Mortality on the Waiting List for Lung Transplantation
in Patients with Idiopathic Pulmonary Fibrosis: A Single-Centre
Experience
David Bennett1•Antonella Fossi1•Elena Bargagli1• Rosa Metella Refini1• Maria Pieroni1•Luca Luzzi2•Claudia Ghiribelli2•Piero Paladini2• Luca Voltolini2• Paola Rottoli1
Received: 6 May 2015 / Accepted: 19 July 2015 Ó Springer Science+Business Media New York 2015
Abstract
Purpose Lung transplantation (LTX) is nowadays accepted as a treatment option for selected patients with end-stage pulmonary disease. Idiopathic pulmonary fibrosis (IPF) is characterized by the radiological and histologic appearance of usual interstitial pneumonia. It is associated with a poor prognosis, and LTX is considered an effective treatment to significantly modify the natural history of this disease. The aim of the present study was to analyse mortality during the waiting list in IPF patients at a single institution.
Methods A retrospective analysis on IPF patients (n = 90) referred to our Lung Transplant Program in the period 2001–2014 was performed focusing on patients’ characteristics and associated risk factors.
Results Diagnosis of IPF was associated with high mor-tality on the waiting list with respect to other diagnosis (p \ 0.05). No differences in demographic, clinical, radi-ological data and time spent on the waiting list were observed between IPF patients who underwent to LTX or lost on the waiting list. Patients who died showed signifi-cant higher levels of pCO2and needed higher flows of O2
-therapy on effort (p \ 0.05). Pulmonary function tests failed to predict mortality and no other medical conditions were associated with survival.
Conclusions Patients newly diagnosed with IPF, espe-cially in small to medium lung transplant volume centres and in Countries where a long waiting list is expected, should be immediately referred to transplantation, delay results in increased mortality. Early identification of IPF patients with a rapid progressive phenotype is strongly needed.
Keywords Idiopathic pulmonary fibrosis Usual interstitial pneumonia Lung transplant Mortality Waiting list
Abbreviations
IPF Idiopathic pulmonary fibrosis UIP Usual interstitial pneumonia LTX Lung transplantation
Introduction
Lung transplantation (LTX) is nowadays accepted as a justified treatment option for selected patients with end-stage pulmonary disease, such as emphysema, cystic fibrosis (CF), pulmonary fibrosis and pulmonary arterial hypertension, who are not or no longer responding to maximal medical therapy, or for whom no effective med-ical or surgmed-ical therapy exists [1,2]. Surgical technique has been consolidated over the years and it does not represent a relevant issue anymore; however, long-term survival is still challenging and BOS represents the principal cause of
& David Bennett david.btt@gmail.com
1 Respiratory Diseases and Lung Transplantation Unit, Internal
and Specialist Medicine Department, Azienda Ospedaliera Universitaria Senese (AOUS), Viale Bracci n° 16, 2nd Floor, 3rd Building, 53100 Siena, Italy
2 Thoracic Surgery Unit, Cardio-Thoracic-Vascular
Department, Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy
death after LTX [3]. Mortality in the waiting list is a major problem and the current survival in end-stage patients awaiting LTX is less than 70–80 %, mainly because lack of donors and late patient referring [1].
Idiopathic pulmonary fibrosis (IPF) is defined as a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown cause with radiological and his-tologic appearance of usual interstitial pneumonia (UIP). It is the most common among the idiopathic interstitial pneumonias (IIPs), occurs primarily in older adults and is characterized by a progressive worsening of dyspnoea and loss of lung function with a very poor prognosis: median survival time is from 2.5 to 3.5 years. Natural history is unpredictable at the time of the diagnosis; the majority of patients demonstrate a gradual progression over time, but others may have an accelerated decline. All IPF patients may experience episodes of acute respiratory worsening that have been termed ‘‘acute exacerbation’’ [4]. Specific comorbidities such as emphysema and pulmonary hyper-tension (PH) impact the disease course [5, 6]. Significant improvements in pharmacological therapy of IPF have been reached in the last years [7–9]. Two new molecules have demonstrated a significant benefit in IPF patients: Pirfenidone, already commercially available in Europe, Japan and India, recently has been approved also from the US FDA [7,8]; Nintedanib, an intracellular inhibitor that targets multiple tyrosine kinases, proved to slow IPF pro-gression [9]. Despite advancing in medical therapy, LTX remains the greatest opportunity for selected IPF patients, with five-year survival rates estimated from 50 to 56 % [4,
10]. IPF is one of the three major LTX indications together with CF and COPD [2], and since the lung allocation score (LAS) introduction it became the first indication in the US [11]. There are no clear criteria to guide precise timing of transplantation, although recommendations have been proposed based on diffusion capacity and/or evidence of progressive disease [1].
