Progressive Early Interstitial Lung Abnormalities in Persons at Risk for Familial Pulmonary Fibrosis: A Prospective Cohort Study

Abstract

Rationale

Relatives of patients with familial pulmonary fibrosis (FPF) are at increased risk to develop FPF. Interstitial lung abnormalities (ILAs) are a radiologic biomarker of subclinical disease, but the implications of very mild abnormalities remain unclear.

Objectives

To quantify the progression risk among FPF relatives with abnormalities below the threshold for ILAs as described by the Fleischner Society and to describe the characteristics of participants with new or progressive ILAs during observation.

Methods

Asymptomatic FPF relatives undergo serial screening high-resolution chest computed tomography. For this analysis, early ILAs (no minimum threshold of lung involvement) were subclassified as mild (all interstitial abnormalities involve <5% of a lung zone) or moderate (any abnormality involves >5%). Identification of new or progressive ILAs on high-resolution chest computed tomography and the development of pulmonologist-diagnosed clinical FPF were defined as progression. Covariate-adjusted logistic regression identified progression-associated characteristics.

Measurements and Main Results

From 2008 to 2023, 273 participants in follow-up procedures were 53.2 ± 9.4 years of age at enrollment, 95 (35%) were men, and 73 of 268 (27%) were ever-smokers. During a mean follow-up period of 6.2 ± 3.0 years, progression occurred among 31 of 211 (15%) of those with absence of ILAs at enrollment, 32 of 49 (65%) of those with mild ILAs, and 10 of 13 (77%) of those with moderate ILAs. Subjects with mild ILAs had 9.15 (95% confidence interval, 4.40–19.00; P < 0.0001) times and those with moderate ILAs had 17.14 (95% confidence interval, 4.42–66.49; P < 0.0001) times the odds of progression as subjects without ILAs.

Conclusions

In persons at risk for FPF, minor interstitial abnormalities, including reticulation that is unilateral or involves <5% of a lung zone, frequently represent subclinical disease.

At a Glance Commentary

Scientific Knowledge on the Subject

Interstitial lung abnormalities (ILAs) are a radiologic biomarker of subclinical familial pulmonary fibrosis. The clinical implications of interstitial abnormalities that occupy less than 5% of a lung zone (and do not meet the current definition for ILAs) remain unclear.

What This Study Adds to the Field

Among asymptomatic persons who are at risk to develop familial pulmonary fibrosis, those with interstitial abnormalities below the current definition for ILAs had substantially elevated risk for progression, approaching that of participants with currently defined ILAs. Reticulation, including unilateral, was identified as an important indicator of early subclinical familial pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) affects ∼1 in 200 U.S. adults 65 years or older (1, 2). The natural history is characterized by progressive symptoms, worsening lung function, and an average life expectancy of 3–5 years after diagnosis (3). Most patients already have moderate lung function impairment and substantial symptom burden at diagnosis (4). Two available disease-modifying treatments do not reverse established fibrosis or mitigate symptoms (5, 6), prompting substantial interest in disease prevention and/or earlier treatment initiation. However, there is a paucity of data about the natural progression of very early “subclinical” disease. This foundational information is required to design disease prevention studies and guide the clinical management of these individuals (7).

Subclinical pulmonary fibrosis has been studied through the lens of interstitial lung abnormalities (ILAs), which are defined by the Fleischner Society as nondependent reticulation, irregular septal thickening, ground glass, traction bronchiectasis, or honeycombing that occupies 5% or more of a lung zone on high-resolution chest computed tomography (HRCT) (8). Fleischner Society–defined ILAs, particularly those with definite fibrosis (i.e., architectural distortion of the lung) are a risk factor for mortality and interstitial lung disease (ILD) diagnoses (9–12). Another subgroup of ILAs, termed “indeterminate ILAs,” defined by focal or unilateral ground glass or reticulation (<5%), are observed on up to 44% of HRCT studies (9, 12, 13). Little is known about the characteristics and outcomes of indeterminate ILAs, as they are often omitted from comparative analyses (9, 10, 12, 14). However, some appear to develop into Fleischner Society–defined ILAs (13) or confer increased mortality compared with subjects without ILAs (11).

Familial pulmonary fibrosis (FPF) occurs when two or more bloodline relatives receive diagnoses of pulmonary fibrosis (15, 16). Relatives of patients with IPF or FPF have a 6- to 100-fold increased risk to develop pulmonary fibrosis (17, 18), so asymptomatic relatives of patients with FPF are an enriched population in which to study the subclinical stage of this relatively rare disease. In our longitudinal screening study of asymptomatic FPF relatives, called the At-Risk for FPF Cohort, interstitial abnormalities on HRCT have been identified among ∼23% of participants at enrollment (16, 19). As this study was initiated before the adoption of current ILA definitions and we intended to comprehensively identify interstitial abnormalities in this population, many of the ILAs we recorded fall into the indeterminate ILA category according to the Fleischner Society. The primary goal of this analysis was to describe the clinical and imaging characteristics of subjects with progressive subclinical FPF and to quantify the progression risk among persons with ILAs below the Fleischner Society threshold compared with those with Fleischner Society–defined ILAs. Some of the results of these studies have been reported in abstract form (20).

