A Survey of Cystic Fibrosis Physicians’ Views on Lung Transplant Referral in the Era of Elexacaftor/Tezacaftor/Ivacaftor

Abstract

Rationale:

In 2015, a survey of cystic fibrosis (CF) physicians showed significant gaps in lung transplant (LTx) referral knowledge. Subsequently, LTx referral guidelines for people with CF were published, and elexacaftor/tezacaftor/ivacaftor (ETI) became available for >80% of people in the United States (US). We sought to assess physicians’ LTx referral knowledge and self-reported referral practices.

Methods:

CF center directors in the US were surveyed about LTx. Questions addressed transplant referral indications, contraindications, testing, and the impact of ETI on referral timing. Thematic analysis was used to assess responses to open-ended questions.

Results:

There were 110/309 (36%) responses. Respondents identified several referral indications, including rapid decline in FEV₁ (93%), recurrent hemoptysis (80%), hypoxemia (79%), and pulmonary hypertension (75%). Over 70% of respondents reported using oximetry, echocardiogram, and blood gas to assess disease severity. Respondents were more likely to find early LTx discussions useful for patients not on modulators versus on modulators (87% vs 63%, p<0.005). Most respondents (66%) reported delaying LTx referral for some patients with FEV₁ 30–40% who met criteria, while 26% had delayed referral for patients with FEV₁<30%. Uncertainty regarding optimal LTx referral timing for patients on ETI was a prominent theme of the qualitative analysis.

Conclusions:

While physician knowledge about LTx referral indications appears improved since the CF referral guidelines were published, uncertainty about referral timing is pervasive, and the guidelines will need to be updated as more data become available about the long-term effectiveness of ETI in advanced lung disease.

Introduction

A prior survey of cystic fibrosis (CF) physicians in the United States (US) in 2015 showed many physicians did not recognize markers of increased disease severity that should prompt LTx referral¹. In May 2019, the Cystic Fibrosis Foundation (CFF) published lung transplant (LTx) referral guidelines for individuals with CF². The guidelines emphasized early education and LTx referral with the goal of reducing death associated with late referral and allowing adequate time for deliberation, evaluation, and modification of barriers to LTx. These guidelines recommended early discussions about LTx to begin annually when forced expiratory volume in one second (FEV₁) is <50% of predicted. LTx referral was recommended for adults when FEV₁ is <30% predicted, FEV₁ <40% predicted with markers of increased disease severity (including pulmonary hypertension, hypoxemia, hypercapnia, or reduced 6-minute walk distance), or FEV₁ <50% predicted and rapidly declining. Referral for children was recommended at an earlier stage of disease: FEV₁ <40% predicted or FEV₁ <50% predicted with markers of increased disease severity.

Five months after the CFF LTx referral guidelines were published, in October 2019, elexacaftor/tezacaftor/ivacaftor (ETI) was approved by the U.S. Food & Drug Administration (FDA). Although the clinical trials demonstrating the effectiveness of ETI excluded patients with FEV₁<40% predicted^{3; 4}, multiple observational studies have shown that ETI improves FEV₁, decreases exacerbations, and decreases the need for supplemental oxygen/noninvasive ventilation (NIV) in people with advanced CF lung disease^5–7. The number of first time lung transplants for CF has declined dramatically in the US since ETI approval from 245 in 2018 to 42 in 2021⁸. Despite this, LTx remains an important option for many individuals with advanced CF lung disease, and there are currently limited data to inform how ETI should impact LTx referral timing.

We conducted a survey of CF physicians in the US to understand current knowledge and LTx referral patterns since publication of the CFF LTx referral guidelines and in the era of ETI. We hypothesized that the CFF referral guidelines would increase knowledge about referral indications. We additionally hypothesized that physicians would report delaying referral for at least some patients on ETI who otherwise meet CFF referral criteria.

