Abstract

Introduction

For selected patients with end-stage chronic lung disease, lung transplantation is an established and effective treatment option [1]. Although survival rates have improved over the last decade, they are still lower compared to other solid organ transplantations due to a high number of complications, e.g., recurrent infection [1] or the development of chronic lung allograft dysfunction (CLAD) [2–4].

The 2013 report of the Registry of the International Society for Heart and Lung Transplantation shows an increase in the median age of lung transplant recipients from 45 to 55 years over the preceding decade [5]. This may increase morbidity and mortality after LTx since older patients are more likely to receive an organ [6]. The shortage of donor organs is a persistent problem resulting in a waiting list mortality of approximately 10–13% [3]. Therefore, not only the characteristics of the recipient are subject to discussion [7, 8], but also how to expand the donor pool and find the best possible match for the respective patient on the waiting list [9].

The debate on organ selection remains controversial regarding the use of older organs for transplantation [10, 11]. In previous studies, the ‘ideal donor’ is described as <55 years of age [9, 10, 12], However, this statement does no longer reflect current practice and over the last decade the use of donors≥55 years of age has been divergently handled by many transplant centres [10, 13–15].

Particularly the impact of the recipient’s underlying pulmonary disease on short and long-term outcome is incompletely understood. Fibrotic and obstructive lung diseases differ not only morphologically, but also regarding the underlying pathophysiology including different immunological alterations. Aside from idiopathic pulmonary fibrosis (IPF), there are many other causes of pulmonary fibrosis such as autoimmune/connective tissue diseases, e.g., rheumatoid arthritis, environmental exposures to coal or silica, or allergens, e.g., bird fancier’s lung [16, 17]. The pathogenesis of IPF is multifactorial, involving various processes that lead to dysregulation in wound healing with widespread scarring of the lungs [16]. It is considered an age-related disease, which usually occurs in patients older than 50 years, and is increasing in both, incidence, and prevalence [18, 19]. Moreover, altered innate and adaptive immune cell responses have both been linked to myofibroblast biology and fibrogenesis [18] and thus to fibrotic lung disease. In the context of lung transplantation, a dysregulated immune system might pose an additional challenge for the postoperative course and long-term survival. Monitoring immunosuppression after lung transplantation is challenging, and drug blood levels alone are insufficient to determine the individual status of immunosuppression [20, 21].

This study aims to analyse the impact of donor age, as well as the impact of the underlying pulmonary diseaseon graft function and short- and long-term outcome in our lung transplant cohort.

Methods

Results

230 patients (120 male, 110 female) underwent lung transplantation at our institution between March 2003 and December 2021. 203 (88%) patients had a double lung transplantation, and 27 (12%) patients had a single lung transplantation. The overall 1-, 5- and 10-year-survival rate was 80%, 67% and 58% respectively (Fig. 1A). Basic donor and recipient characteristics are shown in Table 1.

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Fig. 1

Kaplan-Meier Analysis of survival after lung transplantation. a) Overall post-transplant survival: 1-, 5- and 10-year survival: 80%, 67% and 58%. b) Survival with IPF: 1-, 5-, and 10-year survival 74%, 60%, and 51% vs. 91%, 75%, 66%. c) Survival with COPD: 1-,5- and 10-year survival 91%,80% and 70% vs. 74%, 60% and 51%. The log-rank test was used for the comparison of the survival curves