Methods

At-Risk for FPF Cohort

Eligible participants are asymptomatic first-degree relatives of patients with FPF. After screening and informed consent (institutional review board #080780), participants complete an enrollment questionnaire and an in-person visit with HRCT, a full pulmonary function test (PFT), and blood donation. Invitations to participate in health update questionnaires and in-person follow-up visits are extended until a participant receives a diagnosis of clinical FPF (Figure 1). A clinical FPF diagnosis occurs when “extensive ILAs” are identified on HRCT (see HRCT Protocol and Assessment) or a pulmonologist makes a diagnosis of pulmonary fibrosis. Diagnoses are confirmed via medical record review, seeking documentation of progressive symptoms, PFT and/or HRCT abnormalities, and/or recommendation for diagnostic testing (i.e., lung biopsy) or treatment for FPF or other ILD. This analysis includes participants with at least one follow-up HRCT examination or who received diagnoses of clinical FPF that was not present at enrollment.

Figure 1.

Study procedures and identification of progressive subclinical familial pulmonary fibrosis (FPF). Progressive subclinical FPF is the occurrence of either a clinical FPF diagnosis (the endpoint of screening procedures) or the new development or progression of interstitial lung abnormalities (ILAs) that remain subclinical (these participants may continue screening). Clinical diagnoses are identified using screening high-resolution chest computed tomography (HRCT; on the basis of identification of extensive ILAs) or using the annual questionnaire to capture diagnoses made between screening visits. When a participant reports a new diagnosis, it is confirmed via medical record review, seeking evidence that a pulmonologist documented progressive symptoms, pulmonary function test (PFT) abnormality or HRCT findings, or recommended diagnostic testing (i.e., lung biopsy) or treatment for FPF or other interstitial lung disease. The number of participants with clinical FPF or the new development or progression of ILAs that remain subclinical is summarized by the HRCT number in the study at or after which the event occurred. *Symptoms are assessed by the study coordinator during the informed consent interview, with positive responses reviewed with the investigator to ensure that they are not clearly attributable to interstitial lung disease before proceeding. ^#Age at enrollment is 40–75 years, or within 10 years of the youngest relative’s diagnosis. ^PFTs were added to the study visit protocol in 2017. ^%Those with extensive ILAs on HRCT1 were not invited for annual questionnaires or follow-up visits and are not included in inferential analyses. ^$The health update is distributed annually, and visit invitations are extended every 3–5 years (the schedule has varied with funding availability). HRCT1 = enrollment high-resolution chest computed tomography; HRCT2 = second high-resolution chest computed tomography scan; HRCT3 = third high-resolution chest computed tomography scan; HRCT4 = fourth high-resolution chest computed tomography scan.

The number of copies of MUC5B promoter-region SNP rs35705950 (the gene encoding mucin 5B) and age-adjusted telomere restriction fragment length percentile are measured at enrollment (16). At each questionnaire, shortness of breath is rated as 0 (none) through 5 (been too breathless to leave the house) (see Figure E1 in the data supplement). The percentages of predicted values of PFTs were calculated in Vanderbilt’s PFT laboratory using standard formulas (16).

HRCT Protocol and Assessment

HRCT examinations include a single prone, end-inspiratory series (16). The study radiologist (A.R.G.) reviews each HRCT study in real time, issuing clinical and research reports. Clinical reports describe all parenchymal abnormalities and the change in interstitial abnormalities (absent, resolved, improved, stable, new, or worse) on follow-up HRCT. Change in ILAs is determined by visually comparing the total lung volume involved on the current with the previous HRCT study. Participants receive the clinical report. In the research report, ILAs are categorized as absent, early, or extensive. Extensive ILAs involve >30% of total lung parenchyma or demonstrate definite honeycombing (rows of clustered cysts) (8). Early ILAs have no minimum threshold. Note that the radiologist has discretion to designate ILAs as categorically present or absent. The extent of six interstitial abnormalities is recorded as 0 (absent), 1 (present at <5%), or 2 (present at >5%) in four zones in each lung (see Figure E2). The semiquantitative visual ILA score on each HRCT study is the sum of all zones and abnormalities (range, 0–96).

HRCT studies completed from 2008 to 2018 underwent analysis using the data-driven textural analysis (DTA) method (16, 21–24). This machine learning method quantifies DTA fibrosis as the proportion of lung occupied by reticulation, honeycombing, or traction bronchiectasis.

Longitudinal HRCT Outcomes

Progressive subclinical FPF, the primary dependent variable, is the composite of a clinical FPF diagnosis (not present at enrollment) or subclinical ILA progression, as observed through December 31, 2023. Subclinical ILA progression (new or worsening ILAs) was extracted from the clinical HRCT report description of change in ILAs. When the report did not clearly indicate the timing or overall direction of change, it was adjudicated by the study radiologist (A.R.G.) while reviewing all HRCT examinations for a given subject (see Figure E3). We have previously reported good interobserver agreement on the occurrence of progressive (new or worse) ILAs as ascertained in a similar manner (16).

