Interstitial Lung Disease in Relatives of Patients with Pulmonary Fibrosis

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; idiopathic pulmonary fibrosis; interstitial lung abnormalities; interstitial lung disease; screening.

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.

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.

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 Dl_CO <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.)