The aim of the present study was to analyse mortality during the lung transplant waiting list in IPF patients, focusing on patients’ characteristics and associated risk factors.
Methods
Study SubjectsWe conducted a retrospective analysis on all patients referred to the Lung Transplant Program of the Azienda Ospedaliera Universitaria Senese (AOUS), Siena, Italy, from 2001 to December 2014. 186 patients have been listed in our waiting list; all patients were evaluated at the Res-piratory Disease and Lung Transplant Unit. Diagnosis of IPF was performed according to the actual diagnostic
criteria of the ATS/ERS/JRS/ALAT guidelines and retro-spectively re-evaluated in all patients that came to our observation before guidelines publication [4]. Of all IPF patients included in this study, clinical, functional and radiological data were collected at the time of joining the waiting list, and analysed to identify risk factors and pre-dictors of mortality. Informed consent was obtained from all individual participants included in the study. IPF patients were divided into two groups: patients who underwent to LTX (Group 1) and patients who died while in the waiting list (Group 2). Furthermore, patients were classified according to GAP index [12].
Statistical Analysis
Statistical analysis was performed by GraphPad Prism v 6.0 and SPSS v 16.0. Difference with p \ 0.05 was considered significant. Non-parametric tests were applied; difference between two groups was studied by Mann–Whitney’s test, while analysis of the variance was made by Kruskal–Wallis’ test. Difference of prevalence on contingency tables was analysed by Fisher’s test or Chi square. Data were expressed as mean ± standard deviation.
Results
In the considered period, 186 patients were listed for LTX at our Centre: 108 were affected by pulmonary fibrosis (90 patients with IPF, 83.3 % of all pulmonary fibrosis patients), 32 by COPD, 30 by CF and 16 patients by other conditions. Listed N=186 (90 pts with IPF) Active list N=22 (15 pts with IPF) Lung Transplants N=115 (42 pts with IPF) Single LTx N=61 (35 pts with IPF) Bilateral LTx N=54 (7 pts with IPF) Mortality in waiting list N=49 (33 pts with IPF)
Fig. 1 Global number of patients (and specific number with IPF) who have been listed, underwent to lung transplant (single and bilateral LTX), died awaiting LTX and on active list at our Lung Transplant Program at time of analysis
115 lung transplants were performed (71 male and 44 female; age at LTX 51.4 ± 12.0 years; 54 bilateral LTX, 61 single LTX); the principal indication (58/115, 50.5 %) was pulmonary fibrosis (42 patients were affected by IPF, 72.4 % of all pulmonary fibrosis patients), followed by COPD (20.8 %), CF (18.2 %) and other diseases (10.5 %). In Fig.1global number of patients (and specific number with IPF) who
– have been listed;
– underwent to lung transplants; – died awaiting LTX;
– on active list at our Lung Transplant Program is reported.
IPF patients referred to our Centre (n = 90) were classified into two groups: Group 1, patients who have been transplanted (n = 42); Group 2, patients who died while in waiting list (n = 33). 15 IPF patients were on active list at time of analysis.
