Referral rates and barriers to lung transplantation based on pulmonary function criteria in interstitial lung diseases: a retrospective cohort study

Abstract

Background:

Interstitial lung diseases (ILD) unresponsive to medical therapy often require lung transplantation (LTx), which prolongs quality of life and survival. Ideal timing for referral for LTx remains challenging, with late referral associated with significant morbidity and mortality. Among other criteria, patients with ILD should be considered for LTx if forced vital capacity (FVC) is less than 80% or diffusion capacity for carbon monoxide (DLCO) is less than 40%. However, data on referral rates are lacking.

Objectives:

To evaluate referral rates for LTx based on pulmonary function tests (PFTs) and identify barriers associated with non-referral.

Design:

A single-center retrospective cohort study.

Methods:

The study consisted of ILD patients who performed PFT between 2014 and 2020. Patients with FVC < 80% or a DLCO < 40% were included in the study. Patients with absolute contraindications to LTx were excluded. Referral rates were computed, and a comparison was made between referred and non-referred subjects.

Results:

Out of 114 ILD patients meeting criteria for referral to LTx, 35 were referred (30.7%), and 7 proceeded to undergo LTx. Median time from PFT to referral for assessment was 255 days [interquartile range (IQR) 35–1077]. Median time from referral to LTx was 89 days (IQR 59–143). Referred patients were younger (p = 0.003), had lower FVC (p < 0.001), DLCO (p < 0.001), and a higher rate of pulmonary hypertension (p = 0.04). Relatively better PFT, and older age, were significantly associated with non-referral of patients.

Conclusion:

There is under-referral of ILD patients who are eligible for LTx, which is associated with severe disease and missed opportunities for LTx. Further research is required to validate these findings.

Plain language summary

Lung transplants: addressing referral gaps for lung disease patients

Patients with severe lung diseases that are unresponsive to medical treatments often require lung transplants to enhance their quality of life and survival. Determining the optimal timing for considering a transplant is challenging, as delaying it can lead to complications. Our study aimed to assess how frequently individuals with lung problems, particularly interstitial lung diseases, were referred for lung transplants based on lung function tests. We conducted a retrospective analysis of medical records for patients with lung diseases who underwent lung function tests between 2014 and 2020. We selected patients whose test results indicated impaired lung function, excluding those who were ineligible for lung transplants due to other medical reasons. Subsequently, we examined the number of patients referred for a lung transplant and compared them to those who were not referred. Our findings revealed that out of 114 patients eligible for a lung transplant, only 35 were referred, representing a referral rate of approximately 31%. Among these, only 7 patients actually underwent the transplant procedure. The time elapsed between the lung function test and the referral for a transplant assessment was notably long, averaging around 255 days. Additionally, once referred, patients waited an average of 89 days for the transplant assessment. Referred patients tended to be younger and had more severe lung disease, characterized by lower lung function test results and a higher likelihood of pulmonary hypertension. Conversely, patients who were not referred generally enjoyed better overall health and were older. This discrepancy highlights the missed opportunities for patients to improve their health and quality of life through lung transplantation. Further research is essential to verify the accuracy of these findings, but this study represents a crucial step toward ensuring that individuals with lung diseases receive the appropriate care they require.

Introduction

Lung transplantation (LTx) is a viable option for patients with end-stage lung diseases once all possible conservative treatments have been exhausted.^1,2 Interstitial lung disease (ILD) is a common indication for LTx worldwide,^3,4 and patients with progressive ILDs, unresponsive to therapy, should typically be considered for LTx.^5,6 The difficulty in predicting the pace of disease progression, and therefore the optimal transplant time, supports early referral to a transplant center, particularly for patients with markers of progressive disease.^7,8 Criteria for referral of ILD patients for LTx were proposed by the International Society of Heart and Lung Transplantation (ISHLT) and include (1) histopathologic or radiographic evidence of usual interstitial pneumonia or fibrosing non-specific interstitial pneumonitis regardless of lung function; (2) abnormal lung function with forced vital capacity (FVC) <80% predicted or diffusing capacity for carbon monoxide (DLCO) <40% predicted; (3) any dyspnea or functional limitation attributable to lung disease; (4) any oxygen requirement, even if only during exertion; (5) or for inflammatory ILD, failure to improve dyspnea, oxygen requirement, and/or lung function after a clinically indicated trial of medical therapy. ⁹ The latest iteration of these guidelines has been recently published with no significant modifications in ILD referral criteria. ¹⁰

