Lung transplant referral practice patterns: a survey of cystic fibrosis physicians and general pulmonologists

Lung transplant (LTx) is a potentially life-lengthening procedure for individuals with end-stage lung disease. To be considered a candidate, a patient’s longitudinal pulmonary provider typically makes a referral to a LTx center where the patient then undergoes an extensive medical and psychosocial evaluation. The International Society for Heart and Lung Transplantation (ISHLT) has published guidelines that recommend LTx referral for patients with a 2-year predicted survival of < 50% and a high likelihood of post-transplant survival [1]. The timing of referral is often more nuanced for pulmonologists, involving consideration of numerous patient- and disease-specific factors.

Advanced CF lung disease is the third most common indication for LTx in adults [2]. Disease-specific referral guidelines were first published by the CF Foundation (CFF) in 1998 [3] and revised in 2019 [4]. The original guidelines encouraged referral when a patient’s FEV₁ reached < 30% predicted [3], as estimated two-year survival was < 50% for these individuals at that time [5]. Survival among this cohort has more than tripled in the interval between guidelines [6], however the updated guidelines now recommend early referral for adults with CF when their FEV₁ is: (1) < 50% predicted and rapidly declining, (2) < 40% predicted with markers of shortened survival, or (3) < 30% predicted for all individuals [4].

Irrespective of lung function, additional factors may delay or even preclude a pulmonologist’s referral for LTx evaluation. A survey of CF center directors in 2015 identified physician knowledge regarding non-lung function–based recommendations for referral as a potential barrier to timely referral [7]. This regional survey of pulmonologists seeks to add to this literature by evaluating the potential influence of promising new disease-specific therapies (i.e. triple-combination CF transmembrane conductance regulator [CFTR] modulator therapies) and psychosocial factors including substance use and mental health history, on the timing of physician’s referral. Additionally, the level of work-up pulmonologists typically perform prior to referral and communication expectations from an accepting LTx program were evaluated. We hypothesized that referral patterns would differ between CF and general pulmonary (‘non-CF’) physicians and sought to identify potential areas of intervention to promote early LTx referral by CF providers.

The study protocol was reviewed and approved by the Institutional Review Board of Partners HealthCare (Protocol #:2018P002262).

There were 43/61 (70%) responses to the CF-provider survey, and 25/61 (41%) responses to the non-CF provider survey. Twenty-seven (63%) of the responding CF providers identified that they practice at pediatric CF programs. Of the non-CF pulmonary providers, all 25 reported that they primarily see adult patients (Table 1). The most common disease indication for LTx referral among non-CF providers was interstitial lung disease including idiopathic pulmonary fibrosis (n = 16, 64%), followed by chronic obstructive pulmonary disease (n = 4, 16%), and pulmonary vascular disease (n = 3, 12%). Two (8%) non-CF providers (e.g. pulmonologists not affiliated with a CFF-accredited center) identified CF as their most common disease indication for referral.

Of responding physicians (CF and non-CF combined), a majority (60%) had ≤15 years of practice experience (Table 1). The median number of patients referred for LTx annually by a physician’s practice was 3 and 5 individuals in the CF and non-CF provider groups, respectively. CF providers reported that ≥50% of patients referred to a LTx program in the prior year were prescribed a CFTR-modulator therapy prior to referral.

Responding CF providers primarily identified declining lung function as the primary trigger for referral; 91% would refer for a rapidly declining FEV₁ and 74% would refer for a FEV₁ < 30% predicted. A higher percentage of pediatric than adult CF pulmonologists indicated that a supplemental oxygen requirement, pulmonary hypertension, or refractory/recurrent pneumothorax would trigger their referral (Additional file 3: Figure S1). Referral threshold among CF providers with ≤15 years’ experience (n = 23) was lower than those with > 15 years’ experience (n = 19) with 83 vs. 63%, respectively, referring for an FEV₁ < 30% predicted; 61 vs. 47% for increasing frequency of pulmonary exacerbations; 70 vs. 53% for recurrent hemoptysis; 74 vs. 53% for pulmonary hypertension, and 39 vs. 21% for decreased 6-min walk test (6-MWT) distance.

Most CF and non-CF providers identified active substance use as precluding to referral (Fig. 1a). Specifically, 65% of CF providers and 96% of non-CF providers considered active tobacco use an absolute contraindication for referral. Sixty-three percent of CF providers and 80% of non-CF providers would preclude referral for active alcohol or substance use disorder, and 47% of CF providers and 52% of non-CF providers considered current inhaled cannabis use to be an absolute contraindication for referral. CF providers with more practice experience (> 15 years) were less likely to consider active substance use as an absolute contraindication to referral; only 58% would preclude their referral based on active tobacco, alcohol, or other substance use, and 32% would preclude their referral for current inhaled cannabis use. Few providers identified prior tobacco or other substance use with an extended period of sobriety as a contraindication for referral. Additionally, < 5% of providers in both groups identified current enteral cannabis use as an absolute contraindication.