Significantly higher mortality rate on the waiting list was observed for IPF patients (44 %), compared to COPD (24 %) and CF (10.5 %) (p \ 0.05). No differences in demographic, clinical and radiological data were observed among IPF patients between Group 1 and Group 2 (Table1). Time spent in the waiting list was not signifi-cantly different, but a signifisignifi-cantly higher number of patients in Group 2 (71.4 %) were referred to our Lung Transplant Program from other hospitals and were not previously followed at our Regional Referral Centre for Sarcoidosis and other Interstitial Lung Diseases (p = 0.05). The number of patients with chronic respira-tory failure requiring long-term oxygen therapy (LTOT) was not different between Group 1 and 2 (46.1 % vs. 54.1 %). Arterial blood gas analysis (ABG) showed sig-nificantly higher levels of pCO2 (37.8 ± 3.4 vs. 43.3 ± 3.5 mmHg) in Group 2 patients (p = 0.006). Pulmonary function tests (PFTs) and diffusion lung capacity for carbon monoxide (DLCO) were not different
Table 1 Demographic, arterial blood gas analysis (ABG), pulmonary functional tests (PFTs), 6-min walking test (6-MWT), right heart
catheterization (RHC) data and GAP index from patients with IPF who underwent to LTX (Group 1) and died while in the waiting list (Group 2)
Variables Group 1 Group 2 Significance (p)
N 42 33
Age (years) 57.2 ± 6.5 58.6 ± 6.6 0.24 Sex (male) 34 (80.8 %) 18 (64.2 %) 0.59 Tobacco use 10.4 ± 12.8 11.2 ± 13.4 0.79 Time in waiting list (days) 239.1 ± 206.5 312.6 ± 253.4 0.12 LTOT 24 h 20 (47.6 %) 18 (54.5 %) 0.64 ABG pH 7.44 ± 0 7.42 ± 0 0.36 pO2(mmHg) 72.5 ± 10.0 66.5 ± 10.7 0.26 pCO2(mmHg) 37.8 ± 3.4 43.3 ± 3.5 0.006 PFTs FVC, % pred. 50.4 ± 17.0 51.8 ± 23.3 0.69 FEV1, % pred. 53.0 ± 15.8 52.9 ± 24.7 0.63 RV, % pred. 82.0 ± 23.7 77.7 ± 29.2 0.16 TLC, % pred. 62.4 ± 15.0 61.2 ± 16.2 0.67 DLCO, % pred. 25.9 ± 8.3 26.8 ± 6.7 0.55 KCO, % pred. 51.6 ± 18.9 58.5 ± 24.3 0.37 6-MWT 02-therapy (L/min) 4.2 ± 2.0 7.0 ± 3.0 0.07 Final SpO2(%) 87.7 ± 3.4 86.8 ± 3.2 0.71 Distance (m) 282.5 ± 71.3 215.8 ± 120.1 0.31 Borg 4.6 ± 2.3 6.0 ± 1.8 0.28 RHC mPAP (mmHg) 22.9 ± 6.5 25.5 ± 5.3 0.29 Wedge pressure (mmHg) 10.3 ± 4.8 10.3 ± 4.3 0.87 GAP index Stage I 10 % 6 % 0.68 Stage II 47.4 % 51.5 % 0.81 Stage III 42.6 % 42.5 % 1.00
between the two groups. At 6-min walking test (6-MWT), Group 2 patients needed higher O2-therapy flows to com-plete the test (4.2 ± 2.0 vs. 7.0 ± 3.0 L/min; the differ-ence was at the limit of significance, p = 0.07). Even if not significant, Group 2 patients walking distance was lower and Borg’s dyspnoea scale was higher than patients in Group 1. Right heart catheterization failed to demonstrate a different PH incidence, but in Group 2 patients median value of mean pulmonary arterial pressure (mPAP) were above the cut-off of 25 mmHg required for PH diagnosis (25.5 mmHg). In Table1demographic, blood gas analysis, pulmonary functional tests, 6-MWT and right heart catheterization findings are reported. Comorbidities were not different between the two groups; in particular diabetes mellitus, arterial hypertension, hypercholesterolemia inci-dence and associated medical therapy were not statistically different. As expected, the majority of patients died for disease progression (n = 18, 54.5 %), a third (n = 11, 33.3 %) for acute exacerbation of IPF, the rest for other extra-pulmonary causes. GAP index was not different between the two groups; the majority of patients were classified as stage 2 and 3 in both groups (Table1).
Discussion
IPF prognosis is poor and selected patients may benefit from LTX, the only treatment able to significantly modify patient’s life quality and expectancy in selected patients [1–4]. Due to its heterogeneous clinical course and to the lack of prognostic biomarkers, disease’s phenotype is unpredictable at time of diagnosis (stable, rapidly pro-gressive and acute exacerbators) [4]. Mortality on the waiting list for LTX is a major problem mainly in IPF patients. Time on waiting list is not anymore considered a good indicator for organ allocation and it should be based on clinical conditions; since LAS implementation IPF became the first indication in the US [11]. The results of the present study confirm these observations. Mortality in the waiting list for LTX principally regarded to patients with IPF because of its clinical behaviour with rapid pro-gression compared to other diseases; no difference about time spent on the waiting list was observed between IPF patients who underwent to LTX or passed before, more severe and with advanced disease stages patients showed less probability to get to LTX.
