Abstract
Rationale: Although relatives of patients with familial pulmonary fibrosis (FPF) are at an increased risk for interstitial lung disease (ILD), the risk among relatives of sporadic idiopathic pulmonary fibrosis (IPF) is not known.
Objectives: To identify the prevalence of interstitial lung abnormalities (ILA) and ILD among relatives of patients with FPF and sporadic IPF.
Methods: Undiagnosed first-degree relatives of patients with pulmonary fibrosis (PF) consented to participate in a screening study that included the completion of questionnaires, pulmonary function testing, chest computed tomography, a blood sample collection for immunophenotyping, telomere length assessments, and genetic testing.
Measurements and Main Results: Of the 105 relatives in the study, 33 (31%) had ILA, whereas 72 (69%) were either indeterminate or had no ILA. Of the 33 relatives with ILA, 19 (58%) had further evidence for ILD (defined by the combination of imaging findings and pulmonary function testing decrements). There was no evidence in multivariable analyses that the prevalence of either ILA or ILD differed between the 46 relatives with FPF and the 59 relatives with sporadic IPF. Relatives with decrements in either total lung or diffusion capacity had a greater than 9-fold increase in their odds of having ILA (odds ratio, 9.6; 95% confidence interval, 3.1–29.8; P < 0.001).
Conclusions: An undiagnosed form of ILD may be present in greater than 1 in 6 older first-degree relatives of patients with PF. First-degree relatives of patients with both familial and sporadic IPF appear to be at similar risk. Our findings suggest that screening for PF in relatives might be warranted.
Keywords: familial pulmonary fibrosis, interstitial lung abnormalities, interstitial lung disease, idiopathic pulmonary fibrosis, screening
At a Glance Commentary
Scientific Knowledge on the Subject
Evidence demonstrates that relatives of patients with familial pulmonary fibrosis (FPF) are at an increased risk for interstitial lung disease (ILD). Although the clinical presentation of newly diagnosed cases of FPF and sporadic idiopathic pulmonary fibrosis (IPF) substantially overlap, and patients with FPF and sporadic IPF share many common genetic risk factors, by definition, relatives of patients with “sporadic” IPF are not known to be at an increased risk for ILD.
What This Study Adds to the Field
Our study demonstrates that 31% of first-degree relatives of patients with pulmonary fibrosis had interstitial lung abnormalities (ILA) on computed tomography, whereas 69% were either indeterminate or had no ILA. Of the relatives with ILA, 58% had further evidence for ILD. There was no evidence that the prevalence of either ILA or ILD differed between the relatives of patients with FPF and sporadic IPF. Relatives with decrements in either total lung or diffusion capacity had a greater than ninefold increase in their odds of having ILA. Our findings suggest that screening for pulmonary fibrosis in first-degree relatives might be warranted.
Idiopathic pulmonary fibrosis (IPF), a disorder of progressive lung scarring (1), is most commonly diagnosed as a sporadic or isolated case of IPF in a family (2). In contrast, familial pulmonary fibrosis (FPF), diagnosed when a second case of IPF, or idiopathic interstitial pneumonia, is identified in a family (3), is a less common presentation (with estimates ranging from 0.5% to 20% of IPF cases) (2, 4). The clinical presentation of newly diagnosed cases of sporadic IPF and FPF substantially overlap (3–5). Although studies have identified subsets of asymptomatic relatives from kindred with FPF with evidence for an early stage of FPF (3, 5, 6), the risk of developing an early stage of pulmonary fibrosis (PF) in undiagnosed relatives of patients with sporadic IPF is not known.
There are several reasons to believe that relatives of patients with sporadic IPF could be at increased risk of developing PF. First, studies characterizing chest computed tomography (CT) abnormalities in the general population suggest that early stages of interstitial lung disease (ILD) are more prevalent than previously appreciated and are often unrecognized clinically (7–11). Second, many of the same genetic variants (12–17) are known to be associated with the risk to develop both sporadic IPF and FPF (18, 19). Third, undiagnosed research participants with imaging abnormalities suggestive of ILD have increased allele frequencies for some of the same genetic variants noted to be associated with both sporadic IPF and FPF (6, 7, 20, 21).
