Possible Value of Antifibrotic Drugs in Patients With Progressive Fibrosing Non-IPF Interstitial Lung Diseases

Sebastiano Emanuele Torrisi; Nicolas Kahn; Julia Wälscher; Nilab Sarmand; Markus Polke; Kehler Lars; Monika Eichinger; Claus Peter Heussel; Stefano Palmucci; Francesca Maria Sambataro; Gianluca Sambataro; Domenico Sambataro; Carlo Vancheri; Michael Kreuter


BMC Pulm Med. 2019;19(213) 

In This Article


Eleven patients were included in the analysis. Eight were males (72.72%) and 3 were females (27.27%). There were 5 former smokers (45.45%) and 6 never-smokers (54.54%). The mean age was 62.09 ± 12.80 and 63.72 ± 12.72 years at diagnosis and at antifibrotic initiation respectively. The mean FVC % predicted was 62.82 ± 22.30 while the mean DLCO % predicted was 35.55 ± 10.74 before initiation of the antifibrotic therapy. The mean TORVAN index was 17.18 ± 5.13. Patients were followed for a median follow-up time of 16.6 months before and 11.1 months under antifibrotic treatment. Visual assessment of HRCT findings at baseline is showed in Table 1 while Figure 1 reports automatic histogram-based assessment of 40th and 80th percentiles over the time. According to this result, a significant increase of both indices was observed before antifibrotic initiation followed by a stabilization. Bronchial alveolar lavage was performed in 8 cases before immunosuppressive therapy demonstrating a predominant neutrophilia (12%) in 4 cases, a notable eosinophilia (10%) in one case and no significant lymphocytosis.

Figure 1.

Change in the percentiles (Hounsfield units) of attenuation histogram over the time. Panel a demonstrates change in the 40th percentiles while panel b demonstrates change in the 80th percentiles

Transbronchial cryobiopsy was performed in 9 patients (81.8%). After a multidisciplinary team discussion, patients were classified as unclassifiable-ILD in 6 cases, pleuroparenchymal fibroelastosis (PPFE) in 2 cases, idiopathic-NSIP in 1 case, asbestos-related ILD in 1 case and Hermansky-Pudlak syndrome in 1 case. Of these, three patients may be also considered as interstitial pneumonia with autoimmune features (IPAF) according to established criteria (Table 2).[20] Treatment before antifibrotic drug initiation consisted of corticosteroids (prednisone mean dosage 16.8 ± 11.1 mg/die) in all patients: 5 combined with Azathioprin (150 mg/die), 1 with either methotrexate (7,5 mg/week) or cyclophosphamide (1000 mg i.v. per cycle) (Table 1). After a proven clinical and functional progression, ten patients were treated with pirfenidone (2403 mg/die) and 1 with nintedanib (300 mg/die). Of the 11 patients, 6 continued prednisone (5 mg/die) for a mean time of 8.5 months and 2 continued Azathioprin for a mean time of 4 months after antifibrotic initiation. Median time of antifibrotic treatment was 11.1 (5.2, 14) months.

Median FVC was 56% (2.29 L), 56% (2.07 L), 50% (1.95 L), at time points − 24, − 12, − 6 before initiation, 44% (1.59 L) at time of initiation and 46.5% (1.77 L) at 6 months after initiation of antifibrotic treatment. Median FVC difference was significant between − 12 and − 6 months before initiation (p = 0.004) and also between − 6 and time of initiation (p = 0.005), while no further significant decline was reported between time of initiation and + 6 months (p = 0.17). This last result was obtained comparing data of only eight patients as three patients died before this time due to respiratory failure (Figure 2). Antifibrotic drugs were generally well tolerated. Mean dosage of pirfenidone was 2242 ± 337 mg·day− 1, while for the patient treated with nintedanib mean dosage was 300 mg·day− 1. A dose reduction was needed in 2 cases under pirfenidone treatment: one for rash (case 3) and the other for nausea (case 9), while an early termination was needed in 3 cases due to death following respiratory failure (Table 2). Only one patient experienced acute exacerbations after antifibrotics initiation. Median survival time was 11.1 months since antifibrotic drug initiation (Figure 3).

Figure 2.

Change in FVC % predicted over the time. Footnotes: *this median difference was calculated comparing data of only eight patients as three patients died before the 6 months of follow-up since antifibrotics initiation

Figure 3.

One-year survival of PF-ILD compared to a cohort of 257 IPF patients collected in our center