In our population, IPF patients have been referred to transplantation too late. Despite ISHLT indications, in our experience IPF patients have not been referred at time of diagnosis and joined the waiting list when respiratory function was already significantly deteriorated (half of patients were already on LTOT and DLCO % was less than 30 % in the rest). Late referral impacted on survival;
indeed, a significantly higher number of patients who died in the waiting list were previously followed from other hospitals.
Clinical and radiological data failed to predict mortality. The only factors able to identify patients at high risk were exercise testing and blood gas analysis. Oxygen-therapy flow at the 6-MWT was significantly higher in patients who died in the waiting list; a trend in a reduced walking dis-tance and higher dyspnoea index (Borg’s scale) was also present, confirming 6-MWT as an essential prognostic indicator for IPF patients [13].
Reduced survival was associated with the presence of higher levels of arterial pCO2 at ABG—even if average values were into the normal range for both groups. Res-piratory impairment in patients with pulmonary fibrosis is commonly characterized by the presence of hypoxemia and normo- or hypocapnia; hypercapnia is an inconstant and late finding in advanced stages. Despite Group 2 patients were not hypercapnic (over 45 mmHg) they have been lost in the waiting list, suggesting pCO2to be a reliable prog-nostic marker in this kind of patients.
Pulmonary function tests and DLCO failed to predict mortality in our cohort of patients. This could be due to the limited number of patients enrolled, but it also suggests that, in short periods of observation, the most commonly used index of severity in respiratory medicine (PFTs) seems to be not always able to predict patient disease progression in IPF. This issue is actually a matter of dis-cussion in the IPF community, as it is not yet clear if pulmonary function deterioration or mortality should be adopted as primary endpoint in clinical trials [14]. Mackay et al. analysed IPF mortality in patients awaiting trans-plantation, concluding that disease progression is a more sensitive indicator for transplantation referral than any single physiological measure of disease severity [15].
PH is a fearsome complication in IPF patients and negatively impacts on survival [5,6]. In our population, no significant difference in PH incidence was found, but in Group 2 patients mPAP excessed the diagnostic cut-off for PH of 25 mmHg, sustaining PH assessment in patient risk stratification for LTX.
Analysis of predictors of mortality awaiting transplan-tation is in close relationship with organ procurement and donation issues. In geographic area where donors are lacking, mortality in the waiting lists will be a difficult problem to solve, impacting mainly in patients affected by rapidly progressive diseases such as IPF. In our Country, donation is actually not able to meet the demands (19.3 donors per million of population in 2014) [16]. Great expectancy is placed on ex vivo lung perfusion (EVLP) techniques and donation after cardiac death (DCD) to expand pool of donors [17,18]; however, at the moment, these kinds of programms are still not widely available.
In this perspective, a very careful evaluation on which characteristics will predict a positive outcome in the waiting list for a better risk stratification is necessary. This approach, especially in small to medium volume LTX Centres, might impact for a better and reasonable organ allocation, potentially reducing mortality awaiting LTX.
Research of new IPF biomarkers to address to trans-plantation patients with worse prognosis is strongly nee-ded. Suitable biomarkers have been identified [19–24], and validation on larger populations will permit a routinely clinical application.
In conclusion, the present study, although retrospective and based on a single-Centre experience, suggests that patients with IPF are actually referred to LTX too late. In countries where a long waiting list is expected, patients newly diagnosed with IPF should be immediately evalu-ated for LTX at time of diagnosis and peripheral hospitals should be encouraged to send patients to Transplant Cen-tres as early as possible. According to our data, in IPF patients 6-MWT and pCO2are the most useful parameters to predict mortality on the waiting list. New biomarkers for an early identification of patients with a rapid progressive phenotype are strongly needed for a better organ allocation with the potential to reduce mortality on the waiting list.
Compliance with Ethical Standards Conflict of interest None.
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