On the basis of these findings we hypothesized that relatives of patients with both sporadic and familial PF would be at an increased risk to have an undiagnosed form of PF. To test this hypothesis we recruited and comprehensively characterized undiagnosed first-degree relatives of patients with pulmonary fibrosis recruited at the Brigham and Women’s Hospital (BWH). On the basis of our initial results, we compared the rates of imaging abnormalities and ILD between relatives of patients with sporadic IPF and FPF; we sought to determine the factors that might help to identify those with imaging abnormalities; and, finally, we report the results of clinical evaluations resulting from this screening study.
Methods
Study Design
Please see the online supplement for a detailed description of the study methods. From November of 2016 to September of 2019, 254 patients seen at the BWH with clinical evidence for PF were invited to enroll in a clinical registry (22). Patients with known connective tissue disease or sarcoidosis were excluded. Between March of 2017 and September of 2019, of these 254 patients with PF, 192 (76%) provided additional written informed consent to having their first-degree relatives between 48 and 85 years of age without a known diagnosis of ILD contacted, inviting them to participate in our CGS-PF (Clinical Genetics and Screening for Pulmonary Fibrosis) study. Relatives were ineligible for this study if they did not speak English, had a history of uncontrolled depression or anxiety (23), or were undergoing an evaluation for ILD. During this study period, of 450 letters of invitation issued, 126 (28%) positively responded, and 107 had completed their first initial visit (see Figure 1).
Figure 1.
Flowchart depicting the patients with pulmonary fibrosis enrolled into the clinical registry and the patients that additionally consented to have their relatives contacted for participation in the CGS-PF (Clinical Genetics and Screening for Pulmonary Fibrosis) study. (Left) The timelines for enrollment into a clinical registry for patients with pulmonary fibrosis at the Brigham and Women’s Hospital and the timeline for enrollment into the CGS-PF study, specifically. (Right) The flow of first-degree relatives of patients with pulmonary fibrosis into the CGS-PF study. BWH = Brigham and Women’s Hospital.
These 107 first-degree relatives provided written informed consent to participate in a 2-year study protocol, which included the completion of questionnaires, a physical exam, and genetic counseling; blood sample collection for a complete blood count, liver function testing, immunophenotyping, telomere length assessments (24), and clinical genetic testing; and repeated measures of pulmonary function (PFTs), 6-minute-walk tests, and chest CT scanning. This study was approved by the BWH institutional review board.
Determination of Familial PF and Sporadic IPF
To determine if probands had sporadic IPF or FPF a genetic counselor generated a five-generation pedigree on each proband contributing relatives to this study (see example in Figure E1 in the online supplement). Sporadic IPF was defined by families where the proband was the only known case of ILD in the pedigree; FPF was defined when at least one other person in the pedigree was known to have ILD.
Chest CT Analysis
Relatives completed a single prone volumetric thoracic chest CT at full inspiration. All chest CTs were assessed for the presence of interstitial lung abnormalities (ILA) by up to three readers, as previously described (25). ILA were defined as changes affecting >5% of any lung zone, including nondependent ground-glass or reticular abnormalities, diffuse centrilobular nodularity, nonemphysematous cysts, honeycombing, or traction bronchiectasis, as previously described (7, 25, 26). Indeterminate scans were defined as focal or unilateral ground-glass attenuation, focal or unilateral reticulation, and patchy ground-glass abnormality (<5% of the lung). Chest CTs identified as having ILA were additionally characterized into subsets defined by the presence or absence of pulmonary parenchymal architectural distortion (e.g., traction bronchiectasis or honeycombing) consistent with a fibrotic lung disease (definite fibrosis) (7).
Statistical Analysis
We defined ILD as the presence of ILA with either definite fibrosis or ILA (but without definite fibrosis) with a measurement of TLC <80% or a DlCO <70% of predicted. Bivariate analyses were conducted with Fisher’s exact tests (for categorical variables), and two-tailed t tests or Wilcoxon rank-sum tests (for continuous variables) where appropriate. Confidence intervals (CIs) for the estimates of ILA and ILD prevalence were calculated using a binomial distribution (27). All multivariable analyses were performed using generalized linear models accounting for clustering within family units and adjusted for covariates (including age, sex, and a history of ever smoking) where indicated. Given the small numbers of missing values (see Table 1), relatives missing data were removed from these specific analyses. Receiver operator characteristic curves were generated to obtain areas under the curve and create c-statistics, and Wald tests were used to assess whether clinical variables, including the addition of the reduced telomere length and the MUC5B promoter variant, improved the ability to predict ILA. All analyses were performed using SAS version 9.4 (SAS Institute). P values <0.05 were considered statistically significant.