Although patients with progressive ILD comprise a substantial segment of candidates on the transplant list, there is no published data concerned with the referral rates of this population. Recent studies suggest a significant variation in referral to a specialist center, even after diagnostic tests and pulmonologist evaluation has been performed.^11–13 The aim of this study was to determine adherence to guidelines on referral for LTx of patients with progressive ILDs based on FVC or DLCO criteria. A secondary aim was to identify potential barriers associated with non-referral which could improve patient’s management and ultimately their outcome.

Methods

Study design and patient selection

This was a single-center, retrospective cohort study. The study population comprised of all adult patients diagnosed with ILD based on the American Thoracic Society (ATS)/European Respiratory Society (ERS)/Japanese Respiratory Society/Latin American Thoracic Association guidelines,^14,15 who performed pulmonary function tests (PFTs) at the Sheba Medical Center (Ramat Gan, Israel) between 1 January 2014 and 31 December 2019. Patients with ILD meeting the criteria for LTx candidacy based on PFTs were included. Those with contraindications to LTx, such as active or recent malignancy, significant comorbidities (including left heart failure, significant coronary disease, significant liver injury, etc.), a body mass index exceeding 35 kg/m², severe cognitive impairment, or inadequate social support, were excluded. Follow-up data were obtained from electronic medical records and computerized databases and censored on 31 December 2020. The reporting of this study conforms to the Strengthening the Reporting of Observational Studies in Epidemiology statement. ¹⁶

Operational structure and referral to LTx

During the study period, the Sheba Medical Center Pulmonary Institute operated with a team of experienced pulmonologists responsible for comprehensive care of a wide range of pulmonary conditions, including ILD. Notably, no dedicated ILD clinic existed. Patients referred for LTx were directed to another facility, as Sheba did not perform LTx. In Israel at the time of the study, there existed a sole operational LTx center. This center managed a waiting list of approximately 120 candidates and performed around 50–55 transplants annually. Evaluation of candidacy, timing of referral, as well as timing of listing is based on ISHLT consensus guidelines.^9,10 It is worth highlighting that in Israel there was no age limitation to LTx at the time of the study, and the lung allocation score ¹⁷ was used to prioritize candidates on the waitlist.

Pulmonary function tests

PFT was performed by our institute’s experienced certified pulmonary function technicians. The equipment is periodically tested for accuracy and precision, as part of the quality-control requirements. Tests are accepted if they meet the ATS/ERS acceptability and repeatability criteria.^18,19 When patients had multiple PFTs, the most recent was included.

Review process

A computerized database and electronic patient record were used to identify all patients with a diagnosis of ILD who performed spirometry with/without lung volume measurements. Epidemiological and clinical information, including sex, race, age, smoking status, anti-fibrotic or immunosuppressive therapy, supplemental oxygen use, comorbidities, and co-medications was extracted. Clinical outcomes reported at any point during follow-up were collected for all patients. These outcomes included all-cause mortality, referral to pre-transplant assessment, LTx, acute exacerbation (defined as an acute, clinically significant deterioration of unidentifiable cause in a patient with underlying ILD), ²⁰ and comorbid pulmonary hypertension on echocardiography or right heart catheterization.

Statistical analysis

Demographic characteristics were assessed as counts and percentages for categorical variables, and as standard measures [median and interquartile range (IQR)] for continuous variables. To compare baseline characteristics between groups, Wilcoxon rank-sum test was used for continuous variables and the Chi-squared test or Fisher’s exact test for categorical variables. All analyses were conducted using R statistical software version 3.4.3 (R Foundation for Statistical Computing, Vienna, Austria). Statistical significance was defined as a two-tailed p value ⩽ 0.05.