Materials and Methods

Data collection and study population

An online survey (eTable1) was developed to assess physicians’ experiences with LTx referral for people with CF with special emphasis on the impact of ETI. Questions were adapted from the 2015 survey about CF physicians’ perspectives on LTx referral ¹ and investigators’ clinical experiences. Questions focused on pre-referral patient counseling about LTx (including topics that may be discussed, such as expected survival, the concept of early referral, costs, recovery time, expected quality of life), indications for referral, barriers to referral, and whether ETI has delayed referral. Multiple questions had an optional free response component. Respondents were also asked about demographics, practice environment (adult, pediatric, or affiliate), and clinical experience. The survey was emailed to 309 CF center directors (131 adult physicians, 142 pediatricians, and 36 physicians at affiliate centers) via the CFF on October 16, 2023 and was available until November 10, 2023. The survey was also distributed to the CF center directors in person via QR code at the North American Cystic Fibrosis Conference in November 2023. Participants were offered a $10 gift card. The University of Washington IRB approved the study (study #9762). The IRB waived documentation of informed consent since the study was determined to be minimal risk, and approved consent language was used in the survey.

Data analysis

Descriptive statistics were used to analyze survey responses. The responses of adult physicians were compared with pediatricians for multiple questions. The responses to this survey were compared with the responses from the 2015 survey for several questions. Chi-squared or fisher exact testing was used for comparisons as appropriate. Analyses were performed in STATA 18.0 (StataCorp LLC, College Station, TX). Investigators reviewed all open-ended responses. Questions that received a sufficient number of open-ended responses underwent inductive thematic analysis by two authors (NCB and KJR).

Results

Respondent characteristics

A total of 110 of 309 CF center directors responded to the survey (36% overall response rate, 47% response rate adult physicians) (Table 1). Sixty-one (55%) were adult physicians, 43 (39%) pediatricians, and 4 (4%) worked at affiliate centers that care for adults and children. The majority of respondents (69%) had been in independent practice out of fellowship for over 10 years. Seventy-five (68%) respondents reported caring for people with CF after LTx, while 44 respondents (40%) reported also caring for patients who had undergone LTx for non-CF diagnoses. Adult physicians were more likely than pediatricians to care for people with CF after LTx (80% vs 53%, p=0.005).

Table 1:

Demographics and practice experience of survey respondents grouped by program type. The survey was distributed to 309 Cystic Fibrosis Center Directors, of whom 131 were from Adult Programs, 142 Pediatric Programs, and 36 Affiliate Programs.

	Overall (N=110)	Adult (N=61)	Pediatric (N=43)
CF center type
Adult	61 (55%)
Pediatric	43 (39%)
Affiliate	4 (4%)
Missing	2 (2%)
Gender
Male	54 (49%)	28 (46%)	24 (56%)
Female	46 (42%)	30 (49%)	14 (33%)
Prefer to self-describe	2 (2%)	0	2 (5%)
Skipped	8 (7%)	3 (5%)	3 (7%)
Race
Asian	17 (15%)	12 (20%)	4 (9%)
Black/African-American	1 (1%)	1 (2%)	0
Native American/Alaska Native	0	0	0
Native Hawaiian/Samoan/Pacific Islander	0	0	0
White	80 (73%)	43 (70%)	34 (79%)
Other	4 (4%)	2 (3%)	2 (5%)
Skipped	8 (7%)	3 (5%)	3 (7%)
Ethnicity
Hispanic or Latino	9 (8%)	3 (5%)	6 (14%)
Non-Hispanic or Non-Latino	88 (80%)	52 (85%)	32 (74%)
Skipped	13 (12%)	6 (10%)	5 (12%)
Years practicing independently in CF care (after fellowship)
< 5 years	11 (10%)	8 (13%)	2 (5%)
5 to <10 years	12 (11%)	11 (18%)	1 (2%)
10 to <15 years	27 (25%)	16 (26%)	11 (26%)
>15 years	48 (44%)	21 (34%)	25 (58%)
Skipped	12 (11%)	5 (8%)	4 (9%)
Care for CF patients after lung transplant
Yes	75 (68%)	49 (80%)	23 (53%)
No	25 (23%)	8 (13%)	16 (37%)
Skipped	10 (9%)	4 (7%)	4 (9%)
Care for patients who undergo lung transplant for non-CF diagnoses
Yes	44 (40%)	29 (48%)	13 (30%)
No	57 (52%)	29 (48%)	26 (60%)
Skipped	9 (8%)	3 (5%)	4 (9%)

Lung Transplant Counseling & Discussions

Respondents were more likely to report that early LTx discussions (when FEV₁<50% predicted) were moderately or very useful for patients not on modulators (87%) compared to patients on modulators (64%, p<0.005, Figure 1). There was not a significant difference between adult physicians and pediatricians in the rating of early LTx discussions as moderately or very useful for patients on modulators (58% vs 68% p=0.17) or not on modulators (88% vs 82% p=0.34).

