Blood abnormalities are frequent in patients with TRG mutations: 17–27%, of the patients with TRG mutations and pulmonary brosis present with anemia, 24–41% with macrocytosis, and 8–54% with thrombocytopenia [17, 32]. DKC1, TINF2, and TERC mutations may be more frequently associated with hematological involvement than TERT or RTEL1 mutations [17, 33].

Liver Involvement

Elevated liver enzyme levels or overt liver involvement are detected in 5%–27% of patients with ILD and TRG mutations [17, 32]. Carriers of TRG mutations may present with cryptogenic or secondary liver cirrhosis. In a series of 86 patients who received liver transplantation, 17(20%) had probably deleterious variants of one TRG (based on in silico analyses), though the pathogenicity of the variants was not con rmed. The presence of any TRG variant was associated with an increased number of readmissions within 1 year after liver transplantation (OR = 3.15; 95% CI, 1.22–8.57), but no association with survival was observed [64].

Hepatic manifestations may vary in relatives with the same mutation, from normal to isolated elevation of liver enzyme serum levels, to variable degrees of necrosis, infammation, brosis, and regeneration on liver histology [65]. Among six patients with hepatopulmonary syndrome, the most common histological diagnosis was nodular regenerative hyperplasia (n = 4/6). From the same series, two patients received liver transplantation, but lung brosis developed 18 months and 12 years later, respectively [46].

Other Manifestations

Other manifestations that have been associated with TRG mutations include exudative retinopathies, central neurological disease and cerebral calci cations, gastrointestinal bleeding, radiation sensitivity, infertility, osteoporosis, or renal insuf ciency [54]. With respect to the latter, whole exome sequencing in a cohort of 92 patients with chronic kidney disease of unknown cause identi ed loss-of-function mutations in PARN in 2 probands with tubulointerstitial brosis [66].

Treatment

Antifbrotic Therapy

One post hoc analysis and one retrospective study have been reported on safety and ef cacy of pirfenidone in patients with TRG mutations [28, 67]. A European multicentric retrospective study of 33 patients did not show a bene cial effect of pirfenidone on lung function decline. In fact, decline of FVC was 161.8 ± 31.2 mL/year before treatment and 235.0 ± 49.7 mL/year after pirfenidone initiation [67]. A post hoc analysis of two prospective phase

3 clinical trials (CAPACITY, ASCEND) identi ed 102 patients carriers of rare TRG variants in the IPF cohorts. Those TRG variant positive patients had a more rapid decline in FVC than patients without a rare variant (1.66% vs. 0.83% per month), and pirfenidone reduced the decline of FVC in this subgroup with severe disease [28]. A recent retrospective study con rmed safety and ef cacy of pirfenidone and nintedanib in patients with TRG mutations [68]. In linear mixed effects model, the mean FVC decline was 39 mL per month (95% CI 23–55 mL per month) before treatment, and 22 mL per month (95% CI 17–28 mL per month) in the next 30 months after treatment initiation (p = 0.026) [68].

Telomerase Complex Agonists

Danazol is a synthetic sex hormone with androgenic properties that induces telomerase complex activation in laboratory studies. In a 2-year prospective study of 10 patients with “overt” pulmonary brosis and 15 patients with “subclinical”­

pulmonary brosis, danazol therapy was associated with a stabilization of diffusing capacity of the lung for CO (DLCO), FVC and CT scan ndings [16]. Moreover, treatment with danazol was associated with telomere elongation and a bene-cial hematological response in 79% of the patients (19/24). However, danazol therapy is associated with liver adverse effects and an increased risk of venous thrombosis. A phase I/ II trial (ANDROTELO, NCT03710356) with danazol is ongoing in France, including carriers of a TRG mutation with lung brosis and/or severe hematologic involvement.

Lung Transplantation

Lung transplantation is often discussed in FPF because of the young age of ILD onset in many patients. Five retrospective series reported the outcome of lung transplantation in TRG mutation carriers [53, 69–72]. Hematologic toxicity is a signi cant concern and requires an adjustment of immunosuppression in most patients. Myelodysplastic syndrome or bone marrow failure occurred in some patients and thrombocytopenia requiring platelet transfusion was frequent [69, 70]. In a cohort of 262 lung transplant patients, patients with TERT, RTEL¸ or PARN mutation (n = 31, 11.8%) were recently reported to have a reduced post-transplantation survival (HR = 1.82: 95%CI [1.07–3.08], p = 0.03]) and higher risk of CLAD (HR = 2.88; 95%CI [1.42–5.87], p = 0.004) [72], though this retrospective study did not reveal a higher risk of hematological complication or renal insuf ciency in TRG mutation carriers [72]. Interestingly short telomeres and mutations of TRG have been associated with increased prevalence of CMV infection after lung transplantation [53].

Moreover, in an independent cohort, patients with telomere length less than the tenth percentile before transplant were reported to have a worse survival and also a shorter