Table 1

Basic patient characteristics of donors and recipients

Variable	Recipients				Corresponding Donors
	Overall (n=230)	IPF (n=86)	COPD (n=86)	Other (n=58)
Sex
Male	118 (51%)	53 (38%)	41 (48%)	24 (43%)	112 (49%)	33 (62%)	52 (60%)	27 (47%)
Female	112 (49%)	33 (62%)	45 (52%)	34 (57%)	118 (51%)	53 (38%)	34 (40%)	31 (53%)
Age at LTX (years)
Min Max Median	17 69 58	36 69 59	46 67 60	17 65 58	13 74 51	14 74 51	15 73 52	13 70 51
Age groups (years)
<18 18–29 30–39 40–49 50–59 60–69 >69	1 (0.5%) 9 (4%) 7 (3%) 25 (11%) 91 (40%) 98 (43%) 0 (0%)	0 (0%) 0 (0%) 2 (2%) 11 (13%) 34 (40%) 39 (45%) 0 (0%)	0 (0%) 0 (0%) 0 (0%) 4 (5%) 37 (43%) 45 (52%) 0 (0%)	1 (2%) 9 (16%) 5 (9%) 10 (17%) 20 (34%) 14 (29%) 0 (0%)	10 (04%) 18 (08%) 26 (11%) 54 (23%) 61 (27%) 49 (21%) 12 (05%)	2 (2%) 8 (9%) 12 (14%) 19 (22%) 18 (21%) 22 (26%) 5 (6%)	3 (3%) 8 (9%) 11(13%) 19 (22%) 20 (23%) 20 (23%) 5 (6%)	5 (9%) 2 (3%) 3 (5%) 16 (28%) 23 (40%) 7 (12%) 2 (3%)
BMI at LTX (kg/m2)
Min	14.8	14.8	15.9	15.2	14.2	14.1	18.5	16.3
Max	33.7	33.1	31.1	33.7	46.9	46.9	39.1	34.7
Median	23.1	24.2	22.1	23	24.8	24.2	25.4	24.8
LAS at LTX
Min	31	32	31	32
Max	96	95	83	96
Median	39	45	34	39
Pre LAS*	69 (30%)	32(37%)	21(24%)	16 (28%)
HU	35	19	4	12
U	24	9	12	3
T	7	2	5	0
Donor>55 (%)
LAS era					80 (50%)	27 (50%)	31 (48%)	22 (40%)
Pre-LAS era					13 (19%)	7 (20%)	2 (10%)	4 (7%)
Comorbidity
CHD	38 (17%)	12 (14%)	18 (21%)	8 (14%)
aHT	66 (29%)	27 (31%)	33 (38%)	6 (10%)
DM	44(19%)	17 (20%)	15 (17%)	12 (21%)
Comorbidity Donor
CHD Smoker Median MV (days) Median pO2 (mmHg)					34 (15%) 75 (33%) 3 447	8 (9%) 25 (29%) 3 460	8 (9%) 32 (37%) 3 440	18 (31%) 18 (31%) 3 450
Operation
DLTx SLTx ECMO Intraop. only Intra- + postop. Bridging	203 (88%) 27 (12%) 82 (36%) 70 (85%) 9 (11%) 3 (4%)	74 (86%) 12 (14%) 43 (50%) 36 (84%) 6 (14%) 1(2%)	73 (85%) 13 (15%) 13 (15%) 12 (92%) 1(8%) 0(0%)	56 (97%) 2 (3%) 26 (49%) 22 (38%) 2 (3%) 2 (3%)

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Basic characteristics of donors and recipients. BMI=body Mass Index, COPD=chronic obstructive pulmonary disease, IPF=idiopathic pulmonary fibrosis, EAA=exogenous allergic alveolitis, AAT=alpha-1 antitrypsin deficiency, CHD=coronary heart disease. * in the pre-LAS era, there was no information on the HU/U/T Status for 2 patients in the IPF group

In the whole study cohort, a donor age of ≥55 years at the time of LTx was associated with reduced overall survival (1-, 5- and 10-year survival: 75%, 54%, 37% vs. 84%, 76%, 69%; p=0.0006) and an increased incidence of PGD 2/3 (46% vs. 31%, p=0.03) (Fig. 2). The significantly reduced survival was consistent for donor lungs≥60 and ≥65 years and the also incidence of PGD2/3 was increased for donors≥60 compared to younger donors (Supplementary Figure S3). PGD2/3 and donor age≥55 years were found to be independent predictors of reduced survival in the whole cohort in multivariate analysis (p=0.0005 and p=0.017 respectively) (Table 2). There was no statistically significant impact of donor age on the development of CLAD (p=0.28), however, CLAD was identified as a predictor of reduced survival in univariate analysis (p=0.019). Interestingly, the recipient’s age at the time of LTx did not correlate with the incidence of PGD or long-term survival in either group.