Well-controlled depression or anxiety was notably not identified as a barrier to referral (Fig. 1b). However, 21% of CF providers and 12% of non-CF providers indicated that poorly controlled depression or anxiety despite supportive interventions and/or medications would preclude their referral. Similar to substance use, current difficulty sustaining adherence to daily medical therapy would preclude referral for many: 42% of CF providers and 40% of non-CF providers. However, a prior history of prolonged episodes of poor adherence to medical therapy would preclude < 5% of providers’ referral.

Many CF and non-CF providers identified malignancy within the past 2 years, and untreatable significant dysfunction of another major organ system as barriers to referral (Fig. 1b). CF-related end-stage kidney disease requiring dialysis and malnutrition (body mass index [BMI] < 18.5 kg/m²), were identified as the most common CF-related comorbidities that would preclude referral among CF providers (Fig. 1c). CF providers with ≤15 years of experience were more likely to preclude referral for poorly controlled CF-related diabetes, with 22% identifying this as an absolute contraindication, compared to only 5% of CF providers with > 15 years’ experience.

The potential influence of patient age and current or anticipated disease-specific therapy were also assessed. Both adult and pediatric pulmonologists were asked if pediatric age (≤18 years) would influence the timing of their referral. A third of CF providers and two-thirds of non-CF providers deferred this question (due to practice or preference) but a majority of the responding CF (24/29) and non-CF (5/9) pulmonologists said that pediatric age would not influence the timing of their referral; 2 non-CF providers would potentially delay their referral for pediatric age and the remaining minority of both groups would potentially expedite referral.

Only 7% of CF providers indicated that they would potentially delay referral for patients currently taking a CFTR-modulator (Fig. 2a); however, 33% would delay referral for patients anticipated to soon qualify for a highly effective, CFTR-modulator therapy (Fig. 2b). Stratified by years of practice, CF providers with > 15 years’ experience were more likely to delay referral for anticipated triple combination CFTR-modulator therapy; 42% would potentially delay referral compared to 26% of CF providers with ≤15 years’ experience. Similarly, 44% of non-CF providers indicated that they would potentially delay their referral if they anticipated that their patient would soon qualify for a promising new disease-specific therapy (Fig. 2c).

Seventy-two percent of CF providers indicated that no specific colonizing organism would preclude their referral. Potential organisms that would preclude some provider’s referral included: Burkholderia cepacia complex (any) (7%), Burkholderia multivorans (2%), Burkholderia cenocepacia (23%), Burkholderia dolosa (16%), Burkholderia gladioli (2%), Mycobacterium abscessus (14%), and pan-resistant organisms (5%).

The degree of testing routinely performed by the pulmonologists prior to referral was also examined. A majority of both CF and non-CF providers stated that they routinely obtain an echocardiogram (67 and 92%, respectively), 6-MWT/physical therapy evaluation (67 and 84%), and chest imaging (81 and 96%) (Fig. 3). Non-CF providers obtain a cardiac catheterization and perform age- and gender-specific cancer screening in much higher numbers than their CF provider colleagues (24 and 52%, respectively, vs. 9 and 35%). Conversely, over three quarters of CF providers routinely perform depression or anxiety screening prior to referral, compared to 16% of non-CF providers. CF providers also more commonly perform a psychosocial or psychiatric evaluation prior to referral (40% vs. 4%) and obtain palliative care consultation in higher numbers (21% vs. 4%). Non-CF providers more commonly initiate advanced care planning discussions prior to referral (44% vs. 28%).

Finally, providers where asked what types of communication they typically have with their referring LTx center currently, and their preferred mode(s) of communication peri-evaluation. A majority of CF and non-CF providers identified that they typically receive a letter or e-mail correspondence after the evaluation, which closely matches their preferred frequency of this communication (Fig. 4). Sixty percent of CF providers and 40% of non-CF providers indicated that they would prefer to receive a phone call after the evaluation from a LTx physician or nurse practitioner specifically, however only 23% of CF providers and 16% of non-CF providers stated that they receive this type of communication currently.

Lung transplant is a viable, potential life-extending treatment option with a proven survival benefit for individuals with CF and advanced lung disease [8]. Yet, many individuals with CF die each year without referral for LTx evaluation [6, 9]. Here we describe an in-depth analysis of the LTx referral process for pulmonary physicians, comparing CF and non-CF provider-referral patterns. This study adds to current research on physician-level referral barriers in CF [7] by evaluating the potential impact of substance misuse, psychosocial or medical comorbidity, patient age, and promising new therapies on provider referral, and furthermore identifies areas for improvement in pre-referral evaluation by CF providers, and communication expectations of lung transplant programs by their referring pulmonary providers.

The data yielded from our physician survey is highly relevant to the implementation of the new CFF consensus guidelines [4] which encourage early referral of individuals with CF to LTx programs. The impetus for this change from ‘timely’ to ‘early’ referral is in part due to poor predictive models for survival in advanced CF [6, 22], but primarily to allow individuals to be “medically, psychosocially, and financially prepared for LTx should the need arise” [4], and furthermore, to allow time to address modifiable barriers to LTx such as substance misuse and mental health concerns. Our study suggests that many CF provider’s current practice patterns differ from the updated recommendations, underscoring the need to educate providers on these new guidelines and their rationale.