Independent Variables: Imaging Characteristics at Enrollment

The primary independent variable was derived from the original enrollment HRCT research report. To identify participants who would or would not meet the Fleischner Society benchmark for ILAs, early ILAs (as defined above) were subclassified as “moderate ILAs” (any interstitial abnormality present at >5% in any zone) or “mild ILAs” (no abnormality present at >5%). Of note, extensive ILAs would also meet the Fleischner Society benchmark but do not undergo follow-up screening HRCT in our study (considered a study endpoint) and are excluded from inferential analysis.

Additional (secondary) independent variables included the visual ILA and DTA fibrosis scores on the enrollment HRCT, and specific parenchymal abnormalities and patterns noted in the enrollment clinical HRCT report, extracted using the tool in Figure E4. These variables were included to evaluate the outcomes of visual abnormalities that may fall below our threshold for categorically early ILA (e.g., focal or unilateral reticulation and biapical scarring, which are also excluded from Fleischner Society–defined ILAs) (8) and to assess lung abnormalities (e.g., emphysema) that may be associated with progressive subclinical FPF. In addition, when reticulation, ground glass, or biapical scarring was observed on HRCT in the absence of categorially present early ILAs, they are referenced as “sub-ILA interstitial abnormalities.” To understand the characteristics of progressive subclinical FPF, participant characteristics at enrollment (i.e., age, sex, smoking, MUC5B, and PFT results) and during follow-up (i.e., annualized change in dyspnea and the visual ILA score) were also summarized by longitudinal outcome status.

Statistical Methods

Participant characteristics are summarized as mean ± SD or as numbers and percentages. The association between each independent variable and the dependent variable was estimated using logistic regression. The primary analysis evaluates the odds of experiencing progressive subclinical FPF among those with mild or moderate ILAs compared with absent ILAs at enrollment. Each model included a single independent variable, with age and sex as covariates. Categorical independent variables present among <5% of participants were not tested in regression models. There was no imputation for missing data. Statistical analysis used SAS version 8.3 software (SAS Institute).

Results

Clinical Characteristics of Progressive Subclinical FPF

From 2008 to 2023, 520 participants were enrolled in the study. Of these, 273 participated in follow-up procedures, while 132 were lost to follow-up (invited but did not complete follow-up HRCT or report a clinical FPF diagnosis) and 108 were not yet eligible for follow-up (enrolled since January 1, 2020, and did not report a postenrollment clinical FPF diagnosis). Follow-up participants were 53.2 ± 9.4 years of age at enrollment, 95 (35%) were men, and 73 of 268 (27%) were ever-smokers, generally similar to those lost to follow-up (Table 1). Progressive subclinical FPF was observed in 73 of 273 participants (27%) during a mean follow-up period of 6.2 ± 3.0 years. A few participants had stable (n = 22 [8%]) or improved (n = 2 [1%]) ILAs; no instance of complete resolution was observed. Figure 1 delineates the timing and modality of clinical FPF diagnoses (i.e., extensive ILAs on screening HRCT or pulmonologist) and the number, type (new or worse), and timing of subclinical ILA progression. Those who remained subclinical were 62.5 ± 8.8 years of age at the first instance of new or worse ILAs and 63.3 ± 8.6 years of age at their most recent HRCT examinations. Those with progressive subclinical FPF were older (56.7 ± 9.9 years) than nonprogressors (52.0 ± 9.0 years) (P = 0.0004) at enrollment, numerically more likely to be male (31 [42%] vs. 64 [32%]; P = 0.1), and had lower percentage predicted TLC (93.0 ± 16.2 vs. 102.8 ± 12.4; P = 0.02) and percentage predicted Dl_CO (83.5 ± 13.8 vs. 93.7 ± 13.2; P = 0.04) (Table 1). After enrollment, the annualized change in the visual ILA score was greater in patients with progressive subclinical FPF (1.3 ± 1.6; n = 65) than in nonprogressors (0.04 ± 0.4) (P < 0.0001). The annualized change in self-reported dyspnea was numerically greater in patients with progressive subclinical FPF (0.06 ± 0.3) than in nonprogressors (−0.03 ± 0.3) (P = 0.07). Among patients with progressive subclinical FPF, one (1%) underwent lung transplantation and six (8%) died, while five (3%) nonprogressors died (P = 0.056).

Table 1.