Table 1.
Baseline Characteristics of First-Degree Relatives Stratified by ILA and ILD Status
| Variable* | Participants without ILA† (n = 72; 69%) | Participants with ILA† (n = 33; 31%) | P Values‡ | Participants without ILD† (n = 86; 82%) | Participants with ILD† (n = 19; 18%) | P Values‡ |
|---|---|---|---|---|---|---|
| Relative with sporadic or familial pulmonary fibrosis | ||||||
| Sporadic | 38 (53) | 21 (64) | 0.40 | 46 (53) | 13 (68) | 0.31 |
| Familial | 34 (47) | 12 (36) | 40 (47) | 6 (32) | ||
| Demographic parameters |
||||||
| Age, yr | 58 (52–63) | 61 (56–67) | 0.01 | 58 (52–63) | 61 (56–68) | 0.02 |
| Sex, F | 47 (65) | 17 (52) | 0.20 | 54 (63) | 10 (53) | 0.12 |
| Body mass index | 28 (25–32) | 27 (26–31) | 0.33 | 28 (25–32) | 27 (22–30) | 0.22 |
| Pack-years of smoking | 0 (0–2) | 0 (0–21) | 0.20 | 0 (0–2) | 0 (0–28) | 0.20 |
| Ever smoker | 29 (40) | 15 (45) | 0.67 | 37 (43) | 7 (37) | 0.80 |
| Respiratory symptoms |
||||||
| Frequent cough, yes§ | 15 (21) | 6 (20) | 1.00 | 16 (20) | 5 (26) | 0.54 |
| Frequent shortness of breath, yes§ | 3 (4) | 4 (13) | 0.20 | 4 (5) | 3 (16) | 0.19 |
| Physiologic parameters |
||||||
| FEV1 % of predicted║ | 108 (99–115) | 104 (91–113) | 0.20 | 108 (99–115) | 102 (86–110) | 0.03 |
| FVC % of predicted║ | 110 (99–118) | 100 (88–109) | 0.006 | 109 (98–117) | 97 (86–109) | 0.008 |
| FVC <80% of predicted | 1 (1) | 3 (9) | 0.09 | 2 (2) | 2 (11) | 0.15 |
| FEV1/FVC % | 100 (95–103) | 103 (100–106) | 0.003 | 101 (95–103) | 103 (95–109) | 0.33 |
| TLC % of predicted║ | 104 (96–114) | 96 (84–101) | <0.001 | 102 (95–111) | 88 (80–98) | <0.001 |
| TLC <80% of predicted║ | 0 (0) | 4 (12) | 0.009 | 0 (0) | 4 (21) | <0.001 |
| DlCO % of predicted║ | 87 (80–98) | 73 (62–87) | <0.001 | 87 (78–97) | 62 (55–80) | <0.001 |
| DlCO <70% of predicted | 6 (8) | 13 (39) | <0.001 | 6 (7) | 13 (68) | <0.001 |
| 6MWD, m | 483 (436–521) | 458 (406–525) | 0.29 | 483 (439–521) | 439 (390–525) | 0.35 |
| 6MWD % of predicted║ | 91 (81–102) | 87 (79–98) | 0.29 | 90 (80–102) | 89 (75–96) | 0.50 |
| Rheumatologic testing |
||||||
| Positive ANA, yes | 12 (17) | 6 (19) | 0.91 | 16 (19) | 2 (11) | 0.49 |
| Anti-CCP elevated, yes | 0 (0) | 1 (3) | 0.31 | 0 (0) | 1 (5) | 0.18 |
| Anti-Scl70 elevated, yes | 1 (1) | 0 (0) | 1.00 | 1 (1) | 0 (0) | 1.00 |
| Telomere length¶ |
||||||
| Lymphocyte telomere length <10th percentile for age | 20 (29) | 16 (50) | 0.05 | 26 (32) | 10 (53) | 0.05 |
| Genetic testing** |
||||||
| MUC5B promoter variant | 0.02 | 0.04 | ||||
| 0 | 43 (61) | 14 (42) | 51 (61) | 6 (32) | ||
| 1 | 27 (39) | 16 (48) | 31 (37) | 12 (63) | ||
| 2 | 0 (0) | 3 (9) | 2 (2) | 1 (5) |
Definition of abbreviations: 6MWD = 6-minute-walk distance; ANA = antinuclear antibody; anti-CCP = anti–cyclic citrullinated antibody; anti‐Scl70 = anti–topoisomerase 1; ILA = interstitial lung abnormalities; ILD = interstitial lung disease.
