Early interstitial lung disease in familial pulmonary fibrosis

Abstract

Rationale: Identification of early, asymptomatic interstitial lung disease (ILD) in populations at risk of developing idiopathic pulmonary fibrosis (IPF) may improve the understanding of the natural history of IPF.

Objectives: To determine clinical, radiographic, physiologic, and pathologic features of asymptomatic ILD in family members of patients with familial IPF.

Methods: One hundred sixty-four subjects from 18 kindreds affected with familial IPF were evaluated for ILD. Bronchoalveolar lavage fluid cells were analyzed using flow cytometry. Lung biopsies were performed in six subjects with asymptomatic ILD.

Measurements and main results: High-resolution computed tomography abnormalities suggesting ILD were identified in 31 (22%) of 143 asymptomatic subjects. Subjects with asymptomatic ILD were significantly younger than subjects with known familial IPF (P < 0.001) and significantly older than related subjects without lung disease (P < 0.001). A history of smoking was identified in 45% of subjects with asymptomatic ILD and in 67% of subjects with familial IPF; these percentages were significantly higher than that of related subjects without lung disease (23%) (P = 0.02 and P < 0.001, respectively). Percentages of activated CD4(+) lymphocytes were significantly higher in bronchoalveolar lavage fluid cells from subjects with asymptomatic ILD compared with related subjects without lung disease (P < 0.001). Lung biopsies performed in subjects with asymptomatic ILD revealed diverse histologic subtypes.

Conclusions: Asymptomatic ILD in individuals at risk of developing familial IPF can be identified using high-resolution computed tomography scan of the chest, especially in those with a history of smoking. Lung biopsies from individuals in this cohort with early asymptomatic lung disease demonstrate various histologic subtypes of ILD.

Figure 1.

Representative abnormal high-resolution computed tomography (HRCT) scan images from two first-degree relatives without a prior diagnosis of idiopathic pulmonary fibrosis. (A) shows mild subpleural opacities (arrow) in an asymptomatic 50-year-old man. (B) An HRCT image from his brother, who was a 62-year-old man with progressive exertional dyspnea, shows moderate subpleural fibrosis and honeycombing.

Figure 1.

Representative abnormal high-resolution computed tomography (HRCT) scan images from two first-degree relatives without a prior diagnosis of idiopathic pulmonary fibrosis. (A) shows mild subpleural opacities (arrow) in an asymptomatic 50-year-old man. (B) An HRCT image from his brother, who was a 62-year-old man with progressive exertional dyspnea, shows moderate subpleural fibrosis and honeycombing.

Figure 2.

Pulmonary function and cardiopulmonary exercise tests indicate mild abnormalities in gas exchange. (A) Although the diffusion capacity of carbon monoxide (Dl_CO) percentage of predicted was normal for all but three subjects with asymptomatic interstitial lung disease (ILD), pulmonary function tests showed significantly lower Dl_CO percentage of predicted in subjects with asymptomatic ILD and familial idiopathic pulmonary fibrosis (IPF) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P < 0.02 and P < 0.001, respectively). (B) Dl_CO percentage of predicted for subjects with asymptomatic ILD was significantly lower in those with a history of ever smoking (n = 14) compared with nonsmokers (n = 15) (P < 0.003). (C) A significant difference in the percent reduction of dead space ventilation (VD/VT) during peak exercise was found in subjects with asymptomatic ILD compared with subjects with normal HRCT scans (P < 0.001). Nonsmoker = o, ever-smoker = x.

Figure 2.