Table 2

Univariate and multivariate Cox proportional hazard regression analysis to identify predictors of survival

Variables (n=230)	Univariate, HR (95% CI)	p	Multivariate, HR (95% CI)	p
Sex
Gender (female)	1.653 (1.052–2.597)	0.046	1.247(0.732–2.126)	0.42
Underlying disease
IPF COPD	1.463 (0.919–2.327) 0.572 (0.365–0.896)	0.094 0.003	1.489 (0.847–2.719)	0.12
CLAD*
All patients IPF COPD	2.399 (1.154–4.990) 1.824 (0.581–7.924) 1.741 (0.512–5.917)	0.019 0.24 0.31	1.076 (0.585–1.934)	0.84
PGD2/3
All patients IPF COPD	3.225 (1.985–5.239) 2.202 (1.146–4.234) 3.757 (1.511–9.345)	<0.0001 0.0124 0.017	2.324 (1.447–3.752) 1.808 (0.897–3.744) 0.696 (0.331–1.320)	0.0005 0.10 0.30
Recipient≥55 years
All patients IPF COPD	0.865 (0.539–1.386) 1.114 (0.546–2.273) 0.721 (0.255–2.037)	0.55 0.77 0.50
Donor≥55 years
All patients IPF COPD	2.277 (1.420–3.660) 3.311 (1.646–6.663) 1.065 (0.4002.834)	0.0006 0.0002 0.90	1.817 (1.115–2.975) 2.969 (1.431–6.380)	0.017 0.004
Recipient comorbidity
Diabetes mellitus CHD	1.295 (0.735–2.282) 0.903 (0.591–1.378)	0.37 0.64
Donor comorbidity
Nicotine CHD	0.997 (0.624–1.593) 1.576 (0.751–3.308)	0.99 0.23
Sex
Surgery SLTX All patients
COPD IPF ECMO	1.016 (0.520–1.983) 1.033 (0.297–3.597) 1.246 (0.514–3.021)	0.96 0.96 0.60
All patients COPD IPF	2.480 (1.559–3.943) 3.063 (0.898–10.44) 1.405 (0.731–2.699)	<0.0001 0.013 0.31	2.036 (1.245–3.378) 1.145 (0.542–2.190)	0.005 0.70

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Predictors of survival. IPF=idiopathic pulmonary fibrosis, COPD=chronic obstructive pulmonary disease, ECMO=extracorporeal membrane oxygenation, CHD=coronary heart disease, CLAD=chronic lung allograft dysfunction, *includes all patients that survived at least 6 months. If not mentioned otherwise, the values are calculated for all patients. The information on PGD is missing for one patient

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Fig. 2

a+b: Kaplan-Meier Analysis of survival after lung transplantation: for donors and recipients<55 and ≥55 years of age. c+d: Incidence of primary graft dysfunction grade 2 or 3 in donors and recipients≥55 years of age. For one patient there is no information available on PGD

In the next step, we analysed if there was a differential impact of donor age depending on the recipients’ underlying pulmonary disease. We identified 86 (37%) patients with idiopathic pulmonary fibrosis (IPF) and 86 (37%) patients with chronic obstructive pulmonary disease (COPD). Basic donor and recipient characteristics were comparable in both groups (Table 1). In general, overall survival after LTx was similar in patients with IPF (p=0.094) and increased in patients with COPD (p=0.003) (Fig. 1B+C). Notably, only in patients with IPF, a donor age≥55 years was associated with a higher incidence of severe primary graft dysfunction (PGD2/3) (65% vs. 37%; p=0.016) and with a considerably reduced long-term survival (1-, 5-, and 10-year survival: 62%, 38%, 16% vs. 80%, 76%, 70%; p=0.0002) (Fig. 3). On the other hand, a donor age≥55 had no impact on survival nor the incidence of PGD2/3 in patients with COPD (68% vs. 72%, p=0.90 and 21% vs. 27%, p=0.60 respectively) (Fig. 4). Again, the older age of the recipients was not associated with reduced overall survival or the incidence of PGD2/3 in either group. For patients with IPF, a donor age≥55 years was identified as an independent predictor of reduced survival in multivariate Cox regression analysis (p=0.004) (Table 2). The development of CLAD was not affected by donor or recipient age in either subgroup. As expected, the median LAS score was higher in the IPF group, however, there was no significant difference in the percentage of donor organs>55 years between the groups in the LAS era (Table 1).

