Prognostic Significance of Pulmonary Function Test Abnormalities in Patients with Dyskeratosis Congenita

Introduction: Pulmonary fibrosis (PF) is a known complication in patients with dyskeratosis congenita (DC), reported in 15-20% of patients. PF is more common in older individuals with DC who may or may not have the classical clinical features of DC. PF in younger DC patients has been reported mainly in the setting of hematopoietic cell transplantation (HCT). There are no prospective studies of pulmonary function tests (PFT) in patients with DC.

Objectives: To determine baseline pulmonary function status in patients with DC, association of PFT abnormalities with development or progression of pulmonary disease, and pulmonary outcomes in patients who did or did not receive HCT.

Methods: DC patients older than 5 years of age underwent PFTs as part of a prospective IRB-approved cohort study at the NIH from 2002-2015. Data were obtained from spirometry [forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC)], lung volumes [total lung capacity (TLC)] and carbon monoxide diffusion capacity (DLCO). PFT abnormalities were classified as restrictive (normal FEV1/FVC and low TLC), obstructive (low FEV1/FVC and normal TLC) or mixed (low FEV1/FVC and low TLC) according to the American Thoracic Society Task Force guidelines. A low value was < lower limit of normal adjusted for age, sex, race and height. DLCO was also adjusted for hemoglobin. PFT data were analyzed in relation to the DC triad (nail dystrophy, skin pigmentation, leukoplakia), severe bone marrow failure (BMF needing treatment) and telomere length by flow FISH. Patients were followed through 2015. Pulmonary outcomes were compared in those with or without PFT abnormalities at evaluation and in those who did or did not receive HCT. P value <0.05 was significant.

Results: Fifty-one patients with DC had PFTs, median age 19 yrs (range 6 - 69). Spirometry was abnormal in 16 patients (31%): 13 had restriction, 2 had obstruction, and 1 had a mixed pattern. DLCO was reduced (<80% of the predicted) in 32/49 patients (65%): 17 had mild (>60%), 13 had moderate (40-60%) and 2 had severely reduced (<40%) DLCO. All patients with abnormal spirometry had reduced DLCO compared with 18/35 (48%) with normal spirometry (p<0.0001). Patients with abnormal spirometry were more likely to have moderate/severe diffusion defects (10/16 vs 5/35; p=0.02), and severe BMF (12/16 vs 10/35; p=0.003) than those with normal spirometry. Telomere length and 2 or more features of the DC triad were not associated with PFT abnormality.

Fourteen patients (27%) developed pulmonary disease at a median follow-up of 6 yrs (range 0.1 - 12 yrs) and a median age of 17 yrs (11 - 65): 10 had PF with interstitial honeycomb pattern on chest CT and 4 had pulmonary arteriovenous malformation (AVM) and mild fibrosis. Patients with abnormal spirometry and moderate/severely reduced DLCO were more likely to develop pulmonary disease than those with normal spirometry (12/16 vs 2/35; p<0.0001). Fourteen patients received a HCT (3 prior to and 11 after PFT evaluation) at a median age of 12 yrs (range 3 - 29). Eight of the 14 (57%) developed pulmonary disease 1 - 5 yrs after HCT (median 4 yrs) while 6/37 (16%) non-HCT patients developed PF (p=0.01). Transplanted patients developed pulmonary disease at a younger age than non-transplanted (median age 15 yrs, range 11 - 22 vs 54 yrs, 25 - 65; p=0.001), and had mutations in TINF2 (n=3), RTEL1, DKC1, WRAP53 (1 each); gene unknown (n=2). DC genes mutated in older non-HCT patients with PF were TERC (n=4), TERT (n=1), and unknown (n=1). The independent impact of severe DC phenotype, BMF, and HCT on pulmonary outcome could not be distinguished in young patients as most patients with severe disease had BMF and received HCT. There was no difference in PF among those who did or did not receive radiation for HCT. Four of the 10 deaths were due to PF.

Conclusion: More than 30% of patients with DC have restriction and moderate/severe diffusion defect on PFTs, and these are more common in patients with severe BMF. PFT abnormalities are significantly associated with progression to PF, although they may also signal the presence of AVMs, a less common pulmonary manifestation of DC. PF in older patients is a known manifestation of the telomere biology disorder. It is unclear whether pulmonary disease in young patients is a feature of severe DC or the toxicity of HCT preparative regimens. Larger prospective studies are needed to confirm the predictive value of PFTs for future lung disease in patients with DC.