Pulmonary function and cardiopulmonary exercise tests indicate mild abnormalities in gas exchange. (A) Although the diffusion capacity of carbon monoxide (Dl_CO) percentage of predicted was normal for all but three subjects with asymptomatic interstitial lung disease (ILD), pulmonary function tests showed significantly lower Dl_CO percentage of predicted in subjects with asymptomatic ILD and familial idiopathic pulmonary fibrosis (IPF) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P < 0.02 and P < 0.001, respectively). (B) Dl_CO percentage of predicted for subjects with asymptomatic ILD was significantly lower in those with a history of ever smoking (n = 14) compared with nonsmokers (n = 15) (P < 0.003). (C) A significant difference in the percent reduction of dead space ventilation (VD/VT) during peak exercise was found in subjects with asymptomatic ILD compared with subjects with normal HRCT scans (P < 0.001). Nonsmoker = o, ever-smoker = x.

Figure 2.

Pulmonary function and cardiopulmonary exercise tests indicate mild abnormalities in gas exchange. (A) Although the diffusion capacity of carbon monoxide (Dl_CO) percentage of predicted was normal for all but three subjects with asymptomatic interstitial lung disease (ILD), pulmonary function tests showed significantly lower Dl_CO percentage of predicted in subjects with asymptomatic ILD and familial idiopathic pulmonary fibrosis (IPF) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P < 0.02 and P < 0.001, respectively). (B) Dl_CO percentage of predicted for subjects with asymptomatic ILD was significantly lower in those with a history of ever smoking (n = 14) compared with nonsmokers (n = 15) (P < 0.003). (C) A significant difference in the percent reduction of dead space ventilation (VD/VT) during peak exercise was found in subjects with asymptomatic ILD compared with subjects with normal HRCT scans (P < 0.001). Nonsmoker = o, ever-smoker = x.

Figure 3.

(A) Percentage of lymphocytes in bronchoalveolar lavage (BAL) cells tended to be higher in subjects with asymptomatic interstitial lung disease (ILD) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P = 0.07). (B) Percentage of lymphocytes in BAL cells for subjects with asymptomatic ILD was significantly higher in nonsmokers (n = 15) compared with those with a history of ever smoking (n = 13) (P < 0.008). (C) Percentage of neutrophils in BAL cells was significantly greater in subjects with familial idiopathic pulmonary fibrosis (IPF), and not subjects with asymptomatic ILD, than in subjects with normal HRCT scans (P < 0.001). (D) and (E) demonstrate that CD3⁺/CD4⁺ BAL cells from subjects with asymptomatic ILD had significantly higher percentages of HLA-DR⁺ and CD38⁺ cells compared with subjects with normal HRCT scans (P < 0.001 and P = 0.006, respectively). Nonsmoker = o, ever-smoker = x.

Figure 3.

(A) Percentage of lymphocytes in bronchoalveolar lavage (BAL) cells tended to be higher in subjects with asymptomatic interstitial lung disease (ILD) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P = 0.07). (B) Percentage of lymphocytes in BAL cells for subjects with asymptomatic ILD was significantly higher in nonsmokers (n = 15) compared with those with a history of ever smoking (n = 13) (P < 0.008). (C) Percentage of neutrophils in BAL cells was significantly greater in subjects with familial idiopathic pulmonary fibrosis (IPF), and not subjects with asymptomatic ILD, than in subjects with normal HRCT scans (P < 0.001). (D) and (E) demonstrate that CD3⁺/CD4⁺ BAL cells from subjects with asymptomatic ILD had significantly higher percentages of HLA-DR⁺ and CD38⁺ cells compared with subjects with normal HRCT scans (P < 0.001 and P = 0.006, respectively). Nonsmoker = o, ever-smoker = x.

Figure 3.

(A) Percentage of lymphocytes in bronchoalveolar lavage (BAL) cells tended to be higher in subjects with asymptomatic interstitial lung disease (ILD) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P = 0.07). (B) Percentage of lymphocytes in BAL cells for subjects with asymptomatic ILD was significantly higher in nonsmokers (n = 15) compared with those with a history of ever smoking (n = 13) (P < 0.008). (C) Percentage of neutrophils in BAL cells was significantly greater in subjects with familial idiopathic pulmonary fibrosis (IPF), and not subjects with asymptomatic ILD, than in subjects with normal HRCT scans (P < 0.001). (D) and (E) demonstrate that CD3⁺/CD4⁺ BAL cells from subjects with asymptomatic ILD had significantly higher percentages of HLA-DR⁺ and CD38⁺ cells compared with subjects with normal HRCT scans (P < 0.001 and P = 0.006, respectively). Nonsmoker = o, ever-smoker = x.

