understanding of ILAs is limited: the prevalence of ILAs has varied across studies, the natural history of ILAs is uncertain, and the risk factors for ILAs and their progression are unclear (1, 4).

In this issue of the Journal, Grant-Orser and colleagues (pp. 695–708) identify, review, and statistically aggregate 22 studies (88,325 participants) pertaining to ILAs (5). They report that ILAs have an overall pooled prevalence of 10%, including 7% in lung cancer screening studies, 7% in general population studies, and 26% in at-risk familial (i.e., subclinical ILD) cohorts. They also found that male sex, older age, and a low FVC% predicted were associated with an increased risk of ILAs. Perhaps most importantly, ILAs were associated with increased odds of death.

Taken together, the high pooled prevalence of ILAs in different populations and the association of ILAs with increased mortality indicate that the progression of ILAs to ILD confers a substantial disease burden, suggesting a benefit from screening for ILAs and indicating the need for a standardized management strategy. It also emphasizes the importance of research to inform such screening and management strategies. In this post–COVID-19 era, such research should include the differentiation of ILAs from residual lung abnormalities after COVID-19. In addition, the overlap of risk factors for ILAs and those for ILD or idiopathic pulmonary fibrosis (IPF) indicate that ILA and ILD or IPF may share the same pathogenesis, supporting the view that ILA and ILD or IPF may be the same disease at different stages of evolution (6).

The systematic review has numerous strengths. The importance of the topic should not be underestimated, as delayed detection of ILD is associated with poor quality of life and increased mortality (7, 8). The higher prevalence of ILAs in familial cohorts compared with lung cancer screening and general population cohorts highlights the importance of family history in identifying who is most likely to benefit from screening for ILAs, and also indicates that genetic factors have a role in the onset of ILAs (9). In addition, the risk factors for ILAs identified by the systematic review (i.e., male sex, older age, and lower FVC) indicate populations that may be targeted for screening for ILAs.

The systematic review also has limitations. First, there were inconsistent results across studies (i.e., high heterogeneity indicated by an I² statistic ⩾75%), which suggests that there were differences in the aggregated studies. The authors were unable to identify the cause of the heterogeneity, but possibilities include differences in definitions of ILAs, enrollment criteria, chest CT scan protocols, study duration, and/or study location. There also may have been differences in the characteristics of the study populations, such as age, smoking history, family history, or genetic factors. Future studies should consider standardizing such variables. Second, the systematic review did not independently evaluate the different subcategories of ILAs, which have prognostic significance (1, 2, 10–11). Estimates of the prevalences of the subcategories of ILAs could provide more information about the burden of ILAs or ILD. Third, the prevalence of ILAs increases linearly with age, and age-band analyses demonstrated that ILAs are rare in the population younger than 40 years of age (12). Subgroup analyses based on age may have provided more information if they had been performed, likely prompting the reconsideration of age as an inclusion criterion for ILA screening. Finally, the studies included in the meta-analysis were secondary analyses of various cohort studies (i.e., secondary analyses of lung cancer, smoking, and aged cohort studies). Future research should be directed at ILA cohorts.

In summary, Grant-Orser and colleagues asked three important questions: what is the prevalence of ILAs, what are the risk factors for ILAs, and do ILAs increase the risk for mortality? They addressed these questions by rigorously evaluating all available evidence, providing important insights that will direct future research and inform management until such research is conducted. Although a lot of work remains to be done, the systematic review provides a promising step forward.