Mutations in the telomerase complex (TERT and TR) are associated with pulmonary fibrosis and frequent hematologic manifestations. The aim of this study was to characterize the prognosis of lung ...transplantation in patients with TERT or TR mutations.
Patients with documented TERT or TR mutations who received a lung transplant between 2007 and 2013 in France were identified via an exhaustive search of the lung transplantation network, one expert genetic laboratory, and the clinical research network on rare pulmonary diseases.
There were 9 patients (7 men) with TERT (n = 6) or TR (n = 3) mutations who received a single (n = 8) or a double (n = 1) lung transplant for pulmonary fibrosis. Median age was 50 years (range, 35-61 years) at diagnosis and 52 years (range, 37-62 years) at the time of lung transplantation. Thrombocytopenia was present in 7 patients before lung transplantation. After lung transplantation, 6 patients developed myelodysplasia and/or bone marrow failure, directly contributing to death in 4 cases. Anemia was observed in 9 patients, and neutropenia was observed in 3 patients. The median survival after lung transplantation was 214 days (range, 59-1,709 days).
Patients with mutations of the telomerase complex are at high risk of severe hematologic complications after lung transplantation, in particular, bone marrow failure. Specific recommendations should be developed for appropriate guidance regarding hematologic risk assessment before transplantation and management of the post-transplantation immunosuppressive regimen.
Since 2006 and 2007, patients in France with severe pulmonary hypertension (PH) who are at imminent risk of death, despite optimal treatment in the intensive care unit, are placed on a high-priority ...list (HPL) for heart-lung transplantation (HLT) or double-lung transplantation (DLT). We assessed the effect of this approach on the waiting list and outcomes after transplantation.
We conducted a single-center, retrospective, before-and-after study of consecutive patients with severe group 1, 1', or 4 PH listed for DLT or HLT between 2000 and 2013 (ie, 6 years before and 6 years after HPL implementation).
We included 234 patients. HPL implementation resulted in a significant decrease of the cumulative incidence of death on the waiting list at 1 and 2 years (p < 0.0001). The cumulative incidence of transplantation increased significantly from 48% to 76% after 2 years (p < 0.0001). Overall survival after transplantation was not significantly different between the pre-HPL and post-HPL era. In the HPL period, patients on the regular list who received a transplant had a nonsignificant trend toward improved overall survival compared with those on the HPL who received a transplant (at 1, 2, 3, and 5 years: 85%, 77%, 72%, and 72% vs 67%, 61%, 58%, and 50%; p = 0.053). Finally, survival after listing improved significantly after HPL implementation (at 1, 2, 3, and 5 years: 69%, 62%, 58%, and 54% vs 54%, 45%, 34%, and 26% before the HPL; p < 0.001).
HPL implementation was followed by higher survival of PH patients after registration on the DLT or HLT waiting list and by a higher cumulative incidence of transplantation among waiting-list patients.
Background Pulmonary hypertension (PH) complicating systemic sclerosis (SSc)-related interstitial lung disease (ILD) is usually associated with a poor prognosis. However, data are either lacking or ...scarce on prognostic factors in this condition. The objectives of this study were to compare the survival of patients with ILD-associated PH (PH-ILD) or pulmonary arterial hypertension (PAH) and to determine whether the severity of PH has prognostic value in SSc-associated PH-ILD. Methods Consecutive patients with SSc and PH-ILD (n = 47) or PAH (n = 50) confirmed by right-sided heart catheterization were included in a cross-sectional analysis. PH was classified as mild (mean pulmonary arterial pressure mPAP ≤ 35 mm Hg) or moderate to severe (mPAP > 35 mm Hg). Results As compared with patients with PAH, subjects with PH-ILD were younger, were more frequently men with a history of smoking, had more frequently diffuse SSc, less frequently anticentromere antibodies, and a lower FVC/diffusing capacity of lung for carbon monoxide (D lco) ratio. They had a worse prognosis than patients with PAH (3-year survival of 47% vs 71%, respectively; P = .07). Patients with mild PH-ILD had similar poor outcomes when compared with those with moderate to severe PH-ILD. Pericardial effusion (hazard ratio HR, 2.44; P = .04) and lower D lco (HR, 0.96; P = .01) were the only independent factors predictive of a poor survival in the PH-ILD group. Conclusions Patients with SSc with PH-ILD had a different phenotype and a worse prognosis than those with SSc and PAH. Lower D lco and presence of pericardial effusion were predictive of a poor outcome in PH-ILD, whereas mPAP seemed to have no prognostic significance.