Figure 3.

(A) Percentage of lymphocytes in bronchoalveolar lavage (BAL) cells tended to be higher in subjects with asymptomatic interstitial lung disease (ILD) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P = 0.07). (B) Percentage of lymphocytes in BAL cells for subjects with asymptomatic ILD was significantly higher in nonsmokers (n = 15) compared with those with a history of ever smoking (n = 13) (P < 0.008). (C) Percentage of neutrophils in BAL cells was significantly greater in subjects with familial idiopathic pulmonary fibrosis (IPF), and not subjects with asymptomatic ILD, than in subjects with normal HRCT scans (P < 0.001). (D) and (E) demonstrate that CD3⁺/CD4⁺ BAL cells from subjects with asymptomatic ILD had significantly higher percentages of HLA-DR⁺ and CD38⁺ cells compared with subjects with normal HRCT scans (P < 0.001 and P = 0.006, respectively). Nonsmoker = o, ever-smoker = x.

Figure 3.

(A) Percentage of lymphocytes in bronchoalveolar lavage (BAL) cells tended to be higher in subjects with asymptomatic interstitial lung disease (ILD) compared with subjects with normal high-resolution computed tomography (HRCT) scans (P = 0.07). (B) Percentage of lymphocytes in BAL cells for subjects with asymptomatic ILD was significantly higher in nonsmokers (n = 15) compared with those with a history of ever smoking (n = 13) (P < 0.008). (C) Percentage of neutrophils in BAL cells was significantly greater in subjects with familial idiopathic pulmonary fibrosis (IPF), and not subjects with asymptomatic ILD, than in subjects with normal HRCT scans (P < 0.001). (D) and (E) demonstrate that CD3⁺/CD4⁺ BAL cells from subjects with asymptomatic ILD had significantly higher percentages of HLA-DR⁺ and CD38⁺ cells compared with subjects with normal HRCT scans (P < 0.001 and P = 0.006, respectively). Nonsmoker = o, ever-smoker = x.

Figure 4.

Representative fields from lung biopsies of subjects with asymptomatic interstitial lung disease (A, C, E) and mild pulmonary fibrosis (B, D, F) are shown. A photomicrograph demonstrating hypersensitivity pneumonia-like changes is shown in (A); inset shows an area of mild chronic interstitial inflammation (arrowhead) and a poorly formed granuloma (curved arrow) adjacent to a bronchiole (original magnification, ×10; hematoxylin-and-eosin [H&E] stain). (B) Photomicrograph demonstrating the geographic heterogeneity of usual interstitial pneumonia (UIP); inset shows fibroblast foci (arrowhead) (original magnification, ×4; H&E stain). (C) A photomicrograph demonstrating patchy, temporally uniform interstitial fibrosis is shown; inset shows an area with focal organizing pneumonia in detail (arrowhead) (original magnification, ×4; H&E stain). (D) A photomicrograph demonstrating areas of involved parenchyma alternating with less involved parenchyma that is characteristic of UIP (original magnification, ×4; H&E stain). (E) A photomicrograph demonstrating mild subpleural interstitial fibrosis and organizing pneumonia is shown (original magnification, ×10; H&E stain); inset shows peribronchiolar metaplasia resulting from injury to the small airways (original magnification, ×10; H&E stain). (F) A photomicrograph demonstrating honeycombing in a background of dense fibrous tissue seen in UIP (original magnification, ×4; H&E stain); inset shows nonnecrotizing granulomas adjacent to a bronchiole occasionally observed in the biopsy (original magnification, ×10; H&E stain).

