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INTRODUCTION
During the past decade, ongoing efforts have been made to comprehend the significance of radiologic changes resembling interstitial lung disease (ILD) in undiagnosed individuals. Interstitial lung abnormalities (ILAs) result in adverse clinical outcomes such as reduced lung function, elevated risk of lung cancer, respiratory disease, and mortality.123
ILAs are being increasingly recognized on computed tomography (CT) scans. Large cohorts of smokers who underwent lung cancer screening or participants who underwent epidemiological evaluation (e.g., for cardiovascular risk factors), commonly reported these incidental abnormalities, particularly in old age.2456 However, the reported ILA prevalence ranges from 2.6% to 16.7%, possibly attributable to the definition of ILAs not being standardized and differences in the mean age among the cohorts.2456789 In the study by Hoyer et al.,8 the Danish Lung Cancer Screening Trial cohort (mean age: 60 years, ≥ 20 pack-years of smoking history) demonstrated a high ILA prevalence of 16.7%. However, the population-based MESA cohort (mean age: 62 years) showed a lower prevalence of 4.7%, and the AGES-Reykjavik cohort (mean age: 78 years) reported an ILA prevalence of 7%.29 Moreover, as for ILD and idiopathic pulmonary fibrosis (IPF), ethnic and racial differences might exist for the risk of ILA. However, data on ILA in Asian cohorts are limited.1011
Recently, blood biomarkers are gaining attention as a simple, non-invasive way to identify individuals at risk of ILA and its progression.12 Specific biomarkers—including a number of ageing-related proteins and inflammatory markers (e.g., growth differentiation factor 15, tumor necrosis factor α receptor II, C-reactive protein, and interleukin-6), galectin-3, and blood monocytes—are associated with an increased likelihood of ILA.13141516 Elevated matrix metalloprotease-7 has been shown to predict progression of ILA.17 However, to date, no easy-to-use biomarker has been available for clinical practice. Therefore, this study aimed to evaluate the prevalence of ILA and follow-up outcomes in the Korean health screening population and to assess the risk factors for ILA and progression or development of ILA on follow-up, including biomarkers from a routine blood test.
METHODS
Study design and population
We enrolled adult participants (n = 2,775) who had participated in a health screening programme between January 1997 and April 2007 and underwent serial chest CT imaging > 5 years after baseline. Participants with poor image quality (n = 8) and missing clinical data (n = 178) were excluded, with 2,589 participants being included in the study (Fig. 1).
Fig. 1
Flowchart of the study inclusion process.
CT = computed tomography, ILA = interstitial lung abnormality.
The health screening programme at our center provided comprehensive health examinations and screening for non-communicable diseases, such as cancers. All participants underwent routine laboratory tests, including complete blood count; blood chemistry; lipid profile; and tests for acute-phase reactants, such as the erythrocyte sedimentation rate (ESR) and rheumatoid factor (RF). Additionally, the demographic information, smoking history, and laboratory test results of all participants were collected. Furthermore, available pulmonary function test results from the follow-up were collected (n = 2,355), and spirometry was conducted in accordance with the American Thoracic Society/European Respiratory Society guidelines.18 We could gather information about pre-existing comorbidities and physical discomfort including respiratory symptoms through a questionnaire administered during health screening program for all participants. The survival data of all the participants were retrospectively collected from medical or National Health Insurance of Korea records.
