Lung transplantation in telomerase mutation carriers with pulmonary fibrosis

Abstract

Lung transplantation is the only intervention that prolongs survival in idiopathic pulmonary fibrosis (IPF). Telomerase mutations are the most common identifiable genetic cause of IPF, and at times, the telomere defect manifests in extrapulmonary disease such as bone marrow failure. The relevance of this genetic diagnosis for lung transplant management has not been examined. We gathered an international series of telomerase mutation carriers who underwent lung transplant in the U.S.A., Australia and Sweden. The median age at transplant was 52 years. Seven recipients are alive with a median follow-up of 1.9 years (range 6 months to 9 years); one died at 10 months. The most common complications were haematological, with recipients requiring platelet transfusion support (88%) and adjustment of immunosuppressives (100%). Four recipients (50%) required dialysis for tubular injury and calcineurin inhibitor toxicity. These complications occurred at significantly higher rates relative to historic series (p<0.0001). Our observations support the feasibility of lung transplantation in telomerase mutation carriers; however, severe post-transplant complications reflecting the syndromic nature of their disease appear to occur at higher rates. While these findings need to be expanded to other cohorts, caution should be exercised when approaching the transplant evaluation and management of this subset of pulmonary fibrosis patients.

Figure 1–

Telomerase mutations in lung transplant subjects fall in conserved domains of telomerase reverse transcriptase (TERT) and telomerase RNA (TR). a) Organisation of conserved reverse transcriptase motifs (boxed) with mutations indicated above (n=5). b) TR mutations fall in the P1b and P3 helices within the secondary structure and are near the template-containing pseudoknot domain. Both are predicted to disrupt Watson-Crick base pairing and thus TR stability.

Figure 2–

Post-transplant complications of telomere syndrome cases. a) Telomere length by flow cytometry and fluorescence in situ hybridisation shows significant shortening relative to age-matched controls (TERT, n=2; TR, n=2; clinical telomere syndrome n=1). The telomere length nomogram is based on 400 controls. b) Pre-transplant platelet counts show a majority of patients had thrombocytopenia (<150×10³ platelets mm⁻³). Post-transplant, platelet counts drop further and in several cases into a range that increases the risk of bleeding (<50×10³ platelets mm⁻³). Post-transplant nadir is defined as within the first two weeks. c) Computed tomography image showing cavitary left lung lesion in a patient with pulmonary aspergillosis at 9 months post-transplant. d) Lung histopathology from autopsy in a subject who died from complications of cytomegalovirus pneumonitis. The photomicrograph shows evidence of diffuse alveolar haemorrhage and multiple viral intranuclear inclusions. e and f) Renal biopsies of two individuals who required prolonged dialysis showing tubular irregularity and epithelial cytoplasmic vacuolisation; these findings are highly consistent with calcineurin inhibitor toxicitiy. Biopsies were obtained at 4 months (e) and 10 months (f) post-dialysis, the latter at the time of autopsy. g) Colon biopsy from individual who developed ischaemic colitis on mycophenolate shows extensive puss, crypt dropout and apoptosis. h) Colon biopsy from the same individual 5 weeks after mycophenolate was discontinued shows resolution of the puss, but residual crypt dropout and epithelial apoptosis similar to histological findings described in other telomere syndrome cases and consistent with an underlying telomere-mediated enteropathy.

Figure 3–

Clinical considerations for a) suspecting and b) evaluating patients with pulmonary fibrosis who may have telomere syndromes.