Figure 4.

Representative fields from lung biopsies of subjects with asymptomatic interstitial lung disease (A, C, E) and mild pulmonary fibrosis (B, D, F) are shown. A photomicrograph demonstrating hypersensitivity pneumonia-like changes is shown in (A); inset shows an area of mild chronic interstitial inflammation (arrowhead) and a poorly formed granuloma (curved arrow) adjacent to a bronchiole (original magnification, ×10; hematoxylin-and-eosin [H&E] stain). (B) Photomicrograph demonstrating the geographic heterogeneity of usual interstitial pneumonia (UIP); inset shows fibroblast foci (arrowhead) (original magnification, ×4; H&E stain). (C) A photomicrograph demonstrating patchy, temporally uniform interstitial fibrosis is shown; inset shows an area with focal organizing pneumonia in detail (arrowhead) (original magnification, ×4; H&E stain). (D) A photomicrograph demonstrating areas of involved parenchyma alternating with less involved parenchyma that is characteristic of UIP (original magnification, ×4; H&E stain). (E) A photomicrograph demonstrating mild subpleural interstitial fibrosis and organizing pneumonia is shown (original magnification, ×10; H&E stain); inset shows peribronchiolar metaplasia resulting from injury to the small airways (original magnification, ×10; H&E stain). (F) A photomicrograph demonstrating honeycombing in a background of dense fibrous tissue seen in UIP (original magnification, ×4; H&E stain); inset shows nonnecrotizing granulomas adjacent to a bronchiole occasionally observed in the biopsy (original magnification, ×10; H&E stain).

Figure 4.

Representative fields from lung biopsies of subjects with asymptomatic interstitial lung disease (A, C, E) and mild pulmonary fibrosis (B, D, F) are shown. A photomicrograph demonstrating hypersensitivity pneumonia-like changes is shown in (A); inset shows an area of mild chronic interstitial inflammation (arrowhead) and a poorly formed granuloma (curved arrow) adjacent to a bronchiole (original magnification, ×10; hematoxylin-and-eosin [H&E] stain). (B) Photomicrograph demonstrating the geographic heterogeneity of usual interstitial pneumonia (UIP); inset shows fibroblast foci (arrowhead) (original magnification, ×4; H&E stain). (C) A photomicrograph demonstrating patchy, temporally uniform interstitial fibrosis is shown; inset shows an area with focal organizing pneumonia in detail (arrowhead) (original magnification, ×4; H&E stain). (D) A photomicrograph demonstrating areas of involved parenchyma alternating with less involved parenchyma that is characteristic of UIP (original magnification, ×4; H&E stain). (E) A photomicrograph demonstrating mild subpleural interstitial fibrosis and organizing pneumonia is shown (original magnification, ×10; H&E stain); inset shows peribronchiolar metaplasia resulting from injury to the small airways (original magnification, ×10; H&E stain). (F) A photomicrograph demonstrating honeycombing in a background of dense fibrous tissue seen in UIP (original magnification, ×4; H&E stain); inset shows nonnecrotizing granulomas adjacent to a bronchiole occasionally observed in the biopsy (original magnification, ×10; H&E stain).

Figure 4.

