Aims Patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotic medication and patients with non-IPF fibrosing lung disease often demonstrate rates of annualised forced vital capacity (FVC) decline within the range of measurement variation (5.0%-9.9%). We examined whether change in visual CT variables could help confirm whether marginal FVC declines represented genuine clinical deterioration rather than measurement noise. Methods In two IPF cohorts (cohort 1: n=103, cohort 2: n=108), separate pairs of radiologists scored paired volumetric CTs (acquired between 6 and 24 months from baseline). Change in interstitial lung disease, honeycombing, reticulation, ground-glass opacity extents and traction bronchiectasis severity was evaluated using a 5-point scale, with mortality prediction analysed using univariable and multivariable Cox regression analyses. Both IPF populations were then combined to determine whether change in CT variables could predict mortality in patients with marginal FVC declines. Results On univariate analysis, change in all CT variables except ground-glass opacity predicted mortality in both cohorts. On multivariate analysis adjusted for patient age, gender, antifibrotic use and baseline disease severity (diffusing capacity for carbon monoxide), change in traction bronchiectasis severity predicted mortality independent of FVC decline. Change in traction bronchiectasis severity demonstrated good interobserver agreement among both scorer pairs. Across all study patients with marginal FVC declines, change in traction bronchiectasis severity independently predicted mortality and identified more patients with deterioration than change in honeycombing extent. Conclusions Change in traction bronchiectasis severity is a measure of disease progression that could be used to help resolve the clinical importance of marginal FVC declines.

Background The diagnostic classification “possible idiopathic pulmonary fibrosis (IPF)” is characterised by an inconsistent usual interstitial pneumonia (UIP) pattern on HRCT-scan and a UIP pattern in surgical lung biopsy. Therapeutic management in patients with “possible IPF” is challenging. The clinician must choose between either immunomodulatory agents or anti-fibrotic agents, but evidence is lacking. Methods A multi-centre cohort of 59 patients with “possible IPF” treated with prednisone were retrospectively analysed. Prednisone starting dose was 0.5 mg/kg/day and tapered to 0.15 mg/day/kg in six months. Patient demographics and serious adverse events (SAEs), defined as death and hospital admissions, were collected. Forced vital capacity (FVC) before start of therapy, baseline (start of therapy) and six months after start of therapy were evaluated. Results In 59 prednisone treated “possible IPF” patients, 22% had a SAE: twelve in the first three months on prednisone u003e0.3mg/kg/day and two during the last three months on 5% decrease or death within six months from baseline. Six former smoking patients with an additional histopathological desquamative interstitial pneumonia (DIP) component besides UIP, were responders with a mean increase of 6% FVC. Conclusions Patients with “possible IPF” demonstrated accelerated FVC decline and high incidence of SAEs during high dosed prednisone treatment. Presence of concomitant DIP histopathological pattern is associated with responsiveness to prednisone treatment.

Idiopathic Pulmonary Fibrosis (IPF) is a fatal lung disease, histologically characterized by diffuse interstitial remodeling and patchy inflammation. A significant percentage of IPF patients have a familial form of the disease. Separate reports have identified mutations in Surfactant Protein-C (SFTPC), Surfactant Protein-A2 (SFTPA2), Telomerase Reverse Transcriptase (TERT) or Telomerase RNA component (TERC) in these families. We determined the frequency of mutations in SFTPC, SFTPA2, TERT and TERC in 20 patients with Familial Pulmonary Fibrosis (FPF). Heterozygous non-tolerated sequence changes were detected in 12 out of 20 patients, consisting of 5 SFTPC, 2 SFTPA2 and 5 TERT mutations. Mutations segregated with disease in each family and haplotype analysis showed that identical mutations had arisen independently. Families with SFTPC and SFTPA2 mutations always had evidence of parent-offspring disease transmission, while in families with TERT mutation sibs were affected. Pediatric pulmonary disease occurred only in families with SFTPC mutations. Carriers of an SFTPA2 mutation also suffered from lung cancer. Families with a TERT mutation usually presented as typical IPF and did not show clear symptons associated with other known syndromes of telomere shortening. This is the first report of a cohort of IPF families that is completely sequenced for candidate genes. We could identify a mutation in 60% of patients with FPF. These mutations correlated with a specific disease phenotype. The function of each of the mutated genes is very different, but all indicate towards a central role for the alveolar type II cell in disease pathogenesis.