Results

Study population

A total of 587 patients with ILD had PFT performed at our center between 1 January 2014 and 31 December 2019. The potential study population was composed of 257 patients who met the criteria for referral for LTx based on FVC < 80% or DLCO < 40% predicted. One hundred and forty-three patients were excluded due to contraindications to LTx in accordance with ISHLT consensus guidelines, and the remaining 114 were included in the study cohort. A consort flow diagram describes this in Figure 1.

Figure 1.

CONSORT diagram.

DLCO, diffusion capacity for carbon monoxide; FVC, forced vital capacity; ILD, interstitial lung disease; LTx, lung transplant; PFT, pulmonary function test.

Patient characteristics

Thirty-five (30.7%) patients of the study cohort were referred to LTx and 7 (6.1%) underwent a LTx operation. The referred group was significantly younger [60 years (IQR 51.5–66.5) versus 69 years (IQR 62.5–77), p < 0.001] and more likely to have pulmonary hypertension at the time of referral (67% versus 43%, p = 0.04). Pulmonary function parameters were decreased in the referred group for forced vital capacity in 1 s (FEV1) (49% predicted versus 66% predicted, p < 0.001), FVC (47% predicted versus 62% predicted, p < 0.001), and DLCO (32% predicted versus 56% predicted, p = 0.02). The minimum DLCO in the referred group compared to the non-referred was 24% versus 36% (p < 0.001). There was no difference between referred and non-referred patients with respect to sex, smoking status, comorbidities, anti-fibrotic medications, or mortality rates. When considering differences by LTx operation, comparing patients who underwent LTx operation versus those who were referred to LTx but did not undergo the operation, patients who underwent LTx tended to be younger [55 years (IQR 46–60.5) versus 62.5 years (IQR 52.5–69), p = 0.083] with an elevated BMI (Body Mass Index) [31.1 (IQR 28.53–32.28) versus 24.21 (IQR 22.85–26.35), p = 0.01] with no difference in sex, smoking status, comorbidities, or anti-fibrotic medications.

The median time from most recent PFT to referral to a LTx center was 255 days (IQR 35.5–1077.5 days). The median duration from referral to LTx assessment was 88.5 days (IQR 59.5–142.8). For patients who underwent LTx, the median time from referral to the actual LTx operation was 292 days (IQR 116.5–950 days). Among patients who did not survive until LTx, the median time from referral to the LTx center to the time of death was 412 days (IQR 182–833 days). Data are summarized in Table 1 and in the Supplemental Appendix in Supplemental Tables S1–S5.

Table 1.

Baseline demographic and clinical characteristics of patients eligible for transplant stratified by referral status.

Baseline characteristics	Not referred to LTx (N = 79)	Referred to LTx (N = 35)	p Value
Male, N (%)	40 (50.6)	17 (48.6)	1
Age (years), median (IQR)	69 (62.5–77)	60 (51.5–66.5)	<0.001
Smoking status, N (%)			0.139
Active	1 (1.3)	1 (2.9)
Never	38 (48.1)	11 (31.4)
Passive	0	2 (5.7)
Past	31 (39.2)	17 (48.6)
Unknown	9 (11.4)	4 (11.4)
BMI, median (IQR)	27 (23.4–30.1)	25 (23–29.1)	0.198
Presence of pulmonary hypertension, N (%)	32 (43.8)	21 (67.7)	0.044
Diagnosis of idiopathic pulmonary fibrosis, N (%)	36 (45.6)	21 (60)	0.223
GAP index, median (IQR)	5 (4–6)	5 (4–6)	0.311
Treatment with nintedanib, N (%)	20 (26)	15 (44.1)	0.094
Treatment with prifenidone, N (%)	4 (5.2)	5 (14.7)	0.188
Died, N (%)	24 (30.4)	17 (48.6)	0.098
PFTs
FEV1 % predicted, median (IQR)	65.5 (54.1–79.2)	50 (34.3–60.8)	<0.001
FVC % predicted, median (IQR)	62 (50.6–75)	50 (36.4–59.5)	<0.001
FVC < 80%, N (%)	66 (84.6)	35 (100)	0.034
DLCO < 40%, N (%)	56 (76.7)	32 (97)	0.022
Lowest DLCO value (%), median (IQR)	35 (26–39)	25 (19–30)	<0.001
6-Min walk test distance, meters, median (IQR)	355 (240–437.5)	345 (255–386)	0.693
Comorbidities
Malignancy, N (%)	10 (12.7)	5 (14.3)	1
Liver disease, N (%)	3 (3.8)	0	0.593
Heart failure, N (%)	16 (20.3)	5 (14.3)	0.62
Ischemic heart disease, N (%)	20 (25.3)	7 (20)	0.71
Peripheral vascular disease, N (%)	10 (12.7)	6 (17.1)	0.731
Renal disease, N (%)	8 (10.1)	0	0.12
Time intervals
Time from PFT to referral, days, median (IQR)	NA	255 (35.5–1077.5)	NA
Time from referral to assessment, days, median (IQR)	NA	88.5 (59.5–142.75)	NA
Time from referral to LTx, days, median (IQR)	NA	292 (116.5–950)	NA
Time from referral to death, days, median (IQR)	NA	412 (182–833)	NA