ILA evaluation
For each participant, two chest CT scans were evaluated for imaging analysis, at baseline and last follow-up CT. The median follow-up interval between baseline and follow-up CTs was 7.0 years (interquartile range [IQR], 6.1–8.2). The chest CT scans were evaluated in multiple stages. First, both baseline and last follow-up chest CT scans were independently evaluated for the presence of ILA using the sequential reading method, as previously described.719 This was performed by three readers (J.C., E.J.C., and H.N. with 6, 17 and 22 years of experience in thoracic radiology, respectively) who were blinded to all participant-specific information, prior radiologic interpretations, and radiologic interpretations by other readers. In the sequential reading process, Reader 1 reviewed all images and assigned scores (0: no ILA, 1: equivocal ILA, 2: ILA). CT scans with scores of 1 or 2, along with a random 20% of normal scans (score 0), were assessed by Reader 2, who was blinded to Reader 1’s evaluations. Discrepancies between Readers 1 and 2 were resolved by Reader 3, who independently reviewed the scans without knowledge of the prior assessments. ILA was defined as the presence of non-dependent changes including ground-glass or reticular abnormalities, lung distortion, traction bronchiectasis, honeycombing, and non-emphysematous cysts on chest CT affecting > 5% of any lung zone.20 Focal or unilateral abnormalities or abnormalities involving < 5% of any lung zone were rated as equivocal for ILA.1719 Once scored by the sequential method, a consensus opinion on the ILA subtyping—non-subpleural ILAs (without predominant subpleural localization), subpleural non-fibrotic ILAs (predominantly subpleural without fibrosis), and subpleural fibrotic ILAs (subpleural with pulmonary fibrosis features such as architectural distortion, traction bronchiectasis or bronchiolectasis, and honeycombing)—was provided by the readers after collectively reviewing all of the CT scans.
Finally, all participants with ILA in any of the baseline or follow-up CT scans were simultaneously compared. The paired CT scans were scored by the readers in consensus using a three-point scale, denoting “improvement,” “stable,” and “progression.”1 Progressive change was defined as an increase in the extent or severity of the existing abnormalities or a new appearance of abnormalities. The details regarding the radiologic analysis and CT protocols used are provided in the Supplementary Data 1.
Statistical analysis
Data were presented as mean ± standard deviation, median (IQR), or number (%). Categorical variables were compared using the Pearson’s χ2 and Fisher’s exact tests, and continuous variables were compared using the Student’s t-test. The Cochran-Armitage trend tests2122 were used to detect significant linear associations between increasing age groups and the presence of ILA or equivocal ILA. Unadjusted and multivariable logistic regression models were used to examine the associations of clinical characteristics and blood laboratory findings at baseline or follow-up with ILA defined at the follow-up CT scan. We defined “development” as the emergence of new abnormalities on follow-up CT scans compared to baseline imaging, with the development of ILA referring to cases where ILA is newly detected in participants who had no evidence of ILA on their baseline scans. Progressive ILA was defined as when equivocal ILA or ILA on baseline CT scans exhibited progression on the follow-up CT, or when development of equivocal ILA with fibrosis or ILA was present on the follow-up CT. Variables with a P value < 0.10 were used as candidate variables for multivariable analyses, and a backward stepwise elimination was performed for variable selection.
To evaluate the association between ILA or radiologic patterns of ILA and mortality, we used multivariable Cox proportional hazards models to evaluate the time-to-mortality. Time-to-event (death) was calculated from the date of the follow-up CT scan. Overall survival was adjusted for age, sex, body mass index, smoking status, and pack-years of smoking. The survival rate was estimated using the Kaplan-Meier survival analysis and log-rank test were used for survival analysis. Statistical analyses involved using SPSS version 23.0 (IBM, Armonk, NY, USA) and R version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria, http://www.r-project.org), with statistical significance defined as P < 0.05.
RESULTS
Prevalence and follow-up outcomes of ILA
The mean age of the participants was 48.9 ± 8.2 years at baseline and 56.5 ± 8.3 years at the last follow-up. Among the follow-up cohort, 82.6% were men and 74.6% were ever-smokers.
