Lung transplantation (LTx) represents the ultimate treatment option for patients with end-stage lung disease. People with cystic fibrosis (CF) account for more than one-fifth of lung transplant recipients and demonstrate the highest post-transplant survival rates among all indications (Roux A, 2019). Earlier data from the US registry indicated that pediatric recipients (<18 years) were at higher risk of post-transplant mortality compared with adults (Hayes D Jr, 2016), but more recent evidence suggests that outcomes in pediatric lung transplantation have substantially improved and are now comparable to those of adults (Waseda R, 2018). In particular, a single-center analysis from the Medical University of Vienna, including patients transplanted between 1990 and 2015, demonstrated marked improvement in pediatric outcomes over the past 25 years . More recently, studies have focused on identifying pre-transplant physical condition measures that correlate with favorable post-transplant outcomes in children undergoing lung transplantation (Freiberger D, 2021) .

Overall survival rates after lung transplantation in CF have been reported at approximately 90%, 86%, 79%, 73%, 60%, and 40% at 1, 3, 5, 10, 15, and 20 years, respectively (Fakhro M, 2016). Outcomes have continued to improve over time, although a more recent retrospective analysis from the Toronto Lung Transplant Program reported 1-, 5-, and 10-year survival probabilities of 94%, 70%, and 53%, respectively, among adults without Burkholderia cepacia complex infection (Yeung JC, 2020).

Guidelines for lung transplantation in patients with end-stage lung disease have been published by the International Society for Heart and Lung Transplantation and subsequently updated with CF-specific European recommendations and more recent revisions . In addition, the Cystic Fibrosis Foundation published two consensus document comprising recommendation statements addressing the care of CF lung transplant recipients (Ramos KJ, 2019) (Shah P, 2021).

 Referral for lung transplantation should be considered when anticipated survival from CF-related respiratory disease becomes lower than expected post-transplant survival. Historically, forced expiratory volume in one second (FEV₁) has been the most commonly used prognostic marker, with early reports indicating that FEV₁ <30% predicted was associated with a 50% two-year mortality. Other factors associated with increased mortality risk include hypoxemia, hypercapnia, pulmonary hypertension, reduced six-minute walk distance, and female sex. These variables have been incorporated into prognostic survival models for people with CF, which have been developed and subsequently refined, including models specific to pediatric populations .

Listing for lung transplantation should be considered at a time when survival from respiratory related complications from CF is considered to be less than survival after lung transplantation. Historically, the forced expiratory volume in 1 second (FEV1) has been the most often used functional variable to predict prognosis, with early reports of a FEV1 less than 30% predicted being associated with a 2-year mortality of 50%. Other variables associated with a high risk of death from CF are hypoxia, hypercapnia, pulmonary hypertension, reduced 6-minute walk distance and female sex. From these variables,  predictive models of survival in patients with CF have been (Nkam, L, 2017) developed and, recently, revised (Hajizadeh N, 2021),  also for pediatric CF patients( Solomon M, 2021).

Recently, 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. Respondents identified several referral indications, including rapid decline in FEV₁ (93%), recurrent hemoptysis (80%), hypoxemia (79%), and pulmonary hypertension (75%). Respondents were more likely to find early LTx discussions useful for patients not on modulators versus on modulators (87% vs. 63%, p < .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. 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 (Burdis N, 2024).

Absolute and relative contraindications to lung transplantation continue to evolve as surgical techniques and post-transplant management improve. Although infection with Burkholderia cepacia complex remains associated with increased post-transplant mortality, other factors such as pulmonary hypertension, low body mass index, CF-related diabetes, and female sex have not consistently been associated with worse post-transplant outcomes in more recent analyses (Koutsokera A, 2019) .

Given that a significant proportion of patients die while awaiting transplantation, several organ allocation strategies have been implemented to optimize donor utilization (Ramos KJ, 2022) (Berchuck SI, 2024). To address donor scarcity, approaches such as lobar lung transplantation—particularly for small-sized recipients—and novel donor expansion strategies have been explored . Current methods to mitigate donor shortages include the use of donation after circulatory death donors, organs from selected smoker donors, and ex vivo lung perfusion .

Patients with advanced respiratory failure requiring mechanical ventilation and/or extracorporeal membrane oxygenation can achieve post-transplant outcomes comparable to those of other CF patients . Nonetheless, complications related to lung transplantation remain the second leading cause of death in CF . Early post-transplant mortality (within 30 days) is most commonly due to infection, primary graft dysfunction, cardiovascular failure, and acute rejection. Recent reviews have summarized both established and emerging therapies for managing multidrug-resistant bacterial, mycobacterial, viral, and fungal infections in CF lung transplant recipients (Vazirani J, 2021) .

Beyond the first post-transplant month, bronchiolitis obliterans syndrome—driven by complex immunopathogenic mechanisms and characterized by progressive airflow obstruction—remains the leading cause of chronic rejection and late mortality. Attention to gastroesophageal reflux disease and persistent Pseudomonas aeruginosa colonization of the paranasal sinuses is crucial to reduce BOS risk. Post-transplant lymphoproliferative disease also represents a significant late complication contributing to morbidity and mortality .