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Fig. 3

a+b: Kaplan-Meier Analysis of survival after lung transplantation in patients with IPF for donors and recipients<55 and ≥55 years of age. c+d: Incidence of primary graft dysfunction grade 2 or 3 PGD2/3 in patients with IPF for donors and recipients<55 and ≥55 years of age. The log-rank test was used for the comparison of the survival curves. For one patient there is no information available on PGD. D=donor, R=recipient

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Fig. 4

a+b: Kaplan-Meier Analysis of survival after lung transplantation in patients with COPD for donors and recipients<55 and ≥55 years of age; c+d: Incidence of primary graft dysfunction grade 2 or 3 (PGD2/3 ) in patients with COPD for donors and recipients<55 and ≥55 years of age. The log-rank test was used for the comparison of the survival curves. For one patient there is no information available on PGD. D=donor, R=recipient

Single lung transplantation was performed in 12 (14%) patients with IPF and 13 (15%) patients with COPD. There was no difference in survival in either group compared to patients who underwent double lung transplantation. While more patients in the IPF subgroup were transplanted on ECMO support (43/86), there was no statistically significant association between the use of perioperative ECMO and survival (p=0.31), unlike in the COPD subgroup (p=0.013) and the whole cohort (p=<0.0001) (Table 2).

The cause of death in LTx recipients with IPF was sepsis and consecutive multi-organ failure in 34/49 (69%) of the patients in that subgroup). To further corroborate this hypothesis, we re-analyzed the Torque-teno virus (TTV) load as a possible endogenous marker to reflect immune function in selected patients from our cohort [24]. Interestingly, we found higher TTV-DNA levels after lung transplantation in patients with IPF compared to COPD patients (X²=4.57, p=0.033; Fig. 5). The incidence of CMV reactivation was similar in both groups, COPD and IPF patients (42% vs. 36%). While there was a higher percentage of CMV reactivations in IPF patients with donor organs≥55 years, this did not reach statistical significance (55% vs. 33%, p=0.16).

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Fig. 5

Torque-Teno Virus copy number in patients with IPF and COPD. . Increased copies of Torque-Teno Virus after lung transplantation in patients with IPF compared to patients with COPD as an underlying disease

Discussion

Selecting the best donor for a patient remains a challenge in lung transplantation [9]. In our lung transplant recipient cohort, a donor age of ≥55 years was associated with impaired organ function and reduced survival in patients with IPF.

Conclusions

In lung transplant recipients with IPF, a donor≥55 years of age was associated with a higher incidence of primary graft dysfunction. Moreover, it was revealed as an independent risk factor for reduced survival in the whole cohort and in patients with IPF specifically. Thus, precise recipient selection is crucial. Although we may only hypothesise an altered immune function in selected recipients with IPF, from our viewpoint, older donor organs should be carefully evaluated. Since most studies are based on a heterogeneous recipient cohort, further studies are needed to analyse the impact of the underlying pulmonary disease, as this may be a relevant factor for postoperative graft function and survival.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Acknowledgements

Abbreviations

Author contributions

IM and WJ concepted the study. EDO, AK and IM collected the data. SB and BCF contributed the detection and analysis of the TTV-DNA. EDO and IM performed the statistical analysis and IM wrote the manuscript with input from DS, SF, WJ and BCF. Visualisation: IM and WJ. BP, MC, DS, BCF and WJ reviewed and revised the manuscript.

Funding

No external funding was used for this study.

Open Access funding enabled and organized by Projekt DEAL.

Data availability

The datasets analysed during the current study are available from the corresponding author on reasonable request.

Declarations

Footnotes

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