Participant Characteristics, by Progressive Subclinical FPF Status

Characteristic	Follow-Up Participants				Lost to Follow-Up (n = 132)
	All (n = 273)	No Progression (n = 200)	Subclinical FPF (n = 73)	P Value*
Age (enrollment), yr	53.2 (9.4)	52.0 (9.0)	56.7 (9.9)	0.0004	52.4 (10.1)
Male sex	95 (35%)	64 (32%)	31 (42%)	0.1	57 (43%)
Cigarette smoking status	(n = 268)	(n = 195)	(n = 73)		(n = 124)
Former	73 (27%)	38 (19%)	20 (27%)	0.39	36 (29%)
Current	15 (6%)	12 (6%)	3 (4%)	0.69	12 (10%)
MUC5B GT or TT	106 (39%)	73 (37%)	33 (45%)	0.14	60/130 (46%)
Telomere percentile (enrollment)	33.4 (31.5) (n = 271)	34.2 (31.7) (n = 198)	31.1 (30.9) (n = 73)	0.19	27.7 (29.7) (n = 129)
Symptoms (enrollment)	(n = 268)	(n = 195)	(n = 73)		(n = 124)
Dyspnea score (range, 0–5)	0.6 (1.1)	0.5 (1.0)	0.8 (1.2)	0.055	0.6 (1.1)
Regular cough	45 (17%)	28 (14%)	17 (23%)	0.14	23 (19%)
Regular phlegm production	39 (15%)	26 (13%)	13 (18%)	0.48	29 (23%)
Change in dyspnea score	−0.004 (0.3)	−0.03 (0.3)	0.06 (0.3)	0.07	0.04 (0.4)
Observation time, yr	8.3 (4.4)	8.4 (4.4)	8.1 (4.5)		6.5 (3.9)
n with >1 score	248	183	65		93
PFTs (enrollment)	(n = 94)	(n = 74)	(n = 20)		(n = 38)
FVC, % predicted	100.2 (13.4)	101.1 (12.9)	97.2 (14.9)	0.41	95.5 (13.3)
TLC, % predicted	100.7 (13.8)	102.8 (12.4)	93.0 (16.2)	0.02	98.2 (12.2)
DlCO, % predicted	91.5 (13.9)	93.7 (13.2)	83.5 (13.8)	0.04	88.7 (16.0)
Adjudicated change in ILA				—	—
Never ILAs (on any HRCT study)	176 (64%)	176 (88%)	0
Resolved	0	0	0
Improved	2 (1%)	2 (1%)	0
Stable	22 (8%)	22 (11%)	0
Progressed (new, worse)	47 (17%)	0	47 (64%)
Clinical FPF diagnosis	26 (10%)	0	26 (36%)
Change in visual ILA	0.3 (1.0)†	0.04 (0.4)	1.3 (1.6)†	<0.0001	—
Observation time, yr	6.3 (2.9)	6.2 (2.8)	6.7 (3.1)
HRCT studies per subject	2.2 (0.5)	2.2 (0.5)	2.2 (0.7)
Terminal events				0.056
Death	11 (4%)	5 (3%)	6 (8%)		9 (7%)
Lung transplantation	1 (0.3%)	0 (0%)	1 (1%)		0 (0%)

Definition of abbreviations: FPF = familial pulmonary fibrosis; HRCT = high-resolution chest computed tomography; ILA = interstitial lung abnormality; MUC5B = mucin 5B gene (where T denotes carrying one or two copies of the rs35705950 promoter polymorphism); PFT = pulmonary function test.

Data are expressed as mean (SD) or n (%).

^*Each P value is from a logistic regression model with the named independent variable (i.e., one model per table row) and the covariates age and sex.

^† Eight subjects who were eligible for follow-up but received diagnoses of clinical FPF before completing follow-up visits with HRCT.

Enrollment Imaging Characteristics of Progressive Subclinical FPF

Progressive subclinical FPF was observed among 31 of 211 (15%) of those with absent ILAs at enrollment, 32 of 49 (65%) with mild ILAs, and 10 of 13 (77%) with moderate ILAs. Those with mild ILAs had 9.15 (95% confidence interval [CI], 4.40–19.00; P < 0.0001) times and those with moderate ILAs had 17.14 (95% CI, 4.42–66.49; P < 0.0001) times the odds of progression as those with absent ILAs (Table 2). The clinical and imaging characteristics of participants within these enrollment ILA categories are listed in Table E1 and are similar to those previously reported (9, 16, 19, 21). Notably, the mean DTA fibrosis score was lowest in those with absent ILAs (1.13 ± 1.60), followed by mild (2.84 ± 2.88), moderate (7.04 ± 8.90), and extensive (35.53 ± 19.70) ILAs, aligning well with the expected visual threshold of >5% lung involvement for moderate and >30% for extensive ILAs. Reticulation was noted on the enrollment clinical HRCT report in almost all (112 of 115 [97%]) participants with categorically present ILAs, but more advanced architectural distortion was less common, even among those with moderate (24% with traction, 12% with honeycombing) or extensive (43% with traction, 57% with honeycombing) ILAs. Sub-ILA interstitial abnormalities such as reticulation (6%), ground glass (3%), or biapical scarring (5%) were also observed in a few participants with categorically absent ILAs (see Table E1). Findings such as linear scars (24% of those with absent ILAs, 14% of those with ILAs) and granulomatous disease (37% of those with absent ILAs, 31% of those with ILAs) were observed across ILA categories.

Table 2.