Evidence guiding optimal post-transplant immunosuppressive regimens in CF, particularly in pediatric patients, remains limited.

The role of CFTR modulator therapy after lung transplantation is currently debated, and further studies are required to clarify its risks and benefits in this setting (Kapnadak SG, 2024).

The introduction of ETI has dramatically reduced the need for lung transplantation among people with CF, reflecting substantial improvements in lung function and disease stability. Analyses of the US Cystic Fibrosis Foundation Patient Registry and Organ Procurement and Transplantation Network data demonstrate marked reductions in lung transplant referrals, waitlist additions, and transplant procedures for CF following ETI approval, despite overall increases in lung transplantation nationally. (Pena TA, 2025) (Merlo C, 2025).

Nevertheless, CFTR modulators are not universally effective, do not represent a cure, and CF remains a progressive disease that may ultimately lead to respiratory failure. Lung transplantation therefore continues to be a lifesaving option for selected patients. Recent reviews comprehensively address the current state of lung transplantation in CF, associated challenges, and the evolving landscape in the era of highly effective CFTR modulator therapy (Huang W, 2023).

• Clinical and microbiological criteria to include patients in the waiting list.
• Optimal surgical techniques, organ preservation and intensive care management.
• Optimal post-transplant management of infections, mainly airway infections.
• Optimal immunosuppressive drug therapy.
• CFTR modulators therapy impact
• Partnership between medical providers and PwCF candidate for lung transplant

One recent Cochrane Review (Saldanha IJ, 2018) on immusuppressive drug therapy for preventing rejection following lung tranplantation in CF didn't include any study due to the lack of information specific to people with CF. No RCT have been found restricted to CF patients. Three studies, in which tacrolimus and cyclosporine have been compared in all lung transplant recipients, reported no significant difference in mortality and risk of acute rejection; tacrolimus use was associated with lower risk of BOS and arterial hypertension and higher risk of diabetes mellitus 

One RCT, published in 2000, (Aris RM, 2000),  demonstrated pamidronate efficacy in improving post-transplant osteoporosis.

One study , published in 2001, (Doyle RL, 2001) studied the safety and pharmacokinetics of two different dosages of a new macrolide (RAD), used as immunosuppressive agent in CF patients compared to no-CF patients. The results showed no difference between CF and no-CF people.

One study, published in 2008 (Vilkinson OM, 2008) , showed that the use of telemedicine may enhance the support that a specialist unit can provide for the patients and their families in the pre-transplantation follow-up.

One study , published in 2009 (Vandemheen KL,2009), showed that the use of an evidence-based decision aid, specifically developed for patients with cystic fibrosis referred for lung transplantation, may improve patient knowledge and satisfaction.

One study, published in 2013 (Lobo LJ, 2013)  showed that a good survival after lung transplantation is possible also in CF patients with M. abscessus in airways.

One study (Zeriouh M, 2018) showed that  a taurolidine 2% bronchial lavage might be associated with a reduced proportion of CF patients colonized with multiresistant pathogens, particularly with P. aeruginosa.

About the issue of understanding how people with CF use lung transplant educational resources and how one prepares for having discussions and/or making decisions about lung transplant as a treatment option for advanced CF, US researchers interviewed participants and analyzed the data to understand their preferences for educational content and design. Study participants indicated that didactic resource articles were important to understanding their illness trajectory, while experiential patient stories supported fear reduction and knowledge discovery. When learning about lung transplant participants stated a preference to control the amount of information they receive and preferred a combination of didactic and experiential knowledge (Reid N, 2023)

Elexacaftor/Tezacaftor/Ivacaftor (ETI) for people with CF (PwCF) after lung transplantation (LTx) has been restrained due to uncertainties regarding efficacy and drug interactions. Dutch researchers investigated the benefits and safety of ETI for PwCF post-LTx in 55 subjects. ETI for PwCF post-LTx showed favorable effects on chronic rhinosinusitis, GI symptoms, and quality of life, but not on BMI and HbA1c. Due to its high cost, careful consideration and further studies are required. Monitoring renal function and calcineurin inhibitors trough levels is recommended (van Gemert JP, 2025).  

• Clinical and microbiological criteria to include patients in the waiting list.
• Optimal surgical techniques, organ preservation and intensive care management.
• Optimal post-transplant management of infections, mainly airway infections.
• Optimal immunosuppressive drug therapy
• CFTR modulators therapy impact

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Some studies are ongoing

Prognostic Value of Functional Exercise Test (EFX) in Cystic Fibrosis (NCT02994017). The study was completed but so far no result or publication is available.

Preparation for Lung Transplant Discussions and Decisions Among People With Cystic Fibrosis READY CF 2: A Multi-site RCT; ClinicalTrials.gov ID NCT06030206;study started September 2023, and completion will be around July 2027

To implement a clinical tool utilizing predictors of mortality for patients with Cystic Fibrosis (CF) on the waiting list to identify candidates that should present for urgent medical care  (NCT04687475). The trial is still recruiting.