In the baseline CT scan, ILAs and equivocal ILA were identified in 6 (0.2%) and 7 (0.3%) participants, respectively (Fig. 1). During a follow-up period of > 5 years, 5 of 6 (83.3%) participants with ILA and 6 of 7 with equivocal ILA (85.7%) demonstrated progression, while 9 of 2,576 (0.3%) participants without ILA exhibited newly developed ILA on follow-up CT images (Supplementary Fig. 1). Moreover, 21 of 2,576 (0.8%) participants without ILA had newly developed findings of equivocal ILA on follow-up CT. Among the follow-up CT, ILAs was ultimately identified in 20 (20/2,589, 0.8%) and equivocal ILA in 23 (23/2,589; 0.9%), respectively (Fig. 1). Therefore, the prevalence of ILA and equivocal ILA upon follow-up was 1.7% (43/2,589) (Supplementary Fig. 1). Regarding ILA subtypes, baseline CT revealed subpleural fibrotic and nonfibrotic ILA in 33.3% (2/6) and 66.7% (4/6), while follow-up CT revealed subpleural fibrotic ILA in 65.0% (13/20), subpleural nonfibrotic ILA in 25.0% (5/20), and non-subpleural ILA in 10.0% (2/20). Notably, all participants with subpleural fibrotic ILA and three-quarters of those with subpleural nonfibrotic ILA on baseline CT showed progression. In contrast, one participant with subpleural nonfibrotic ILA (1/4, 25%) showed improvement of ground-glass opacities upon follow-up.
Risk factors associated with the presence of ILA
The demographic and clinical characteristics of the study cohort at baseline and follow-up, stratified by ILA status, are presented in Table 1 and Supplementary Table 1, respectively. Compared with participants without ILA, those with ILA were more frequently ever-smokers and demonstrated an older age, a higher ESR level, and lower albumin level at both baseline and follow-up (Table 1). Moreover, among the participants with ILA who underwent pulmonary function tests at the follow-up exhibited decreased forced vital capacity (FVC) and forced expiratory volume in 1 second /FVC ratio (Table 1) than those of the participants without ILA. Furthermore, there was no significant difference in prevalence each comorbidity in terms of ILA status (Supplementary Table 2). Participants with ILA showed more frequent exertional dyspnea compared with those without ILA (Supplementary Table 2, P = 0.006). In the multivariable logistic analysis for the evaluation of demographic and clinical risk factors (at follow-up) associated with the presence of ILA defined at follow-up CT scans, ILA was associated with older age, ever-smoking, lower hemoglobin and serum albumin levels, and higher ESR levels, when compared with participants without ILA (Table 2).
Table 1
Comparison of the clinical characteristics of the study population according to the presence of ILAa
Data are presented as mean ± standard deviation or number (%).
ILA = interstitial lung abnormality, BMI = body mass index, WBC = white blood cell, RBC = red blood cell, Hb = hemoglobin, ESR = erythrocyte sedimentation rate, PT = prothrombin time, Cr = creatinine, BUN = blood urea nitrogen, TG = triglyceride, HDL = high-density lipoprotein, LDL = low-density lipoprotein, HbA1c = glycated hemoglobin, RF = rheumatoid factor, FEV1 = forced expiratory volume in 1 second, FVC = forced vital capacity, % pred = percentage of predicted value.
aEvaluated based on the follow-up chest computed tomography images.
bNo ILA vs. equivocal ILA; cNo ILA vs. ILA.
Table 2
Logistic regression analysis for risk factors associated with the presence of interstitial lung abnormalitya
OR = odds ratio, CI = confidence interval, BMI = body mass index, WBC = white blood cell, RBC = red blood cell, Hb = hemoglobin, ESR = erythrocyte sedimentation rate, PT = prothrombin time, SCr = serum creatinine, BUN = blood urea nitrogen, TG = triglyceride, HDL = high-density lipoprotein, LDL = low-density lipoprotein, HbA1c = glycated hemoglobin, RF = rheumatoid factor.
aEvaluated based on the follow-up chest computed tomography images.
Notably, the prevalence of ILA or equivocal ILA increased with age (Cochran-Armitage trend test, P < 0.001; Supplementary Fig. 2). The prevalence of ILA and equivocal ILA was 3.5% and 7.1% in participants aged 60–70 years and those aged ≥ 70 years, respectively.
