Lung transplantation (LTx) is the ultimate treatment option for patients with end-stage lung disease. Cystic Fibrosis patients represent more than one-fifth of the lung graft recipient population and they have the highest rates of post-LTx survival (Roux A, 2019) . Data from the USA Registry (Hayes D Jr, 2016) had showed that children (<18 years old patients) are at higher risk of post-transplant mortality than adults, but a recent survey about all patients younger than age 18 years who underwent primary lung transplantation at Medical University of Vienna between 1990 and 2015 has showed that outcomes for pediatric lung transplantation have improved over the past 25 years and have become comparable to those for adult transplantation (Waseda R, 2018)
Reported percentages of CF patients survival, on the whole, are 90%, 86%, 79%, 73%, 60% e 40% at 1, 3, 5, 10, 15 e 20 years respectively after transplantation (Fakhro M, 2016) The results may become better and better overtime (Roux A, 2019), even if in a more recent retrospettive analysis by Toronto lung transplant Center (YeungJC, 2020) the 1-, 5-, and 10-year probabilities of survival in adults who were BCC-negative were 94%, 70%, and 53%, respectively and complications from lung transplant remain the second most common cause of death in cystic fibrosis (Li SS, 2018).
LTx guidelines, for patients affected by all the end-stage lung diseases, have been published by the International Society for Heart and Lung Transplantation (Orens JB, 2006), updated later as Specific European Lung Transplantation Guideliness in Cystic Fibrosis (Hirche TO, 2014) and recently revised (Ramos KJ, 2019)
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 also recently (Nkam, L, 2017) developed. However, as affirmed, also recently (Morrell MR, 2016) (Bansal A, 2019), predicting survival remains a challenge in CF patients.
The absolute and relative contraindications for lung transplantation are constantly in flux as surgical techniques and management of complications has improved over the past decade (Morrell MR, 2016). Recently, it has been affirmed (Koutsokera A, 2019) that, while B. cepacia complex remains associated with a higher post-LTx mortality, pulmonary hypertension, low BMI, CFRD and female gender have resulted not associated with post-LTx higher mortality.
Because, up to now, a considerable number of patients die on the waiting list before suitable organs become available, donor organ allocation has been realized in some countries to optimize donor use (Gottlieb J, 2014) (Vock DM, 2017), (Liss, 2019) and new procedures to increase the number of possible donors have been investigated (Valenza F, 2016).
To face the problem of the relative unavailability of donors, above all for small-size recipients, the lobar lung transplantation both from living-donor (Barr ML, 2005), and from deceased donors (Stanzi A, 2014) (Mendogni P, 2017) has been performed with good results.
Moreover, the so-called 'high-emergency waiting list' for patients with an abrupt worsening of their respiratory function, has been organised in the last decade in almost all the countries. Patients with respiratory failure requiring mechanical support with ventilation and/or extracorporeal membrane oxygenation can mantain outcomes comparable with the other patients with CF (Morrell MR, 2016). (Roux A, 2019)
Most early deaths (within 30 days) following lung transplantation for CF are caused by infection (Lobo LJ,2014) primary graft dysfunction, cardiovascular failure, and acute graft rejection. After the first month, bronchiolitis obliterans syndrome (BOS), caused by a complex immuno-pathogenetic process and characterized by progressive airflow obstruction, is the major cause of rejection and death. It was stressed that close attention to gastroesophageal reflux disease (Mendez BM, 2012) and to persistent Pseudomonas aeruginosa (Pa) colonization of paranasal sinuses (Vital D, 2012) is needed to prevent BOS in CF transplanted patients. Post-transplant lymphoproliferative disease (PTLD) is another important late cause of morbidity and mortality following lung transplantation (Lowery EM, 2017). Up to now (Burcharm P, 2017) there is limited evidence for the optimal post-LTx immunosuppression regimen in patients with CF, particularly in children (Sweet SC, 2017).
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.
What is known
One recent Cochrnae 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
- 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.
Some studies are ongoing
Extracorporeal Photopheresis as Induction Therapy to Prevent Acute Rejection After Lung Transplantation in Cystic Fibrosis Patients ( NCT03500575)
Prognostic Value of Functional Exercise Test (EFX) in Cystic Fibrosis (NCT02994017)
Prognosis Contribution of the 6 Minute Walk Test in Cystic Fibrosis : Prospective Multicenter Study (NCT02538575)