DLCO, diffusion capacity for carbon monoxide; FEV1, forced vital capacity in 1 s; FVC, forced vital capacity; IQR, interquartile range; LTx, lung transplant; PFT, pulmonary function test.

Factors associated with non-referral to LTx

Several factors potentially associated with non-referral to LTx were assessed using univariable and multivariable logistic regression models as demonstrated in Figures 2 and 3. The presence of pulmonary hypertension [odds ratio (OR) 0.37, CI 0.15–0.88, p = 0.028], and GAP stage 2 (a clinical prediction tool that estimates prognosis in patients with idiopathic pulmonary fibrosis based on sex, age, and lung physiology) were associated with the referral of patients to LTx assessment. On the other hand, GAP stage 1 (OR 7.5, CI 2.12–47.59, p < 0.007), relatively better FVC (OR 1.05, CI 1.03–1.06, p < 0.001), and DLCO (OR 1.09, CI 1.04–1.14, p < 0.001) measurements were associated with non-referral, as well as older age (OR 1.04, CI 1.01–1.08, p = 0.005). Other factors including BMI, 6-min walk test, smoking status, or sex did not appear to have a significant association with a referral.

Figure 2.

Clinical factors and their association with non-referral to LTx (univariable analysis).

Figure 3.

Clinical factors and their association with non-referral to LTx (multivariable analysis).

After adjusting for PFT, age, sex, and BMI using a multivariable analysis, relatively better FVC (OR 1.07, CI 1.02–1.12, p = 0.006), DLCO (OR 1.09, CI 1.03–1.16, p = 0.005), and older age (OR 1.06, CI 1.01–1.11, p = 0.015) were associated with non-referral to LTx assessment.

Discussion

This retrospective cohort study aimed to describe referral adherence of patients with ILDs to LTx based on lung function criteria, and characterize barriers associated with non-referral. Our findings suggest under-referral of potential LTx candidates with only less than a third of eligible subjects being referred to LTx at a median time of 255 days. This median time of 255 days may underestimate the actual time from PFT to referral, as it was determined based on the most recent PFT, without taking into account previous PFTs that would have met the criteria for referral to LTx. Older age, absence of pulmonary hypertension, and better FVC or DLCO emerged in our study as barriers associated with non-referral to LTx. Surprisingly, there are few data in the literature describing the process of patient referral or estimates of adherence to referral criteria. To the best of our knowledge, the level of adherence found in this study is the only one reported in the scientific literature for LTx.

It is generally recommended to consider LTx when the patient is symptomatic during daily living activities and survival is expected to be limited to 2–3 years, which represents the upper end of the usual waiting time. ²¹ Early referral for consideration of LTx is highly desirable.^22,23 It allows an orderly process of assessment and management of areas of concern prior to active listing. Referral to LTx assessment has the added advantage of providing patients access to specialized care, including clinical trial enrollment and lung rehabilitation programs. Furthermore, early referral probably enhances an individual patient’s chance of surviving to transplant and minimizes the trauma and distress of waiting while desperately ill. ²⁴ Late referral reduces the chance of surviving to transplant and is associated with heightened patient anxiety scores while waiting.^25,26 Based on this available data, the ISHLT has published several consensus statements/guidelines on the selection and listing criteria for lung transplant and recommends early referral to a transplant center for progressive lung diseases that have a projected poor prognosis. ⁴ The recent ATS consensus document even recommends that transplant discussion should be performed at the time of diagnosis. ¹³