Data are shown as n (%) or median (interquartile range) where appropriate.
Data missing for reports of cough (n = 4), shortness of breath (n = 3), lymphocyte telomere length (n = 4), and genetic testing (n = 2).
First-degree relatives without ILA include both those initially scored as having no ILA or those indeterminate for ILA. ILD is defined by the presence of ILA with definite fibrosis (including measures of architectural distortion such as traction bronchiectasis or honeycombing) or in those with ILA but without definite fibrosis and evidence for a restrictive lung deficit (a TLC <80% of predicted) or a reduction in gas exchange (a DlCO <70% of predicted).
Fisher’s exact tests (for binary variables) and paired t tests or Wilcoxon rank-sum tests (for continuous variables where appropriate).
Frequent cough and shortness of breath were defined by a report of symptoms occurring at least several days a week over the past 3 months; those with symptoms only occurring occasionally or with a chest infection were defined as not having frequent respiratory symptoms.
Predicted values for FEV1 and FVC are derived from Crapo and colleagues (36). Percent of predicted TLC is based on American Thoracic Society/European Respiratory Society guidelines (37). Predicted values are derived from Miller and colleagues (38). Predicted values for 6MWD are derived from Enright and colleagues (39).
Telomere lengths were obtained from 6-panel flow fish (Repeat Diagnostics). Only data on lymphocyte telomere lengths are reported.
MUC5B promoter variant refers to those who have at least one copy of the minor allele of the MUC5B promoter polymorphism (rs35705950), with 0 referring to homozygotes for the major allele, 1 referring to heterozygotes for the minor allele, and 2 referring to homozygotes for the minor allele.
Results
Characteristics of Relatives of Patients with PF
One hundred and seven undiagnosed first-degree relatives (relatives) of patients with PF from 53 families (mean = 2 relatives per family, range = 1–13 relatives per family) completed the first initial visit in the CGS-PF study. For ease of exposition, and because of small sample sizes, one relative (1%) of a patient with nonspecific interstitial pneumonitis and one relative (1%) of a patient with chronic hypersensitivity pneumonitis were removed from further analyses. Of the remaining 105 relatives, 46 (44%) relatives were members of 21 families (40% of the families) with FPF, and 59 (56%) were members of 32 families (60% of the families) where one member was known to have IPF (sporadic IPF).
ILA and ILD in Relatives of Patients with PF
Of the 105 relatives enrolled in the CGS-PF study, 33 (31%; 95% CI, 23–41) had ILA, whereas 72 were either indeterminate (n = 36; 34%) or had no ILA (n = 36; 34%). Of the 33 relatives with ILA, 19 (58%) met our diagnostic criteria for ILD (ILD prevalence, 18%; 95% CI, 11–27). Of the 19 relatives with ILD, 13 (68%) were classified as having ILD on the basis of CT evidence for definite fibrosis, whereas 6 (32%) relatives had ILA without definite fibrosis and a DlCO <70% of predicted. All four relatives with a TLC <80% of predicted had definite fibrosis on their chest CT images. The prevalence of ILA and ILD was similar when all relatives reporting frequent cough or shortness of breath (n = 24; 23%) were excluded (32% and 17% for ILA and ILD, respectively).
Baseline characteristics of relatives stratified by the presence or absence of ILA and ILD are included in Table 1 (relatives without ILA include those both without ILA and those indeterminate for ILA). Compared with those without ILA, those with ILA were older and had relative reductions in their measures of FVC, TLC, and DlCO. Relatives with ILA were also more likely to have reduced lymphocyte telomere lengths and had increased copies of the minor allele of the MUC5B promoter polymorphism (rs35705950). When relatives without ILD were compared with relatives with ILD, similar trends were noted (see Table 1). Similarly, in multivariable analyses, reduced measures of FVC, TLC, and DlCO and increasing copies of the MUC5B promoter polymorphism (rs35705950) were associated with an increased odds to have both ILA and ILD, respectively (see Table 2). Although reduced lymphocyte telomere length measures were associated with an increased odds to have ILA in multivariable analyses, this finding was not statistically significant for ILD (see Table 2).