Enrollment Imaging Characteristics Associated with Progressive Subclinical FPF

Characteristic at Enrollment	No Progression (n = 200)	Subclinical FPF (n = 73)	Progression Risk for Characteristic*
			aOR (95% CI)	P Value
Real-time ILA status
Absent ILAs	180 (90%)	31 (42%)	Reference	—
Mild ILAs	17 (8%)	32 (43%)	9.15 (4.40–19.00)	<0.0001
Moderate ILAs	3 (2%)	10 (13%)	17.14 (4.42–66.49)	<0.0001
Visual ILA score (range, 0–96)	0.5 (1.8)	4.5 (6.6)	1.36 (1.20–1.53)	<0.0001
DTA fibrosis score	1.3 (1.9) (n = 176)	2.9 (4.8) (n = 68)	1.16 (1.03–1.32)	0.02
Reticulation unilateral	7 (4%)	6 (8%)	4.89 (1.49–16.07)	0.009
Bilateral	15 (8%)	40 (55%)	15.37 (7.26–32.51)	<0.0001
Ground glass unilateral	8 (4%)	6 (8%)	1.95 (0.63–6.02)	0.25
Bilateral	3 (2%)	7 (10%)	7.28 (1.75–30.18)	0.006
Nontraction bronchiectasis†	6 (3%)	2 (3%)	N/A	N/A
Traction bronchiectasis unilateral	2 (1%)	6 (8%)	N/A	N/A
Bilateral	1 (0.5%)	1 (1%)	N/A	N/A
Honeycombing unilateral	2 (1%)	3 (4%)	N/A	N/A
Bilateral	1 (1%)	4 (5%)	N/A	N/A
Linear scar unilateral	36 (18%)	6 (8%)	0.55 (0.21–1.45)	0.22
Bilateral	12 (12%)	6 (8%)	0.56 (0.21–1.47)	0.24
Consolidation†	2 (1%)	0 (0%)	N/A	N/A
Centrilobular nodules unilateral	2 (1%)	0 (0%)	N/A	N/A
Bilateral	1 (1%)	2 (3%)	N/A	N/A
Mosaic attenuation or air trapping	1 (1%)	0 (0%)	N/A	N/A
Osteophyte-adjacent fibrosis	7 (4%)	3 (4%)	N/A	N/A
Biapical scarring	13 (7%)	12 (16%)	3.35 (1.39–8.04)	0.007
Old granulomatous disease	74 (37%)	29 (40%)	0.96 (0.54–1.71)	0.90
Pleural thickening or scar	3 (2%)	0 (0%)	N/A	N/A
Acute infectious or inflammatory	2 (1%)	1 (1%)	N/A	N/A
Emphysema	6 (3%)	7 (10%)	2.55 (0.77–8.40)	0.13
Dependent atelectasis	36 (18%)	10 (14%)	0.59 (0.27–1.29)	0.18
Respiratory motion artifact	9 (5%)	3 (4%)	N/A	N/A

Definition of abbreviations: aOR = adjusted odds ratio; CI = confidence interval; DTA = data-driven textural analysis (machine learning method for quantification of lung fibrosis); FPF = familial pulmonary fibrosis; ILA = interstitial lung abnormality; N/A = not applicable (<5% of cohort has predictor characteristic, so inferential analysis was not conducted).

Data are expressed as n (%) or mean (SD).

^*Each logistic regression model contained the named independent variable (i.e., one model per table row) and the covariates age and sex.

^† None was bilateral.

Among the secondary independent variables evaluated, the odds of progressive subclinical FPF were elevated in participants with higher visual ILA scores (adjusted odds ratio [aOR], 1.36 per 1-point increase [95% CI, 1.20–1.53]; P < 0.0001) and DTA fibrosis scores (aOR, 1.16 per 1-point increase [95% CI, 1.03–1.32]; P = 0.02), those with unilateral (aOR, 4.89 [95% CI, 1.49–16.07]; P = 0.009) or bilateral (aOR, 15.37 [95% CI, 7.26–32.51]; P < 0.0001) reticulation compared with no reticulation, and those with bilateral ground glass (aOR, 7.28 [95% CI, 1.75–30.18]; P = 0.006) or the biapical scarring HRCT pattern (aOR, 3.35 [95% CI, 1.39–8.04]; P = 0.007) at enrollment (Table 2).

Biapical Scarring and Sub-ILA Interstitial Abnormalities

The biapical scarring HRCT pattern, an unexpected risk factor for progressive subclinical FPF, was evaluated in more detail. Biapical scarring was present at enrollment among 9% (25 of 273) of participants in follow-up procedures, including 12 with and 13 without progressive subclinical FPF (participant-level data are provided in Table E2). Because reticulation, another risk factor for progressive subclinical FPF, was common in those with biapical scarring (13 of 25 [52%]), the association between biapical scarring and progressive subclinical FPF was assessed after stratifying by reticulation (Table 3). Among those with reticulation, the proportion with progressive subclinical FPF was similar in those with (69%) and those without (67%) biapical scarring (odds ratio, 1.09 [95% CI, 0.30–4.03]; P = 0.25). Among those without reticulation, the proportion with progression was numerically higher in those with (25%) compared with those without (12%) biapical scarring, although this was not statistically significant (odds ratio, 2.35 [95% CI, 0.59–9.28]; P = 0.14). Representative HRCT images of nodular subpleural consolidations at the lung apices (i.e., biapical scarring) include one participant with minor but detectible reticulation present at enrollment and subtle progression of both features over 5.4 years of follow-up (Figure 2A). Another participant had biapical scarring without other interstitial features at enrollment, then had development and further progression of reticulation over 13.1 years (Figure 2B). Finally, a participant with reticulation at the apices and in the right lower lobe with subtle progression during 11.5 years is depicted in Figure 2C.

Table 3.