Despite the guidelines advising early referral to LTx, the low referral rates may be attributable to several factors. It is possible that identifying patients who may benefit from LTx assessment is difficult for general practitioners or pulmonologists who do not routinely manage advanced ILD cases as part of their daily practice or within a dedicated ILD clinic. Previously, published international guidelines on patient referral and selection to LTx were intended to address this gap; however, the low referral rate raises the possibility of lack of physician acquaintance with this information. Alternatively, under-referral may reflect problems with local access to a transplant center, societal or cultural issues, or priorities of the regional or national healthcare system. Triggers for referral according to this study include worse lung function, and the presence of pulmonary hypertension. Both factors are markers of disease progression in ILD and absolute, or relative decline in FVC and DLCO have been used to define progression in patients with ILD, ²⁷ while the presence of pulmonary hypertension (PH) in patients with idiopathic pulmonary fibrosis (IPF) has been associated with impaired pre-transplant survival. ²⁸ Collectively, these findings of advanced disease strongly suggest that referral was delayed and carried out later in the evolution of the disease process.

Another point of interest concerns advanced age as a factor limiting referral to LTx. Although age alone should not dictate lack of eligibility for LTx, and in fact is not a limitation to LTx candidacy in Israel, our study suggests that older age may be associated with lower rates of referral. Previous studies have shown that older patients are at increased risk for pre- and post-transplant mortality. ²⁹ This was reflected in the early published guidelines of the ISHLT in 1998, recommending 60 years of age to be the upper age limit for bilateral LTx because of a significantly worse survival rate. ³⁰ Subsequently updated guidelines in 2006 started an age greater than 65 years to be a relative contraindication for LTx, ³¹ but this was changed in the 2015 guidelines which do not specify an upper age limit for listing. ⁴ Although older age (specifically recipients over 60 years old) is generally associated with increasing risk for LTx complications, some single-center reports indicate similar survival as younger recipients in carefully selected older candidates. ³² Because of global demographic changes, older patients are increasingly undergoing LTx. The number of LTx recipients aged 60 years or more increased worldwide from approximately 20% in the year 2000 to more than 40% in 2012. ³³ In our study, 45.6% of the non-referred patients were diagnosed with IPF, a disease more common in the older population, and possibly not referred on the basis of age criteria alone. It is worth noting that LTx in patients over the age of 60–65 is a change in practice of the last decade which many physicians may not be aware or may not have implemented into their practice.

Our findings should be interpreted in light of several limitations. Firstly, the retrospective nature of this single-institution experience may limit the generalizability of the results. Secondly, patients were included in this study based solely on PFT measurements, whereas in practice, the selection process of appropriate candidates is meticulous, and involves a complex constellation of factors. Despite a rigorous chart review process, it is impossible to cover with absolute confidence all considerations of the referring physician. Moreover, ISHLT guidelines, which are used in this work as a reference for referral to LTx, are generally based on expert consensus and have a relatively quick trigger for referral of patients with ILD with the rationale that these patients, and particularly patients with IPF, may quickly progress from stable to near death. Therefore, the motive behind the guidelines is not to miss patients who could be helped with transplant. In real life, the clinician is faced with a much larger set of conditions and considerations that include unmeasurable factors such as patient preference and psychosocial factors that could not have been taken into account in this type of study. Finally, many differences exist between medical practices, healthcare systems, and referral criteria in place. Our findings relative to patient referral in light of the pulmonary function criteria are not easy to compare, as this has not been studied previously.

Conclusion

Referral for LTx evaluation is a poorly studied process and based on our observations, patients are often under-referred. Increased awareness of the current guidelines and early referral to LTx assessment of patients with ILD is needed in order not to miss the window of opportunity. It is imperative that referral pathways and management strategies are established for assessment at the earliest possible stage. Further study is needed to see whether these findings are ubiquitous and to improve our understanding of the factors affecting timely referral for transplantation.