Background Precapillary pulmonary hypertension (PH) is a complication of pulmonary Langerhans cell histiocytosis (PLCH) associated with increased mortality. However, outcomes and efficacy of ...pulmonary arterial hypertension (PAH) therapies in patients with PH complicating PLCH (PLCH-PH) remain unknown. Methods Consecutive patients with PLCH with PH confirmed by right-sided heart catheterization were included in the study. Characteristics at baseline and during follow-up as well as survival were analyzed. Results Twenty-nine patients were studied. Baseline characteristics of patients with PLCH-PH were as follows: 83% of patients in World Health Organization (WHO) functional class III to IV, mean 6-min walk distance of 355 ± 95 m, mean pulmonary arterial pressure (mPAP) of 45 ± 14 mm Hg, cardiac index of 3.2 ± 0.9 L/min/m2 , and pulmonary vascular resistance (PVR) of 555 ± 253 dyne/s/cm5 . Use of PAH therapy in 12 patients was followed by an improvement in mPAP (56 ± 14 mm Hg and 45 ± 12 mm Hg, P = .03) and PVR (701 ± 239 dyne/s/cm5 and 469 ± 210 dyne/s/cm5 , P = .01) between baseline and follow-up evaluations. No significant oxygen worsening was observed in the treated group. The 1-, 3-, and 5-year survival estimates of the 29 patients were 96%, 92%, and 73%, respectively. Except a trend toward a better survival rate associated with the use of PAH therapy, WHO functional class was the only variable significantly associated with death. Conclusions In this group of patients, PAH therapies improved hemodynamics without oxygen worsening or pulmonary edema. WHO functional class was the only prognostic factor identified. Prospective clinical trials focusing on this population of patients are warranted.
Bi-allelic mutations of the EIF2AK4 gene cause heritable pulmonary veno-occlusive disease and/or pulmonary capillary haemangiomatosis (PVOD/PCH). We aimed to assess the effect of EIF2AK4 mutations on ...the clinical phenotypes and outcomes of PVOD/PCH.
We did a population-based study using clinical, functional, and haemodynamic data from the registry of the French Pulmonary Hypertension Network. We reviewed the clinical data and outcomes from all patients referred to the French Referral Centre (Pulmonary Department, Hospital Kremlin-Bicêtre, University Paris-Sud) with either confirmed or highly probable PVOD/PCH with DNA available for mutation screening (excluding patients with other risk factors of pulmonary hypertension, such as chronic respiratory diseases). We sequenced the coding sequence and intronic junctions of the EIF2AK4 gene, and compared clinical characteristics and outcomes between EIF2AK4 mutation carriers and non-carriers. Medical therapies approved for pulmonary arterial hypertension (prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase type-5 inhibitors) were given to patients according to the clinical judgment and discretion of treating physicians. The primary outcome was the event-free survival (death or transplantation). Secondary outcomes included response to therapies for pulmonary arterial hypertension and survival after lung transplantation. A satisfactory clinical response to specific therapy for pulmonary arterial hypertension was defined by achieving New York Heart Association functional class I or II, a 6-min walk distance of more than 440 m, and a cardiac index greater than 2·5 L/min per m
at the first reassessment after initiation of specific therapy for pulmonary arterial hypertension.
We obtained data from Jan 1, 2003, to June 1, 2016, and identified 94 patients with sporadic or heritable PVOD/PCH (confirmed or highly probable). 27 (29%) of these patients had bi-allelic EIF2AK4 mutations. PVOD/PCH due to EIF2AK4 mutations occurred from birth to age 50 years, and these patients were younger at presentation than non-carriers (median 26·0 years range 0-50.3 vs 60·0 years 6·7-81·4 years; p<0·0001). At diagnosis, both mutations carriers and non-carriers had similarly severe precapillary pulmonary hypertension and functional impairment. 22 (81%) of mutations carriers and 63 (94%) of non-carriers received therapy approved for pulmonary arterial hypertension. Drug-induced pulmonary oedema occurred in five (23%) of treated EIF2AK4 mutations carriers and 13 (21%) of treated non-carriers. Follow-up assessment after initiation of treatment showed that only three (4%) patients with PVOD/PCH reached the predefined criteria for satisfactory clinical response. The probabilities of event-free survival (death or transplantation) at 1 and 3 years were 63% and 32% in EIF2AK4 mutations carriers, and 75% and 34% in non-carriers. No significant differences occurred in event-free survival between the 2 groups (p=0·38). Among the 33 patients who had lung transplantation, estimated post-transplantation survival rates at 1, 2, and 5 years were 84%, 81%, and 73%, respectively.
Heritable PVOD/PCH due to bi-allelic EIF2AK4 mutations is characterised by a younger age at diagnosis but these patients display similar disease severity compared with mutation non-carriers. Response to therapy approved for pulmonary arterial hypertension in PVOD/PCH is rare. PVOD/PCH is a devastating condition and lung transplantation should be considered for eligible patients.
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