Association of Biapical Scarring with Progressive Subclinical FPF, Stratified by Reticulation Status at Enrollment

Biapical Scarring	Subclinical FPF		OR (95% CI)	P Value
	No	Yes
Reticulation present (n = 68)
No	18 (33%)	37 (67%)	1.09 (0.30–4.03)	0.25
Yes	4 (31%)	9 (69%)
Reticulation absent (n = 205)
No	169 (88%)	24 (12%)	2.35 (0.59–9.28)	0.14
Yes	9 (75%)	3 (25%)

Definition of abbreviations: CI = confidence interval; FPF = familial pulmonary fibrosis; OR = odds ratio.

Figure 2.

Progressive biapical scarring pattern. (A) A male patient in his 30s with subtle reticulation in the central apices (top row, boxes) that progressed during 5.4 years of follow-up. More posteriorly (bottom), there was nodular subpleural consolidation (i.e., biapical scarring; arrows) with suspected air bronchograms (arrowhead) that also progressed. Apical reticulation was noted in the clinical report, but this individual was classified as having categorically absent interstitial lung abnormalities at enrollment in real time. (B) A female patient in her 50s with nodular subpleural consolidation at the apices (arrows), present at enrollment and roughly stable across time. There was no reticulation at enrollment, but subpleural reticulation developed bilaterally by 8.1 years and significantly progressed by 13.1 years (white boxes) after enrollment, with development of patchy ground glass (gray boxes). (C) A female patient in her 50s with nodular subpleural consolidation at the apices (arrow) that was stable across scans. Fine reticulation was present in the bilateral apices and right base (white boxes) and progressed during 11.5 years of follow-up. All high-resolution chest computed tomography images were taken with the patient in the prone position and instructed to complete an inspiratory breath hold and are displayed with the right lung on the left side of the image.

In addition, to better understand the implications of sub-ILA interstitial abnormalities, the characteristics of patients with progressive or nonprogressive sub-ILAs were summarized and compared with those among patients who had no interstitial abnormalities (categorically absent ILAs and no sub-ILA abnormalities; “no ILAs”) or had mild ILAs at enrollment (Table 4). As expected, within each enrollment ILA category (no ILAs, sub-ILAs, and mild ILAs), patients with progressive subclinical FPF were slightly older at enrollment than nonprogressors. No such trend was observed for sex, smoking status, or enrollment symptoms, although numerically more participants with mild ILAs that progressed reported regular cough (25% vs. 7% among those with nonprogressive mild ILAs). Among those with no ILAs at enrollment, the enrollment DTA fibrosis score was similar in patients with progressive subclinical FPF (i.e., new ILAs) compared with nonprogressors (1.0 ± 1.1 vs. 1.1 ± 1.6). In patients with sub-ILAs, both the visual ILA score (0.6 ± 0.8 vs. 1.4 ± 3.5) and the DTA fibrosis score (1.3 ± 0.9 vs. 2.0 ± 3.3) were slightly lower at enrollment in patients with progressive subclinical FPF than nonprogressors, while the opposite trend was observed among those with categorically early ILAs. Patients with sub-ILAs with progressive subclinical FPF were considerably more likely to have reticulation (71% vs. 21%) and less likely to have ground glass (0% vs. 21%) at enrollment than nonprogressors; a similar trend was observed among those with mild ILAs. This further highlights the idea that reticulation, in particular, is an early feature of progressive subclinical FPF. Of note, two participants without any interstitial abnormalities and one participant with sub-ILAs at enrollment received diagnoses of clinical FPF during mean HRCT observation times of 8.3 ± 2.8 and 6.9 ± 3.9 years for these enrollment ILA groups, respectively. Figure 3 provides representative HRCT images of new ILAs and progressive sub-ILAs.

Table 4.