Figure 1:

Usefulness of early discussions about lung transplant (when FEV₁<50% predicted) when patients are vs are not on modulators, p<0.005.

The majority of respondents (65%, eFigure 1) felt very prepared to counsel patients about LTx, and the vast majority (84%) thought it was very important to feel prepared to counsel patients. Adult physicians were more likely to feel very prepared than pediatricians (77% vs 47%, p=0.018), but the importance of feeling prepared was rated similarly between adult physicians and pediatricians.

The most commonly addressed topics in LTx counseling were markers of disease severity (95%), contraindications/barriers to transplant (92%), and the concept of early referral (93%, Supplement eTable1). The least commonly addressed topics were cost (10%), waiting list time at local transplant center (26%), and the recovery time/process (30%). Compared to pediatricians, adult physicians were more likely to counsel about the recovery process (14% vs 38%, p=0.002), the evaluation process (48% vs 70%, p=0.04), social support (48% vs 70%, p=0.04), and quality of life (43% vs 72%, p=0.007).

Indications and Contraindications to Lung Transplant Referral

The most commonly reported indications for LTx referral were rapid decline in FEV₁ (93%), FEV₁<30% predicted (93%), and noninvasive ventilation (NIV) for hypercapnia (89%, Table 2A). The least commonly reported referral indications were pulmonary disease exacerbation requiring ICU admission (46%), increasing frequency of exacerbations requiring antibiotics (55%), and recurrent or refractory pneumothorax (74%). Compared to pediatricians, adult physicians were more likely to refer for increasing frequency of exacerbations (45% vs 63%, respectively, p=0.047). Compared to the 2015 survey, respondents were now more likely to report referral for rapid decline in FEV₁ (93% vs 79%, p<0.01), refractory or recurrent pneumothorax (74% vs 47%, p<0.01), recurrent hemoptysis (80% vs 66%, p<0.05), pulmonary hypertension (75% vs 54%, p<0.01), and supplemental oxygen (79% vs 56%, pp<0.01, Table 2A).

Table 2A:

Indications that would trigger referral to lung transplant program. 2B: Contraindications that would prevent referral to lung transplant program. Overall answers from 2023 survey were compared to overall answers from 2015 survey. Adult physicians in 2023 were compared to pediatricians in 2023. Bold values are statistically significant with p-values denoted:

Table 2A
Indications for lung transplant referral	2023 Overall (N=106)	2015 Overall (N=114)	Adult Physicians in 2023 (N=60)	Pediatricians in 2023 (N=42)
Rapid decline in FEV1	99 (93%)	90 (79%) **	58 (97%)	37 (88%)
FEV1 <30% predicted	98 (92%)	107 (94%)	55 (92%)	41 (98%)
Non-invasive mechanical ventilation for hypercapnia	94 (89%)	96 (84%)	55 (92%)	35 (83%)
Recurrent hemoptysis not controlled by embolization	85 (80%)	75 (66%) *	47 (78%)	35 (83%)
Supplemental oxygen requirement	84 (79%)	64 (56%) **	49 (82%)	33 (79%)
Pulmonary hypertension	79 (75%)	62 (54%) **	47 (78%)	29 (69%)
Refractory or recurrent pneumothorax	78 (74%)	53 (47%) **	47 (78%)	29 (69%)
Increasing frequency of pulmonary exacerbations requiring antibiotics	58 (55%)	57 (50%)	38 (63%) *	19 (45%)
Pulmonary exacerbation with ICU admission	49 (46%)	38 (33%)	32 (53%)	15 (36%)
Other	4 (4%)	N/A	4 (7%)	0
None	0	N/A	0	0
Table 2B
Contraindications to lung transplant referral	2023 Overall (N=103)	2015 Overall (N=114)	Adult Physicians in 2023 (N=58)	Pediatricians in 2023 (N=41)
Patient preference not to be referred	52 (51%)	N/A	32 (55%)	18 (44%)
None-CF program does not make the determination about transplant candidacy	43 (42%)	N/A	20 (34%) *	23 (56%)
Substance abuse	42 (41%)	N/A	28 (48%)	11 (27%)
Burkholderia cenocepacia	30 (29%)	63 (55%) **	22 (38%) *	6 (15%)
Tissue diagnosis of cancer	26 (25%)	74 (65%) **	20 (34%) **	4 (10%)
Poor adherence to CF care recommendations	26 (25%)	N/A	14 (24%)	11 (27%)
Lack of adequate social support	20 (19%)	N/A	12 (21%)	7 (17%)
Mycobacterium abscessus	19 (18%)	25 (22%)	15 (26%) **	2 (5%)
Inadequate nutritional status (i.e. BMI<18%)	15 (15%)	33 (29%) *	10 (17%)	5 (12%)
CF-related end-stage kidney disease requiring dialysis	11 (11%)	50 (44%) **	7 (12%)	3 (7%)
CF-related liver cirrhosis	8 (8%)	18 (16%)	5 (9%)	2 (5%)
CF-related diabetes, poorly controlled	7 (7%)	18 (16%)	4 (7%)	3 (7%)
Depression/Anxiety	5 (5%)	10 (9%)	3 (5%)	1 (2%)
Older age (>65 years)	4 (4%)	N/A	2 (3%)	2 (5%)
Other	4 (4%)	31 (27%)	4 (7%)	0
Osteoporosis	3 (3%)	1 (1%)	2 (3%)	1 (2%)
Pulmonary hypertension	1 (1%)	1 (1%)	1 (2%)	0
CF-related sinus disease, extensive	1 (1%)	0	1 (2%)	0
Other multi-drug resistant pathogens (e.g. Pseudomonas, Achromobacter)	1 (1%)	3 (3%)	1 (2%)	0
GERD	0	0	0	0

^*p<0.05,

^**p<0.01

The most commonly cited potential contraindications to LTx referral were patient preference not to be referred (51%), substance abuse (41%), Burkholderia cenocepacia (29%), poor adherence to CF care recommendations (25%), and tissue diagnosis of cancer (25%, Table 2B). Notably, 42% of respondents reported that there were no contraindications to referral, since the CF program does not make determination about transplant candidacy. Compared to pediatricians, adult physicians were more likely to not refer for cancer (10% vs 34%, p=0.007), Burkholderia cenocepacia (15% vs 38%, p=0.17), and Mycobacterium abscessus (5% vs 26%, p=0.006). Pediatricians were more likely than adult physicians to report that there are no contraindications for LTx referral (56% vs 34%, p=0.047). Compared to the 2015 survey, respondents were less likely to report end-stage kidney disease (11% vs 44%, p<0.01), inadequate nutritional status (BMI<18 kg/m²) (15% vs 29%, p<0.05), tissue diagnosis of cancer (25% vs 65%, p<0.01), and Burkholderia cenocepacia (29% vs 55%, p<0.01) as contraindications to referral.

Role of Patient Preference on Lung Transplant Referral

When asked how frequently patient preference was the main reason for delaying or deferring LTx referral, 14% of the respondents replied ‘always’, 36% replied ‘often’, 42% replied ‘rarely’, and 2% replied ‘never’ (eTable1), without a significant difference between adult physicians and pediatricians.

Survey comments revealed differing attitudes about the role of patient preference in the referral process (Table 3, Section A & eTable 2, Section A). Multiple respondents emphasized the importance of patient education about transplant as well as the desire for patients to have at least one visit with the transplant team to ensure that the patient was fully educated about transplant before making a decision. Additionally, several comments described the evolution of how patients’ decision making can change over time. However, other comments expressed concern about transplant referral without patient buy-in.

Table 3.