Risk factors associated with progressive ILA
Progressive ILA was demonstrated in 1.0% (28/2,589) of the participants. Compared with participants without ILA or non-progressive ILA, those with progressive ILA upon follow-up exhibited older age; higher proportions of ever-smokers; elevated levels of white blood cell (WBC) counts, ESRs, and glycated hemoglobin levels; and lower serum albumin and higher RF levels at baseline (Supplementary Table 3). Multivariable logistic regression analysis revealed that older age (adjusted OR, 1.16, P < 0.001); ever-smoking (adjusted OR, 19.36, P = 0.006); and higher WBC (adjusted OR, 1.27, P = 0.002), ESR (adjusted OR, 1.06, P < 0.001), and RF (adjusted OR, 9.27, P = 0.002) levels at baseline were independent risk factors for progressive ILA upon follow-up (Table 3).
Table 3
Logistic regression analysis for risk factors associated with the progressive ILAa
ILA = interstitial lung abnormality, OR = odds ratio, CI = confidence interval, BMI = body mass index, WBC = white blood cell, RBC = red blood cell, Hb = hemoglobin, ESR = erythrocyte sedimentation rate, PT = prothrombin time, SCr = serum creatinine, BUN = blood urea nitrogen, TG = triglyceride, HDL = high-density lipoprotein, LDL = low-density lipoprotein, HbA1c = glycated hemoglobin, RF = rheumatoid factor, CT = computed tomography.
aProgressive ILA was defined when equivocal ILA or ILA on baseline CT scans showed progression upon follow-up CT, or when equivocal ILA with fibrosis or ILA was newly developed upon follow-up CT.
ILA and mortality
Over a median follow-up duration of 9.8 years from the time at follow-up CT scan and 17.3 years from the time at baseline CT scan, 5/20 (25.0%) participants with ILA, 6/23 (26.1%) participants with equivocal ILA, and 95/2,546 (3.7%) participants without ILA identified on follow-up CT died. We observed that ILA and equivocal ILA at the follow-up CT were associated with an increased risk of death (adjusted hazard ratio [aHR] for equivocal ILA, 3.73, 95% confidence interval [CI], 1.47–9.42, P = 0.005; aHR for ILA, 4.01, 95% CI, 1.57–10.22, P = 0.004; adjusted for age, sex, body mass index, smoking status and pack-years) when compared with those without ILA (Table 4, Fig. 2A). Additionally, progressive ILA was associated with an increased risk of death (aHR, 3.92, 95% CI, 1.98–7.78, P < 0.001; Table 4, Fig. 2B) when compared with those without ILA or those with non-progressive ILA.
Table 4
Cox proportional analysis evaluating the association of mortality with ILAs or associated imaging findings on follow-up computed tomography scans
HR = hazard ratio, CI = confidence interval, ILA = interstitial lung abnormality, GGO = ground-glass opacity, UIP = usual interstitial pneumonia.
aMultivariable Cox proportional hazard analyses were performed for each variable of interest after adjusting for age, sex, body mass index, smoking status, and pack-years of smoking.
bHR cannot be estimated due to a small number of events.
cAnalysis was performed after excluding participants with traction bronchiectasis/bronchiolectasis and/or honeycombing (n = 2,279).
dAnalysis was performed after excluding participants with reticulation, traction bronchiectasis/bronchiolectasis, and/or honeycombing (n = 2,269).
Fig. 2
Kaplan-Meier survival curves comparing the survival probabilities of participants with no ILA or nonprogressive ILA and those with progressive ILA at the follow-up. (A) Survival curve comparing participants with no ILA, equivocal ILA, and ILA. (B) Survival curve comparing participants with no ILA, nonprogressive ILA, and progressive ILA.
ILA = interstitial lung abnormality.