Table 2.
Associations between Pulmonary Function Measures and ILA and ILD
| ILA Association [OR (95% CI), P Value]* | ILD Association [OR (95% CI), P Value]* | |||
|---|---|---|---|---|
| Adjusted† | Adjusted + Covariates‡ | Adjusted† | Adjusted + Covariates‡ | |
| Pulmonary function measure§ | ||||
| FVC % of predicted | 1.5 (1.1–2.0), P = 0.01 | 1.5 (1.1–2.0), P = 0.01 | 1.6 (1.1–2.3), P = 0.02 | 1.6 (1.1–2.4), P = 0.01 |
| TLC % of predicted | 2.0 (1.4–2.9), P < 0.001 | 2.1 (1.5–3.1), P < 0.001 | 2.4 (1.4–4.2), P = 0.001 | 2.5 (1.5–4.4), P < 0.001 |
| DlCO % of predicted | 1.9 (1.3–2.7), P < 0.001 | 2.3 (1.5–3.5), P < 0.001 | 2.6 (1.6–4.4), P < 0.001 | 4.4 (2.2–8.5), P < 0.001 |
| DlCO <70% of predicted | 7.2 (2.4–21.2), P < 0.001 | 8.6 (2.7–27.5), P < 0.001 | — | — |
| TLC <80% or DlCO <70% of predicted | 8.1 (2.7–24.0), P < 0.001 | 9.6 (3.1–29.8), P < 0.001 | — | — |
| Telomere length║ | ||||
| Lymphocyte telomere length <10th percentile for age | 2.5 (1.0–5.8), P = 0.04 | 2.7 (1.0–7.1), P = 0.05 | 2.4 (0.9–6.6), P = 0.09 | 2.7 (0.9–8.5), P = 0.08 |
| Genetic testing¶ | ||||
| MUC5B promoter | 2.5 (1.2–5.2), P = 0.01 | 3.6 (1.5–8.4), P = 0.003 | 2.7 (1.1–6.6), P = 0.03 | 4.0 (1.5–10.6), P = 0.005 |
Definition of abbreviations: CI = confidence interval; ILA = interstitial lung abnormalities; ILD = interstitial lung disease; OR = odds ratio.
ORs reported for continuous metrics of FVC, TLC, and DlCO are for the odds of having ILA per 10% of predicted decrement in the measure.
“Adjusted” analyses are the results from generalized linear models that account for familial relationship.
“Adjusted + covariates” analyses are the results from generalized linear models that include covariates for age, sex, and history of smoking, as well as accounting for familial relationship.
Predicted values for FVC are derived from Crapo and colleagues (36). Percent of predicted TLC is based on American Thoracic Society/European Respiratory Society guidelines (37). Predicted values for DlCO are derived from Miller and colleagues (38).
Telomere lengths were obtained from 6-panel flow fish (Repeat Diagnostics).
MUC5B promoter refers to those with increasing copies of the minor allele of the MUC5B promoter polymorphism (rs35705950) using an additive genetic model.
ILA and ILD in Sporadic and Familial Relatives with PF
As noted in Tables 1 and E1, the differences in the prevalence of ILA (and ILD) among relatives recruited from a patient with sporadic IPF as compared with FPF were not statistically significant. ILA were present in 21 (36%; 95% CI, 24–49) of the 59 relatives of a patient with sporadic IPF and in 12 (26%; 95% CI, 14–41) of the 46 relatives recruited from kindred affected with FPF. ILD was present in 13 (22%; 95% CI, 12–35) of the 59 relatives recruited from a patient with sporadic IPF and in 6 (13%; 95% CI, 5–26) of the 46 relatives recruited from kindred affected with FPF. Similarly, in multivariable generalized linear models adjusting for covariates, there was no evidence that the prevalence of either ILA or ILD was different between relatives recruited from families with sporadic IPF as compared with FPF (odds ratio [OR], 1.7; 95% CI, 0.7–4.4; P = 0.27 and OR, 2.3; 95% CI, 0.8–6.7; P = 0.19 for ILA and ILD, respectively). Data from four siblings recruited from a patient with a diagnosis of sporadic IPF are presented in Figure 2.
Figure 2.