Section A: Participants were asked for comments regarding patient preference not to be referred for lung Tx and how that affects their referral practice. Section B: Participants were asked for comments or recommendations related to the timing of referral for LTx or discussions about LTx in the ETI era. Themes (bold) of responses were identified using thematic analysis. Representative quotes for each theme are shown

A. Themes Regarding Patient Preference Not to Undergo LTx Referral	Exemplar Quotes
Patient preference may change	“In our clinic, if a patient tells us they are not interested in transplant referral, we do discuss how their thoughts may be dynamic and change over time such that we will continue to discuss this longitudinally to ensure they have updated information about the role of lung transplant and indication for lung transplant referral.”
Need for lung transplant education	“I think there is a misconception among patients that transplant is an admission of failure, or beyond what they deserve. Patient education is needed.”
Duty to refer always	“Referral is my responsibility; listing is up to the transplant center. So, there are no hard stops for my referral.”
Lung transplant is not the right choice for everyone	“I think the patient needs to be motivated for this process to work”.
Logistics can impact patient preference	“Cost, travel time, patient not believing it’ll be an option are common barriers”
B. Themes Regarding LTx Referral in the ETI Era	Exemplar Quotes
Clinical uncertainty makes LTx timing difficult	“Difficult to determine appropriate timing for listing in some with initial improvement on ETI but still severe markers of disease”
Early referral is still important	“I believe early referral is the best. Getting a lung transplant is not an easy decision to make. The more the patient and the family know about it, the best.”
Patient factors and institutional logistics impact referral timing	“This survey does not capture the special circumstances each patient may bring to the transplant referral process...i.e., it is complex regarding pathogens and co-morbidities. Some Centers have the capability to address very difficult referrals.”
LTx is rare in pediatrics	“I answered a few of these questions as if we were in the pre-ETI era. I do not have any patients on ETI who have an FEV1 < 50% predicted or other indications for lung transplantation. Now that we are starting ETI therapy at younger ages, it is going to be exceedingly rare that we refer a pediatric patient (< 18 years of age) for lung transplant consideration.”

Testing for markers of increased disease severity

When asked how frequently the following test results are considered when deciding whether to refer for transplant, 70% of respondents reported ‘always’ or ‘often’ for 6 minute walk test, 74% for exertional testing for desaturation, 72% for nocturnal oximetry, 81% for echo, and 84% for blood gas (eTable1). There was no significant difference between adult physicians and pediatricians.

Delays in Lung Transplant Referral

In terms of referral practices, 66% of respondents reported that ETI had delayed LTx referral for patients with FEV₁ between 30% and 40% predicted who meet CFF referral criteria (Figure 2). Adult physicians were more likely to report delaying referral (81%) compared to pediatricians (41%, p<0.005).

Figure 2:

Percentage of physicians who reported that ETI delayed lung transplant referral for patients with FEV₁ 30–40% who meet current CFF referral recommendations stratified by adult physicians and pediatricians, p=0.001 (Top). Percentage of physicians who reported that ETI had delayed lung transplant referral for patients with FEV₁<30% who meet current CFF referral recommendations stratified by adult physicians and pediatricians, p=0.012 (Bottom).

In contrast, only 26% of respondents reported ETI had delayed referral for patients with FEV₁<30% predicted (Figure 2). A similar proportion of pediatricians (67%) and adult physicians (60%) reported that ETI had not changed referral. However, pediatricians were more likely to express uncertainty about how ETI had changed referral patterns (21%) compared to adult physicians (3%, p=0.003).

Respondents were more likely to report delaying transplant referral for patients with FEV₁ 30–40% than FEV₁<30% (61% vs 24%, p<0.001). The most commonly listed reasons for referral delay in FEV₁ 30–40% predicted were decreased exacerbation frequency (97%), improved FEV₁ (82%), and patient’s clinical sense of wellbeing (88%, eTable1). The most commonly listed reasons for referral delay in FEV₁<30% predicted group were the same.