When compared with participants without relevant findings of ILA on the follow-up CT scan, specific imaging patterns relevant to ILA were associated with a variable increase in the rate of mortality (Table 4). Furthermore, participants with subpleural fibrotic ILA (aHR, 3.92, 95% CI, 1.20–12.75, P = 0.023), honeycombing (aHR, 20.83, 95% CI, 4.41–98.39, P < 0.001), traction bronchiectasis/bronchiolectasis (aHR, 4.60, 95% CI, 1.81–11.70, P = 0.001), nonemphysematous cysts (aHR, 3.25, 95% CI, 1.27–8.31, P = 0.014), and usual interstitial pneumonia (UIP) or probable UIP patterns (aHR, 5.00, 95% CI, 2.36–10.60, P < 0.001) demonstrated increased rates of all-cause mortality compared with those without relevant imaging patterns of ILA and those without ILA; however, reticulation alone without traction bronchiolectasis/bronchiectasis or honeycombing did not demonstrate a significantly increased risk of mortality.
DISCUSSION
ILA is being increasingly recognized on chest CT scans, enabling an early detection of preclinical ILD. ILA is associated with adverse clinical outcomes, including progression of ILA upon follow-up, with increased mortality and decreased lung function12523; however, data from the Asian population are limited. The present study demonstrated the prevalence of ILA and risk factors for progressive ILA in a longitudinal follow-up of the middle-aged Korean participants who underwent health check-ups. The overall prevalence of ILA among participants with a mean age of 56 years was 0.8% (1.7% for ILA or equivocal ILA), which was lower in comparison with previous studies (2.6–17.0%)245624; however, this prevalence increased with the age of the participants. Furthermore, radiologic progression of ILA was common, observed in 83.3% of the participants; all participants with subpleural fibrotic ILA and three-quarters of those with subpleural nonfibrotic ILA at baseline demonstrated progression. Baseline factors associated with the progressive ILA upon follow-up included older age; ever-smoking status; and elevated WBC, ESR, and RF levels.
Recent studies demonstrated that ILAs are more prevalent in smokers and participants aged > 50 years with MUC5B promoter polymorphism positivity, with prevalence increasing with age.725 Tsushima et al.6 reported a prevalence rate of ILA was 2.6% in a Japanese lung cancer screening cohort with a mean age of 57.2 years. Among the participants with ILA, 43.8% exhibited progression over a 4-year period. Additionally, Western cohort studies have estimated the prevalence of ILA at 7–10%.24524 These findings differ from those of the present study and Tsushima et al.'s study.6 Ethnic and racial differences may contribute to variations in the risk of ILA. However, the lower prevalence of ILA in our study may be due to differences in age distribution, with a higher proportion of younger participants compared to previous cohorts. In the study by Putman et al.,2 the AGES-Reykjavik cohort, with a mean age over 70 years, reported an ILA prevalence of 7%. Similarly, the Framingham Heart Study (FHS) cohort, with a mean age of 62.0 years, showed a prevalence of 7%, and the mean age of the ILA group within this cohort was 70 years.23 When specifically analyzing the older adults in our study cohort, we found a similar prevalence of ILA as reported in previous studies, specifically the prevalence of ILA and equivocal ILA reached 7.1% in participants aged ≥ 70 years. The mean age of participants with ILA in our study was in the mid-60s, which was consistent with previous studies, with age range of 60–75 years.22026
In our study, elevated blood WBC counts at baseline were associated with progressive ILA upon follow-up CT. Kim et al.16 demonstrated that elevated blood monocyte counts were associated with ILA and its progression. Increasing evidence indicates that innate immunity, particularly the mononuclear phagocyte system, plays a crucial role in the pathogenesis of pulmonary fibrosis.27 Monocytes and monocyte-derived alveolar macrophages play a critical role in lung fibrosis by secreting profibrotic mediators such as TGF-β and CCL18, which drive epithelial-mesenchymal transition, fibroblast activation, and extracellular matrix deposition, ultimately promoting tissue remodeling and fibrosis.27
In our study, higher ESR and RF levels were also associated with progressive ILA after adjusting for age and smoking.282930 ESR is a common laboratory marker that reflects the extent of systemic inflammation.28 In this study, the mean ESR was higher in individuals with progressive ILA than in those without ILA or non-progressive ILA. Similarly, a previous study reported that ESR is occasionally elevated in patients with IPF.31 Elevated ESR in participants with progressive ILA may reflect elevated systemic inflammation, even at a subclinical level, and chronically elevated systemic inflammation may affect the progression or development of ILA on subsequent follow-up. High titers of RF in patients with suspected ILD may indicate the presence of a connective tissue disease. Rarely, these patients may later develop a defined connective tissue disease that meets diagnostic criteria.32 However, as elevated RF can be nonspecific, which can increase with age in the general population, an increased risk of progressive ILA in participants with high RF may also reflect elevated systemic inflammation rather than the underlying risk of subclinical autoimmune disease.