Characteristics of Participants with Progressive or Nonprogressive Sub–ILA

	Enrollment HRCT Status*
	No ILAs (n = 190)		Sub-ILAs (n = 21)		Mild ILAs (n = 49)
	Progressive Subclinical FPF
Characteristic	Yes (n = 24 [13%])	No (n = 166 [87%])	Yes (n = 7 [33%])	No (n = 14 [66%])	Yes (n = 32 [65%])	No (n = 17 [35%])
Age at enrollment, yr	53.4 (8.4)	51.1 (8.9)	55.2 (12.2)	54.1 (9.1)	59.6 (10.0)	58.2 (7.6)
Male sex	7 (29%)	54 (34%)	4 (57%)	4 (29%)	15 (47%)	5 (29%)
Ever cigarette smoker	5 (21%)	37 (23%)	3 (43%)	5 (36%)	11 (34%)	7 (47%)
Symptoms at enrollment
Dyspnea score (range, 0–5)	0.8 (1.0)	0.5 (1.1)	0.04 (0.08)	0.3 (0.5)	0.9 (1.4)	0.5 (1.1)
Regular cough	4 (16%)	25 (15%)	0 (0%)	1 (7%)	8 (25%)	1 (7%)
Total ILA score at enrollment	0 (0)	0 (0)	0.6 (0.8)	1.4 (3.5)	4.7 (3.0)	3.2 (2.8)
DTA fibrosis score at enrollment	1.0 (1.1) (n = 24)	1.1 (1.6) (n = 146)	1.3 (0.9) (n = 6)	2.0 (3.3) (n = 14)	3.3 (3.4) (n = 31)	2.1 (1.9) (n = 14)
HRCT findings at enrollment
Reticulation	0 (0%)	0 (0%)	5 (71%)	3 (21%)	31 (97%)	16 (94%)
Ground glass	0 (0%)	0 (0%)	0 (0%)	3 (21%)	8 (25%)	7 (41%)
Nontraction bronchiectasis	0 (0%)	2 (1%)	1 (14%)	2 (14%)	1 (3%)	2 (11%)
Traction bronchiectasis	0 (0%)	0 (0%)	0 (0%)	0 (0%)	4 (13%)	3 (18%)
Honeycombing	0 (0%)	0 (0%)	0 (0%)	0 (0%)	4 (13%)	3 (18%)
Linear scar	7 (30%)	42 (25%)	1 (14%)	2 (14%)	3 (9%)	3 (18%)
Osteophyte-adjacent fibrosis	1 (4%)	5 (3%)	1 (14%)	1 (7%)	1 (3%)	1 (6%)
Biapical scarring	0 (0%)	0 (0%)	3 (43%)	10 (71%)	7 (21%)	3 (17%)
Clinical FPF diagnosis	2 (8%)	0 (0%)	1 (14%)	0 (0%)	14 (44%)	0 (0%)
Annualized change in dyspnea	−0.01 (0.4)	−0.04 (0.3)	0.04 (0.08)	0.06 (0.2)	0.1 (0.4)	−0.01 (0.1)
Annualized change in total ILA	0.6 (0.4)	0.05 (0.3)	0.9 (0.6)	−0.1 (0.3)	1.9 (2.0)	0.1 (1.0)
HRCT observation time, yr	8.3 (2.8)	6.2 (2.8)	6.9 (3.9)	7.4 (3.4)	5.6 (2.0)	5.7 (2.8)

Definition of abbreviations: DTA = data-driven textural analysis (machine learning method to quantify lung fibrosis); FPF = familial pulmonary fibrosis; HRCT = high-resolution chest computed tomography; ILA = interstitial lung abnormality.

Data are expressed as mean (SD) or n (%).

^*The enrollment HRCT status is based on a combination of the categorical ILA status in the research HRCT report and key interstitial abnormalities (reticulation, ground glass, biapical scarring) noted in the clinical HRCT report. Those with No ILAs had categorically Absent ILAs and no clinically reported interstitial abnormalities. Those with Sub-ILAs had categorically Absent ILAs and at least 1 clinically reported interstitial abnormality. Those with Mild ILAs had categorically Early ILAs that did not meet the Fleischner Society benchmark.

Figure 3.

The radiologic features of the earliest stages of pulmonary fibrosis: sub-interstitial lung abnormality (ILA) interstitial abnormalities. (A) A female patient in her 40s with absent ILAs at enrollment who developed reticulation in several areas bilaterally by 9.1 years after enrollment (white boxes). (B) A male patient in his 40s with absent ILAs at enrollment, with reticulation developing in several areas bilaterally by 11.3 years after enrollment (white boxes). (C) A male patient in his 60s with “osteophyte”-associated reticulation in the medial right lower lobe (top row, black boxes). More inferiorly (bottom row), there was very subtle irregular reticulation in the extreme bases that progressed by 6.6 years later (gray boxes); the enrollment high-resolution chest computed tomography (HRCT) study was classified as demonstrating absent ILAs in real time. (D) A female patient in her 30s had absent ILA at enrollment but had subtle, focal reticulation that progressed across 9.8 years (gray boxes), including several new areas of subtle reticulation (white boxes). These changes could be seen across multiple levels in the lower lungs (upper and lower rows). All HRCT images were taken with the patient in the prone position and instructed to complete an inspiratory breath hold and are displayed with the right lung on the left side of the image.

Discussion

In our prospective, ongoing At-Risk for FPF Cohort, we determined that participants with mild ILAs that would not likely meet the Fleischner Society threshold for categorically present ILAs had a substantially elevated risk for experiencing progressive subclinical FPF, approaching that of participants with moderate ILAs that would likely meet the Fleischner Society threshold. Reticulation, including unilateral (5 times the odds of progression compared with no reticulation) or bilateral (15 times the odds), was identified as an important indicator of early subclinical FPF. In addition, our unique cohort and methods of HRCT assessment enabled several important observations about the earliest stages of subclinical FPF, including 1) a long latency period for and subtle progression of early ILAs toward clinically overt disease, which may occur over a decade or longer, and 2) the identification of biapical scarring as a potential indicator of subclinical disease. Overall, progressive subclinical FPF was observed among 27% of our participants during an average observation period of ∼6 years, including 10% (of the overall follow-up cohort) who received diagnoses of clinical FPF and 17% who remained subclinical, highlighting high risk among relatives of patients with FPF to develop progressive FPF.