Uncertainty about appropriate timing of LTx referral and listing for patients on ETI was a prominent theme from qualitative analysis of open-ended responses (Table 3, Section B & eTable2, Section B). Multiple respondents mentioned a desire for more data and updated LTx referral guidelines. Despite the prolonged clinical stability ETI may offer a patient with advanced lung disease, many respondents still thought early referral and patient education were important. Several people mentioned that logistics can impact referral timing. Good relationships between the CF Center and LTx program were highlighted as facilitators to discussing timing of referral and identifying potential barriers to transplant. Finally, several comments also mentioned patients were not always receptive to referral due to feeling well.

Anticipated need for future lung transplant

There was significant variability and uncertainty regarding how frequently people with CF will need LTx in the future. Fourteen percent of respondents thought ‘nearly all patients’ would need LTx, 13% thought ‘approximately 50%’, 43% thought ‘5–10% of patients’, 11% thought ‘nearly none’, and 17% ‘did not know’. Pediatricians were more likely to think nearly no patients would need LTx compared to adult physicians (21% vs 3%, p=0.005). There was no significant association between how often respondents thought patients would need LTx in the future vs importance of feeling prepared to discuss transplant.

Discussion

Overall, this national survey of CF Center Directors in the US showed improved knowledge about LTx referral compared to the 2015 survey, but still significant uncertainty regarding optimal LTx referral timing for patients on ETI. The majority of participants reported that they have delayed referral for at least some patients on ETI with FEV₁ 30 to 40% predicted who otherwise meet CFF referral criteria, while a significant minority of participants reported referral delay for some patients with FEV₁<30%. Ongoing research about prognostication for patients with advanced lung disease on ETI is essential to inform discussions about prognosis in CF clinic and improve referral timing. While physician knowledge about indications for referral appears improved since the CFF guidelines were published, uncertainty about the timing of LTx referral is pervasive and the guidelines will need to be updated as more data become available about the long-term effectiveness of ETI in advanced disease.

Lung Transplant Referral Guidelines for People with CF

Knowledge regarding LTx referral and markers of increased disease severity was improved compared to the 2015 survey before the CFF guidelines were published¹. In terms of pre-referral testing, only 15% of respondents in 2015 stated that they considered the components of a patient’s lung allocation score, which includes 6-minute walk test distance, pulmonary artery pressures, and supplemental oxygen requirement, when making a referral decision. In contrast in our current study, >70% respondents indicated that they consider 6-minute walk test, echocardiogram, blood gas, and/or oximetry when making referral decisions. In terms of contraindications, 43 (39%) of respondents agreed that there were no contraindications to referral since the CF center does not determine transplant candidacy. This is consistent with CFF referral guidelines which recommend referring to at least two transplant programs before determining a patient is not a transplant candidate. The profile of respondents to the 2015 survey was similar to the 2023 survey with 48% adult physicians, 34% pediatricians, and 14% of physicians who worked at affiliate centers¹. Overall, these findings support our hypothesis that the CFF LTx referral guidelines improved knowledge amongst CF physicians related to referral indications and markers of increased disease severity, although the survey did not specifically ask whether the respondents were familiar with the guidelines.

Lung Transplantation in Pediatric vs Adult Practice

There were multiple differences between pediatric and adult physicians. Adult physicians were more likely to feel very prepared for transplant discussions and to address specifics of the transplant evaluation process. Pediatricians were more likely to think that nearly no patients would need a LTx in the future. The 2022 CFF registry report shows that advanced lung disease has become rare in pediatrics: 96% of individuals with advanced lung disease were older than 18 years old⁹. This trend will likely continue especially since the FDA lowered the age of ETI approval to 2 years old in August 2023. It is possible that ETI may be available for even younger children in the future similar to ivacaftor which has been approved for infants as young as 1 month old in the US. With fewer children with advanced CF lung disease, LTx has become rare in pediatrics, with only 4 of 43 lung transplants for CF in 2022 in the US occurring in children, according to Organ Procurement and Transplantation Network (OPTN) data. Despite the rarity of LTx in pediatrics, it is important for pediatricians to be prepared to discuss LTx with patients since early routine discussion of LTx can decrease stigma and decisional conflict for patients¹⁰. Additionally, patients may adopt their providers’ attitudes about transplant¹⁰ and may view needing a LTx as an adult as a personal failure if they were told as a child that nobody with CF needs a LTx anymore. The value of anticipatory guidance for LTx as a potential treatment option in the distant future still remains as we face uncertainty about what the future of CF looks like in the era of ETI.