The screening information for four siblings in a family identified through a case initially felt to be sporadic idiopathic pulmonary fibrosis. The first sibling was identified as having interstitial lung disease (ILD) on the basis of imaging findings consistent with “definite fibrosis” alone. The second sibling was identified as having ILD on the basis of both imaging findings consistent with “definite fibrosis” and reduced measures of TLC and diffusion capacity for carbon monoxide. The third sibling was identified as having interstitial lung abnormalities alone on the basis of the presence of subpleural reticular changes on chest computed tomography imaging without “definite fibrosis” and pulmonary function test results that were within normal limits. The fourth sibling was identified as having ILD on the basis of both imaging findings consistent with “definite fibrosis” and reduced measures of TLC and diffusion capacity for carbon monoxide. The white and red boxes in the row labeled MUC5B promoter genotype identify each member of this family as a heterozygote for the minor allele of the MUC5B promoter polymorphism (res35705950). COPD = chronic obstructive pulmonary disease; CT = computed tomography; ILA = interstitial lung abnormalities; IPF = idiopathic pulmonary fibrosis.
Comparably, similar numbers of families affected by sporadic IPF and FPF had at least one relative diagnosed with ILA and ILD, respectively. ILA were present in at least one relative from 13 (41%) of the 32 families identified by a patient with sporadic IPF and in 9 (43%) of the 21 kindred affected with FPF. ILD was present in at least one relative from 7 (22%) of the 32 families identified by a patient with sporadic PF and in 5 (24%) of the 21 kindred affected with FPF. Additional comparisons are presented in the online supplement and Table E1.
Risk Stratification in Relatives of Patients with PF
Of the 33 relatives with ILA, 14 (42%) had either a TLC <80% of predicted or a DlCO <70% of predicted, compared with only 6 (8%) of the 72 relatives who did not have ILA. Compared with a multivariable model that includes familial relationship, age, sex, and a history of smoking (c-statistic = 0.67; 95% CI, 0.56–0.78) the addition of either a TLC <80% of predicted or a DlCO <70% of predicted improved model accuracy by 10% (c-statistic = 0.77; 95% CI, 0.67–0.87; P = 0.06; for the model comparison, see Figure 3); however, this finding was not statistically significant. By comparison, a multivariable model that includes familial relationship, age, sex, and a history of smoking (c-statistic = 0.66; 95% CI, 0.54–0.77), the addition of either a TLC <80% of predicted or a DlCO <70% of predicted, assessments of reduced telomere length, and MUC5B promoter genotype resulted in a statistically significant improvement of model accuracy by 14% (c-statistic = 0.82; 95% CI, 0.74–0.91; P = 0.005; for the model comparison, see Figure 3).
Figure 3.
Three receiver operating characteristic (ROC) curves for predicting interstitial lung abnormalities among first-degree relatives of patients with pulmonary fibrosis. (A) The ROC curve for the inclusion of age, sex, and a history of smoking. (B) A comparison of ROC curves including an ROC curve for the inclusion of age, sex, and a history of smoking alone, to an ROC curve for the inclusion of age, sex, and a history of smoking and a physiologic decrement (defined as a TLC <80% of predicted or a DlCO <70% of predicted). (C) A comparison of ROC curves including an ROC curve for the inclusion of age, sex, and a history of smoking alone, to an ROC curve for the inclusion of age, sex, and a history of smoking, physiologic decrement, measures of reduced lymphocyte telomere length, and MUC5B promoter genotype. (Small differences in the c-statistic for the baseline ROC curve in C are the result of the exclusion of five relatives missing either telomere length or genetic testing results.)
