Pleuroparenchymal fibroelastosis associated with telomerase reverse transcriptase mutations

To the Editor:

We read with great interest the article by Newton et al. [1]. They found that mutations in the telomere maintenance machinery genes (telomerase reverse transcriptase (TERT), telomerase RNA component (TERC), regulator of telomere elongation helicase 1 and poly(A)-specific ribonuclease) led to variable interstitial lung disease (ILD) phenotypes that were universally progressive [1]. We were particularly interested by the evidence for the first time in the literature of a telomere-related gene mutation associated with pleuroparenchymal fibroelastosis (PPFE). PPFE represented eight out of the 77 (10.4%) cases with genetic aberrations, which is intriguing compared with the rarity of disease among ILDs. Indeed, a possible familial propensity for the development of PPFE was originally suggested by our earlier report of three affected sisters [2]. According to other published studies, a family history of ILD is observed in 17–57% of PPFE patients [3–5].

Similarly, from 2006 to 2015, 12 patients with a diagnosis of PPFE were referred to our department for further advice; of these, 10 were investigated for TERT and TERC mutations. TERT mutations were identified in five (50%) cases (table 1). Noticeably, a patient with a history of “pulmonary fibrosis” in his sister, chronic liver disease and unexplained cardiomyopathy, was negative for TERT and TERC but was not tested for regulator of telomere elongation helicase 1 and poly(A)-specific ribonuclease. As in the article, our study included a preponderance of females (four out of five) (age 41–63 years). Three patients had a familial background of ILD, all had a low body mass index (mean 18.8 kg·m⁻²), and pneumothorax or pneumomediastinum occurred in four cases. The delay between ILD and PPFE diagnosis was quite long, ranging 14–45 months. High-resolution computed tomography (HRCT) was typical of PPFE in all cases, and was pathologically confirmed in four patients (three surgical lung biopsy (SLB), one lung explant). Our patients had rapidly progressive fibrosis, with a mean decline in diffusing capacity of the lung for carbon monoxide of 6.1% per year and a decline in forced vital capacity (FVC) of 3.7% per year. At the end of follow-up, two patients were transplanted without major haematological complications and one succumbed to an acute exacerbation following video-assisted thoracoscopy performed for pleurodesis and SLB. One untreated patient is doing well and the other continues to progress under pirfenidone. Regarding the non-mutated patients, one was transplanted, two had stable pulmonary function, and two died from terminal respiratory failure. There was no difference between groups in the mean yearly decline in FVC (−3.7% in the mutated patients versus −2.6% in the non-mutated; p=0.4).

Our data are consistent with those of Newton et al. [1] and suggest the importance of searching telomere-related gene mutations in patients with PPFE even without a family history of ILD. These findings also raise pathogenic questions.

Interestingly, two patients presented Sjögren's syndrome. Autoimmune features have already been described in PPFE [4]. Data indicate that both telomerase activity and telomerase length are modified in various systemic immune-mediated diseases, including Sjögren's syndrome [8, 9]. Accelerated telomeric erosion in immune cells resulting from inflammation could lead to premature cellular senescence and increased apoptosis, responsible for a loss of control of the immune system [8]. One may hypothesise that telomerase mutation could favour autoimmune diseases like Sjögren's syndrome.

Although pleuroparenchymal changes were typical of PPFE, with an obvious predilection for upper lobes, it is remarkable that four of our patients also demonstrated a minor interstitial fibrosis in the lower regions at HRCT, with a pathological pattern most reminiscent of usual interstitial pneumonia (UIP) in the lower parts at SLB in three patients. In a study of 12 PPFE patients by Reddy et al. [4], all seven cases with multiple biopsies showed a pattern of pathological involvement in the lower lobes, which was noted upon HRCT and corresponded with UIP in three cases. Similarly, in the study by Oda et al. [10], nine out of 11 patients meeting radiological criteria for the diagnosis of PPFE were histologically confirmed as having PPFE with UIP, including three with a family history of ILD. However, our patients and those previously reported have shown a disease presentation clearly distinct from idiopathic pulmonary fibrosis.

It is as yet unclear whether elastosis and the more common collagen fibroproliferation are distinctive pathways of chronic scarring, and whether they may reflect discrete responses to primarily different lung damages or in differently susceptible subjects. A Brazilian group has demonstrated that elastic deposition accompanies collagen deposition in the major forms of acute and chronic idiopathic interstitial pneumonias [11]. Hirota et al. [12] have analysed serial lung biopsies from four PPFE patients and suggested that prior interstitial inflammation or acute lung injury may be the primum movens of disease. Enomoto et al. [13] have indicated that the amount of elastic fibres is significantly reduced in the lower than in the upper lobes in PPFE as well as in UIP. Furthermore, Miele et al. [14] described a spontaneous pulmonary fibrosis in aged donkeys that shared similarities with human PPFE with a localised fibrosis in the uppermost and dorsal zones. In addition, PPFE features overlap with those of apical caps, the prevalence of which increases in the elderly and may be related to microscopic tears in tissue substructure caused by the weight of the lung itself [15].

Taken together, these data suggest that the extracellular matrix, when exposed to lung injury, responds as a whole with remodelling of all its components. Patients with telomere-related gene mutation may be predisposed to tractional injury to the peripheral lung [16]. During the extracellular matrix remodelling process, the differential degree of elastosis reaction and collagen fibroproliferation between the upper and lower lobes may be due to the fact that the lung zones are subjected to different mechanical strains, with upper development of PPFE and concomitant or subsequent development of UIP in the bases.