Role of patient preference in the referral

Half of respondents reported patient preference was ‘always’ or ‘often’ the primary reason for delaying or deferring transplant referral. This has decreased since the 2015 survey when 80% of respondents stated patient preference to not undergo LTx was ‘always’, ‘often’, or ‘sometimes’ the primary reason to defer referral ¹. We agree that people often need time to emotionally process the idea of transplant. Transplant discussions can bring up feelings of fear^{10; 11}, shame (viewing the need for transplant as a personal failure)¹⁰, and unworthiness (already lived past expected age of survival)^{11; 12}. Additionally, patient willingness to consider transplant may change over time¹¹. We also agree with the respondents’ sentiment about the need to ensure proper education about transplant before a patient makes a final decision. Patients often have inaccurate knowledge about LTx such as overly pessimistic expectations of post-transplant survival^{10; 13}. Notably, qualitative interviews with people with CF have identified survival, quality of life, recovery, and cost as important topics in LTx counseling¹⁴. Although LTx will not be the right decision for everyone, iterative discussions over time, including with the transplant team, and with up to date, CF-specific transplant information could improve the decision making process.

Increased Clinical Uncertainty about Timing of LTx in the Era of ETI

The number of lung transplants has significantly decreased for people with CF since the advent of ETI with 245 first time lung transplants in 2018 in the US compared to 42 transplants in 2022⁸. Additionally, in France 61/65 patients listed for LTx were able to come off the transplant list after ETI initiation¹⁵. Many respondents mentioned that the prolonged stability offered by ETI has increased clinical uncertainty related to timing of LTx referral. Clinicians currently face the dilemma of the benefit of early referral to allow for enough time for evaluation and deliberation versus the concern of wanting to avoid transplant too early. People with CF have a median life expectancy after LTx of 9.9 years¹⁶. The survival benefit of LTx is less certain as people on ETI are likely to live longer with advanced lung disease. However, since ETI has only been approved since 2019 and 2020 in the US and Europe, respectively, the long-term effectiveness in advanced lung disease remains unknown. One observational study of ivacaftor in patients with advanced lung disease showed initial FEV₁ improvements returned to pre-medication baseline after 5 years¹⁷. Overall, our study supports the need for more data about the long-term effectiveness of E and updated LTx referral guidelines as more data become available.

Limitations

Our study had several limitations. Our survey response rate was only 37%, though it was 47% amongst adult physicians. It is possible that the physicians who responded to the survey are more interested in or more knowledgeable about LTx compared to those who did not respond, potentially limiting the generalizability of our findings. Forty percent of respondents reported that they also care for patients who undergo LTx for non-CF diagnoses indicating they may work at a center with a LTx program. However, we did not specifically ask if respondents were LTx physicians. Another limitation is that the responses are physician self-report of referral/testing patterns instead of measurements of actual referral/testing patterns. For example, despite >70% of respondents stating that they use additional testing such as blood gas, echocardiogram, or 6-minute walk test, the 2022 CFF Patient Registry report showed only 35% of patients with advanced lung disease received at least one of these tests, down from 48% in 2019⁹ (although the accuracy of the additional testing elements in the advanced lung disease portion of the registry has not been formally validated to our knowledge). This difference may be due in part to decreased outpatient visits since the COVID-19 pandemic or due to a higher proportion of physicians engaged with LTx who responded to the survey while real-world data show overall use of testing is lower. Additionally, when assessing whether ETI has delayed LTx for patients with a low FEV₁, we did not give an answer option “not applicable in my practice” which may have applied to some respondents, especially pediatricians. At least one respondent reported answering some questions as if we were still in the pre-ETI era. Finally, every patient brings a unique set of circumstances when it comes to transplant referral, meaning there are nuances in referral decisions not captured by our survey.

Conclusion

While physician knowledge about indications for referral appears improved since the CFF guidelines were published, uncertainty about the timing of LTx referral is pervasive and the guidelines will need to be updated as more data become available about the long-term effectiveness of ETI in advanced disease.