In the present study, we defined progressive ILA as the development or progression of ILA or equivocal ILA upon follow-up. As in previous studies, equivocal ILA was characterized by focal or unilateral abnormalities, involving < 5% of any lung zone.17 Hunninghake et al.7 reported a relatively large proportion of equivocal ILA in the FHS cohort and observed no significant association between the presence of the MUC5B variant and equivocal ILA. However, some participants with equivocal ILA—particularly equivocal ILA with fibrosis—might have true ILA, not as a transient finding but with more subtle abnormalities and less abnormalities relevant to ILA as demonstrated in our study. Accordingly, some participants progressed from equivocal ILA to ILA and exhibited lower FVC than those of participants with ILA.
Furthermore, we demonstrated that participants with progressive ILA and imaging features reflecting fibrotic ILA had an increased mortality rate, which was consistent with the findings of previous studies.133 Among the subtypes of ILA proposed by the Fleischner Society, the subpleural fibrotic subtype is more likely to progress and to be associated with mortality.20 In fact, subpleural fibrotic ILA and evidence of fibrosis on CT, including honeycombing and traction bronchiolectasis/bronchiectasis, have consistently demonstrated an association with increased mortality.13334 Recently, Hata et al.33 demonstrated that traction bronchiectasis/bronchiolectasis is associated with poorer clinical outcomes and that the severity of traction bronchiectasis is associated with shorter survival in the COPDGene cohort. Similarly, in our study, traction bronchiectasis and bronchiectasis were independently associated with mortality; however, reticulation alone without traction bronchiolectasis/bronchiectasis or honeycombing was not independently associated with mortality. Therefore, recognising and quantifying the extent of fibrosis, including traction bronchiectasis and/or bronchiolectasis, might be useful in predicting disease progression and related mortality in ILA, particularly in ILA without honeycombing.
This study had certain limitations. First, the number of participants with ILA and progressive ILA was small, limiting the statistical power and generalizability of our study results. However, we observed similar results in the prevalence analysis across different age groups, consistent with the findings from other studies. Second, the data regarding specific cause of death was unavailable. Although an increased risk of respiratory death was identified in the AGES-Reykjavik study, data regarding cause of death was also not available in other cohorts due to difficulties in collecting this information.2 Third, for the baseline CT scan, we included a relatively high proportion of chest CT scans with thicker slice intervals (10 mm or 20 mm rather than 5 mm) and various nondedicated CT protocols for the evaluation of ILD, including low-dose or enhanced chest CT. This may have resulted in an underestimation of subtle findings relevant to ILA on the baseline CT scan, leading to the low prevalence of ILA in our study. Finally, this study was conducted in a Korean population, which may limit the generalizability of our findings to other ethnic groups. Therefore, future prospective, large-scale cohort studies including diverse ethnicities are needed to address these limitations.
In conclusions, ILA was uncommon among middle-aged Korean health screening participants but showed an age-related increase and significant long-term negative effects on mortality. Several factors such as age, smoking history, and inflammatory markers contributed to progressive ILA. Early detection and regular monitoring of ILA in high-risk groups are crucial for improving survival outcomes.
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