Representative fields from lung biopsies of subjects with asymptomatic interstitial lung disease (A, C, E) and mild pulmonary fibrosis (B, D, F) are shown. A photomicrograph demonstrating hypersensitivity pneumonia-like changes is shown in (A); inset shows an area of mild chronic interstitial inflammation (arrowhead) and a poorly formed granuloma (curved arrow) adjacent to a bronchiole (original magnification, ×10; hematoxylin-and-eosin [H&E] stain). (B) Photomicrograph demonstrating the geographic heterogeneity of usual interstitial pneumonia (UIP); inset shows fibroblast foci (arrowhead) (original magnification, ×4; H&E stain). (C) A photomicrograph demonstrating patchy, temporally uniform interstitial fibrosis is shown; inset shows an area with focal organizing pneumonia in detail (arrowhead) (original magnification, ×4; H&E stain). (D) A photomicrograph demonstrating areas of involved parenchyma alternating with less involved parenchyma that is characteristic of UIP (original magnification, ×4; H&E stain). (E) A photomicrograph demonstrating mild subpleural interstitial fibrosis and organizing pneumonia is shown (original magnification, ×10; H&E stain); inset shows peribronchiolar metaplasia resulting from injury to the small airways (original magnification, ×10; H&E stain). (F) A photomicrograph demonstrating honeycombing in a background of dense fibrous tissue seen in UIP (original magnification, ×4; H&E stain); inset shows nonnecrotizing granulomas adjacent to a bronchiole occasionally observed in the biopsy (original magnification, ×10; H&E stain).

Figure 4.

Representative fields from lung biopsies of subjects with asymptomatic interstitial lung disease (A, C, E) and mild pulmonary fibrosis (B, D, F) are shown. A photomicrograph demonstrating hypersensitivity pneumonia-like changes is shown in (A); inset shows an area of mild chronic interstitial inflammation (arrowhead) and a poorly formed granuloma (curved arrow) adjacent to a bronchiole (original magnification, ×10; hematoxylin-and-eosin [H&E] stain). (B) Photomicrograph demonstrating the geographic heterogeneity of usual interstitial pneumonia (UIP); inset shows fibroblast foci (arrowhead) (original magnification, ×4; H&E stain). (C) A photomicrograph demonstrating patchy, temporally uniform interstitial fibrosis is shown; inset shows an area with focal organizing pneumonia in detail (arrowhead) (original magnification, ×4; H&E stain). (D) A photomicrograph demonstrating areas of involved parenchyma alternating with less involved parenchyma that is characteristic of UIP (original magnification, ×4; H&E stain). (E) A photomicrograph demonstrating mild subpleural interstitial fibrosis and organizing pneumonia is shown (original magnification, ×10; H&E stain); inset shows peribronchiolar metaplasia resulting from injury to the small airways (original magnification, ×10; H&E stain). (F) A photomicrograph demonstrating honeycombing in a background of dense fibrous tissue seen in UIP (original magnification, ×4; H&E stain); inset shows nonnecrotizing granulomas adjacent to a bronchiole occasionally observed in the biopsy (original magnification, ×10; H&E stain).

Figure 4.

Representative fields from lung biopsies of subjects with asymptomatic interstitial lung disease (A, C, E) and mild pulmonary fibrosis (B, D, F) are shown. A photomicrograph demonstrating hypersensitivity pneumonia-like changes is shown in (A); inset shows an area of mild chronic interstitial inflammation (arrowhead) and a poorly formed granuloma (curved arrow) adjacent to a bronchiole (original magnification, ×10; hematoxylin-and-eosin [H&E] stain). (B) Photomicrograph demonstrating the geographic heterogeneity of usual interstitial pneumonia (UIP); inset shows fibroblast foci (arrowhead) (original magnification, ×4; H&E stain). (C) A photomicrograph demonstrating patchy, temporally uniform interstitial fibrosis is shown; inset shows an area with focal organizing pneumonia in detail (arrowhead) (original magnification, ×4; H&E stain). (D) A photomicrograph demonstrating areas of involved parenchyma alternating with less involved parenchyma that is characteristic of UIP (original magnification, ×4; H&E stain). (E) A photomicrograph demonstrating mild subpleural interstitial fibrosis and organizing pneumonia is shown (original magnification, ×10; H&E stain); inset shows peribronchiolar metaplasia resulting from injury to the small airways (original magnification, ×10; H&E stain). (F) A photomicrograph demonstrating honeycombing in a background of dense fibrous tissue seen in UIP (original magnification, ×4; H&E stain); inset shows nonnecrotizing granulomas adjacent to a bronchiole occasionally observed in the biopsy (original magnification, ×10; H&E stain).