When defining ILAs, the Fleischner Society and other groups studying subclinical pulmonary fibrosis in the general population have used a “severity” threshold of 5% involvement of a lung region, with interstitial abnormalities below that considered indeterminate (8–10, 13, 14). The Fleischner Society further indicated that the statement applied to those abnormalities that were detected incidentally and suggested that abnormalities detected while screening persons at high risk might instead be referred to as “preclinical disease” (8). In this analysis, we adopted the ILA terminology regarding the imaging finding and reported that 77% of those with ILAs which would meet the Fleischner Society severity threshold experienced progression. This finding lends support to the idea that ILAs likely represent preclinical disease when observed in a first-degree FPF relative. Notably, 65% of those with ILAs that would not meet the Fleischner Society severity threshold also experienced progression, suggesting that this group is also highly enriched for preclinical disease. Limited information is available regarding long-term implications of ILAs below the Fleischner Society severity threshold in the general population or other high-risk groups (e.g., connective tissue disease), but several studies indicate that a small proportion with indeterminate ILAs may progress to Fleischner Society–defined ILAs or experience increased mortality (11–13).

Our methods of HRCT evaluation, combined with the accumulation of a substantial number of patients with long-term follow-up, enabled us to observe the onset of categorically early ILAs in 24 participants and to tease out the implications of sub-ILA interstitial abnormalities. These results highlight the slow and subtle nature of progression during this early stage of disease. Those who developed ILAs added 0.6 points per year to their visual ILA scores (range, 0–96) during an average of >8 years of HRCT observation time. Extrapolated to 5 years, this is akin to developing an interstitial abnormality at <5% in three lung regions that were not previously involved. The dyspnea score was effectively unchanged, on average, in this group during follow-up. Another notable finding was that the DTA fibrosis score (i.e., the proportion of lung with reticulation, traction bronchiectasis, or honeycombing) at enrollment was only minimally higher in patients with sub-ILA interstitial abnormalities or categorically present but mild ILAs compared with absent ILAs, suggesting that more sensitive methods for automated HRCT analysis or non-HRCT biomarkers are needed to identify individuals at risk to progress toward ILAs. This analysis was limited by a small number of participants per subgroup.

We used the clinical HRCT reports to evaluate the implications of the biapical scarring pattern, which is currently excluded from the common definition of ILAs (8). Biapical scarring is sometimes termed “apical cap” when mild and presumed nonpathologic or pleuroparenchymal fibroelastosis (PPFE) when it is more extensive and/or is associated with symptoms (25). Biapical scarring was observed in 9% of our cohort at enrollment, and progression events occurred among 48% of those with biapical scarring, compared with 27% of the overall cohort. Participants with biapical scarring without reticulation had ∼2 times the odds of progression compared with those without biapical scarring or reticulation, suggesting that it may be associated with progressive subclinical FPF independently of reticulation. Interestingly, many of those with biapical scarring without initial reticulation developed reticulation during follow-up, including in and/or away from the apices. Furthermore, although both components can progress, the rate and timing appear to be dyssynchronous in many cases. In another cohort of asymptomatic FPF relatives, the “PPFE pattern” accounted for 15% of all ILAs (26), and in a different study, 10% of patients with FPF with telomere biology disorders had the PPFE pattern (27). Although the number of participants in our study with biapical scarring was small, these results suggest that it may indicate subclinical FPF.

This study has several limitations. First, we note that more than half of the ILA progression events comprised detectable but subjectively mild radiologic progression. It remains to be seen if these individuals will develop clinically significant FPF during their lifetimes. However, with an average age of ∼63 years at the time of the most recent screening HRCT, we believe that most will go on to develop clinically significant disease.

Second, the subgroup with moderate ILAs was extrapolated from the visual HRCT scores, not evaluated a priori for Fleischner Society–defined ILAs. Despite this, there was excellent alignment of the observed DTA fibrosis score with the expected proportion of lung involved in mild ILAs at 2.8 (Fleischner Society–indeterminate ILAs would involve <5% of lung) and moderate ILAs at 7.0 (Fleischner Society–defined ILAs would involve >5% of lung).

Third, the frequency of follow-up visit invitations was variable across the study period, and visits were not compulsory. These factors may have introduced bias, particularly if the likelihood to follow up differed on the basis of outcome-relevant factors. No major differences were observed in the enrollment characteristics in those who participated in or were lost to follow-up. In addition, although a robust number of participants had more than one HRCT study with a visual ILA score, only a minority had more than one DTA fibrosis score; thus, analysis of DTA data was limited to the enrollment HRCT examination. In this study, 10 HRCT characteristics were tested in inferential analyses. If applying a conservative (Bonferroni) false discovery rate control, only those P values <0.005 would be interpreted as indicating statistical significance.

Finally, although several similar cohorts screen at-risk FPF relatives for ILAs (26, 28–30), none has accumulated enough participants with prolonged observation time to allow external validation of our findings.

Conclusions

This analysis of data from the At-Risk for FPF Cohort provides valuable insights about the earliest stages of subclinical FPF, including a high rate of progression among individuals with focal and/or unilateral reticulation and the slow, subtle nature of progression during the earliest stage. Importantly, the observation that ILAs are typically present for a decade or more before the development of architectural distortion or substantial symptoms highlights both the feasibility of secondary prevention of pulmonary fibrosis and the importance of a longer duration of observation in trials to develop appropriate preventive interventions.