Results Disclosure
As of December 2019, follow-up visits had been arranged, and results were disclosed to 92 (88%) of the 105 relatives. On the basis of the results of the initial tests conducted in the CGS-PF study, we recommended referrals for 29 (32%) of these 92 relatives, of whom 20 (69%) have pursued clinical care to date (three visits are pending). Referrals were recommended for relatives identified with ILD and for non-ILD indications as described below. (Relatives with ILA, but without further evidence for ILD, were recommended to continue to follow in the CGS-PF study for annual evaluations.) Of the 20 subsequent clinical assessments, 13 relatives (65%) were referred for a suspicion of ILD. Six (46%) of the 13 relatives have been diagnosed with IPF/FPF, one (8%) patient has been diagnosed with rheumatoid arthritis–associated ILD, and six (46%) were recommended to have longitudinal follow-up testing for more definitive clinical diagnoses. Five (83%) of the six relatives newly diagnosed with IPF/FPF were treated with standard antifibrotic therapy, one of whom is being considered for lung transplantation (on the basis of longitudinal decline in his PFTs despite antifibrotic therapy). The diagnoses for the seven relatives referred for evaluation of non-ILD indications were for isolated reductions in DlCO (n = 2; evaluations are ongoing), iron deficiency anemia, congestive heart failure, metastatic prostate cancer (now being treated with combined radiation and chemotherapy), a pancreatic tail mass, and cavitary lung nodules (resulting in a lung biopsy most consistent with respiratory bronchiolitis–associated ILD and a cessation of vaping by the relative).
Discussion
Our study demonstrates that first-degree relatives of patients with both FPF and sporadic IPF have a high prevalence of ILA and undiagnosed ILD. These results suggest that, in a subset of patients with IPF, the term “sporadic disease” may be inaccurate as it implies that undiagnosed first-degree relatives are not at substantial risk of developing PF. Our results further support the evolving concept that screening of undiagnosed first-degree relatives of patients with FPF can facilitate early detection. Furthermore, our findings demonstrate that pulmonary function testing, telomere length assessments, and genetic testing may help to risk stratify first-degree relatives for undiagnosed ILA both when they are a member of a kindred affected with FPF and when only one member of the family is known to have PF.
To our knowledge, this is the first study to systematically assess for ILA and ILD risk in undiagnosed sporadic relatives of patients with IPF. These results challenge our current concepts of FPF and sporadic IPF. Arguably, the term “sporadic” IPF appears to be a misnomer for a subset of the families we characterized, as the prevalence of ILA and ILD observed among these sporadic relatives is substantially greater than would be expected in the general population. Specifically, the lower bound of the 95% CI for our estimate of ILA prevalence in sporadic first-degree relatives (24%) is substantially greater than prior estimates of ILA prevalence derived from a general population samples (7–11%) (7, 8, 28). The elevated rates of ILA observed among first-degree relatives support the concept that shared genetic determinants, environmental exposures, or both likely play a substantial role in the risk for PF among families in general.
Although our study demonstrates no statistically significant differences between the rates of ILA and ILD among relatives of patients with FPF and sporadic IPF, the reduced prevalence of ILA and ILD among relatives with FPF observed in our study deserves some mention. First, it is possible that the more established risk of PF among relatives of patients with FPF resulted in an increased recruitment of relatives motivated by this awareness alone in contrast to relatives of patients with sporadic IPF who may have been more likely to be motivated by some unmeasured increase in their personal respiratory symptoms. Although we cannot rule out the possibility that studies in larger cohorts could demonstrate greater differences in ILA and ILD between relatives of patients with FPF and sporadic IPF, our study demonstrates that the current distinctions (and expectations) for disease risk among undiagnosed first-degree relatives are not that different between families where a single member is, or when multiple members are, known to have PF.
In addition to suggesting that the term sporadic IPF might belie the latent prevalence of FPF, our results support the notion that screening first-degree relatives might be an effective strategy to detect PF in earlier stages. Our findings demonstrate that PFTs can help to risk stratify relatives of patients with PF into those most likely to have chest CT abnormalities. As expected, physiologic decrements were less common in those without ILA (∼8%), whereas decrements in total lung and diffusion capacity were present in ∼42% of relatives with ILA. These findings suggest that future clinical efforts to detect undiagnosed disease among first-degree relatives might rationally consider initially screening with PFTs (in conjunction with auscultation for abnormal lung sounds) (29) to limit the small but measurable increases in malignancy risk conferred by chest CTs (30). We urge caution in extrapolating the expectation of these physiologic decrements to other populations where a more diverse array of pulmonary and nonpulmonary disorders might be expected. Although our study suggests that the inclusion of telomere length testing and MUC5B promoter genotype to pulmonary function tests may add to risk prediction in first-degree relatives, some relatives without measured risk factors had ILA, and other relatives with higher risk profiles did not. These findings suggest that simple models based solely on single tests alone will likely be insufficient to characterize individual risk in relatives, and we suggest that replication in larger populations is necessary to help determine model validity.
Approximately 18% of the undiagnosed first-degree relatives in the CGS-PF were felt likely to have ILD and were offered clinical evaluations. On the basis of a relatively small number of recommended referrals, we estimate that over 75% of those offered a clinical referral will schedule a follow-up appointment. In select cases, additional assessments of CGS-PF participants led to a diagnosis of IPF/FPF and the initiation of antifibrotic therapy. Although several clinical trials have demonstrated that the benefits of antifibrotic therapy (31, 32) are observed in patients with mild disease severity (33, 34), it should be noted that patients with IPF included in these clinical trials had established, clinical disease and were not identified through screening efforts. Therefore, we stress that although at-risk relative screening may be effective in identifying some cases of IPF/FPF and some cases of preclinical cases of PF, we lack evidence to recommend early therapeutic intervention in those early stages of PF currently. Future studies assessing the role of early institution of antifibrotic therapy should be considered in newly diagnosed cases of PF identified among relatives of patients with known disease.
Our study has several additional limitations. First, we cannot rule out the possibility that some unmeasured factor could, in part, explain the high rates of ILA and ILD we observed in the CGS-PF study that was more common among the relatives we contacted who chose to participate (28%) as compared with the relatives we contacted who did not (72%). Although our data do not suggest that respiratory symptoms alone explain the increased rates of ILA and ILD that we observed in our study, we cannot rule out the possibility that participating relatives may have had greater concerns about their lung health than relatives who did not participate. In addition, as PF is considered to be an age-related disorder (35), we expect that the older mean age of the CGS-PF population may partially account for these elevated prevalence rates. Second, although our data demonstrate that first-degree relatives of patients with sporadic IPF may be at an increased risk for ILD, small sample size may limit our power to detect important differences between relatives of patients with FPF and sporadic IPF. Finally, although longitudinal analyses are planned for the CGS-PF population, the current limited duration of follow-up may underestimate the prevalence of relatives that will experience PFT decrements or will develop imaging abnormalities over time.
In conclusion, our study demonstrates that greater than 1 in 6 older first-degree relatives of patients with both familial and sporadic PF may have an undiagnosed form of ILD. Although further work characterizing risk is necessary, our results suggest that PFTs, and perhaps genetic testing, may help to risk stratify older first-degree relatives who warrant formal imaging studies. If identifying PF in its earliest stages is a worthy goal, expanding efforts to screen relatives seems like a reasonable place to start.
Supplementary Material
Acknowledgments
Acknowledgment
The authors acknowledge that this work was supported in part by generous gifts from the families of David Herlihy and George Spilios to help with the creation and maintenance of research registries for Interstitial Lung Disease Group at the Brigham and Women Hospital. The authors also thank the patients and families for agreeing to participate in this study.
Footnotes
G.M.H. is supported by NIH grants R01 HL111024, R01 HL135142, and R01 HL130974. S.E.-C. is supported by NIH grant R01 HL130275. R.K.P. is supported by NIH grant K08 HL140087. B.A.R. is supported by NIH grants R01 HL118455, R01 HL130974, R01 HL123546, U19 AI095219, and P01 HL132825. I.O.R. is supported by NIH grants U01 HL133232 and R01 HL130974. This work was supported by an NIH grant from the NHLBI (R01 HL130974) and by the Brigham and Women’s Hospital Precision Medicine Initiative.
Author Contributions: Study design: G.M.H., B.A.R., and I.O.R. Acquisition, analysis, or interpretation of the data: G.M.H., L.D.Q.-A., N.E.C., J.M.M.M., S.P.D.F., M.A.B., L.D., S.N.G.-S., D.A.L., S.G., S.E.-C., H.J.G., R.K.P., H.H., B.A.R., and I.O.R. Critical revision of the manuscript for important intellectual content: G.M.H., L.D.Q.-A., N.E.C., J.M.M.M., S.P.D.F., M.A.B., L.D., S.N.G.-S., D.A.L., S.G., S.E.-C., H.J.G., R.K.P., H.H., B.A.R., and I.O.R. Statistical analysis: G.M.H. Obtained funding: G.M.H., B.A.R., and I.O.R.
This article has an online supplement, which is accessible from this issue’s table of contents at www.atsjournals.org.
Originally Published in Press as DOI: 10.1164/rccm.201908-1571OC on February 3, 2020
Author disclosures are available with the text of this article at www.atsjournals.org.
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