Since 1985 lung transplantation has been an option for some patients with CF and end stage lung disease. Most transplant centres now perform a bilateral sequential lung transplant procedure in preference to a heart-lung transplant. The former has the advantage of leaving the patient with his/her own heart.
When to refer for lung transplant
It is customary to make decisions about the need for transplantation about two years before the operation is likely to be essential. Reference to a two year survival rate is based on the average two year waiting time for a lung allograft in the USA (Nathan, 2005). The referring physician needs to allow sufficient time for (a) the assessment at the transplant centre and (b) the availability of donor lungs. The decision when to refer is always difficult. Wait too long, and we risk missing the chance. Go on the list too early, and the patient’s prognosis with transplant might be worse than without. We should always remember that earlier referral is likely to be in the best interests of the patient with advanced disease, allowing time for proper management before listing (Minai & Budde, 2005).
As a ‘rule of thumb’, patients are referred to the transplant centre when their FEV1 falls to about 30% of predicted normal. How useful is this criterion? Should other seemingly important variables be factored into the equation, such as the rate of decline in respiratory function, quality of life, more frequent need for intravenous therapy or poor weight profile? There is no easy answer. Some reports advise that we should not put too much emphasis on the percent predicted FEV1 value alone. In Australia only one of 30 patients dying from 1994-1999 had an FEV1 <30% predicted normal two years before death (Robinson & Waltz, 2000). Among patients with an FEV1 less than 30% predicted, median survival in a large American CF Centre was 4.6 years with 25% of patients living over six years (Doershuk et al, 1999). In Israel patients with an FEV1 <30% survived longer than patients post-lung transplant, median 7.3 years vs. 3.5 years (Augarten et al, 2001).
Other predictors of two year mortality (Noone & Egan, 2002; Mayer-Hamblett et al, 2002) include increasing hospitalisation and use of intravenous antibiotics (odds ratio for death 3.5 for those treated for more than two respiratory exacerbations annually), lower weight and height percentiles, lower lung function (each litre increase in FEV1 reduces the odds of dying within two years by 9%) and Burkholderia cepacia complex (Bcc) or Psudomonas aeruginosa infection (odds ratio for death 4.1 for those infected with either pathogen compared to those not infected, and 1.6 for Bcc compared to P. aeruginosa infection). These studies concluded that although these variables can predict reasonably well patients who will survive, they will not reliably predict those who will die within two years (Noone & Egan, 2002). Although a multivariate model showed an FEV1 <30% predicted, a PaCO2 >50 mm Hg and the use of nutritional intervention associated with a higher risk of death, patients with an FEV1 >30% predicted had a higher risk only when the PaCO2 was >50 mm Hg while the risk of death with an FEV1 <30% was not influenced by the PaCO2 value (Belkin et al, 2006). Sophisticated models may be no more informative in the end than using the benchmark of an FEV1 value of less than 30% predicted.
The rate of decline in lung function over the preceding three years was not significant when compared to the most recent value in Mayer-Hamblett’s study (Mayer-Hamblett et al, 2002), but Rosenbluth et al advise routine evaluation of the rate of decline in lung function as well as maintaining the 30% predicted FEV1 criterion for referral. They identify poor nutrition and concurrent infection with P. aeruginosa and S. aureus as significant risk factors for a rapid decline in lung function. Identification of those patients with a rapid fall in FEV1 by reference to the best percent predicted value in each calendar year is recommended as superior, in these patients, to waiting for the value to fall to 30% predicted or less. Rosenbluth et al argue that this approach will not unnecessarily burden the transplant centres as the decision to refer and the decision to proceed to transplantation are independent of each other (Rosenbluth et al, 2004).
Liou et al concluded that only transplant recipients with a predicted five-year survival between 0% to 30% derive a survival benefit from transplantation. Patients with a predicted five-year survival of 50% or greater have a worse prognosis with surgery than without. These figures do not apply to patients with Bcc genomovar III cenocepacia infection or to those being ventilated (Liou et al, 2001; Liou et al, 2002).
Outcome after lung transplant
Transplantation has proved an increasingly effective form of treatment and some of the first patients with CF who received heart-lung transplants are still alive and healthy. Egan et al (North Carolina, USA) reported an actuarial survival rate of 81% at one year, 59% at five years and 38% at ten years (Egan et al, 2002). The UK national study and the Italian figures similarly report a 56% and 58% actuarial four year survival (Ganesh et al, 2005; Quattrucci et al, 2005). The Danish results show an actuarial survival of 80% at five years and 70% at eight years (Bech et al, 2004) compared to an 11% survival after two years for patients listed but not transplanted. Mean FEV1 increased from around 25% pre-transplant to 79% one year post transplant (Mendeloff, 1998). More recent data from the Freeman hospital reports a 1, 3, 5 and 10 year survival of 82%, 70%, 62% and 51% respectively (personal communication). Successful transplant is associated with a substantial improvement in quality of life (Vermulen et al, 2004).
It is rarely necessary to refer children for transplant but it is nonetheless a viable option with success rates equivalent to those achieved with adult patients (Mallory & Spray, 2004). The Toronto group (Solomon et al, 2004) boasted an overall 92% one, three and five year survival in 17 paediatric patients (13 with CF).
Complications associated with lung transplant
A major late complication in children and adults is obliterative bronchiolitis (OB), (Mallory & Spray, 2004; Solomon et al, 2004; Quattrucci et al, 2005). This is a narrowing of the small airways in the transplanted lungs that can cause end stage lung disease very similar to CF. Actuarial freedom from developing OB has been reported between 84% and 90% at one year, 41% and 48% at five years, and 24% and 31% at nine to 10 years (Egan et al, 1998), although more recent reports are better, suggesting a figure around 65% at six years (Quattrucci et al, 2005). Although intensive treatment can halt the progress of OB in many patients, we need a greater understanding of its pathophysiology if we are to improve long term post-transplant results.
The worse outcome in lung, compared to liver or kidney, transplant surgery is largely because of the occurrence of OB in the former, but the direct communication between the lungs and the outside environment with susceptibility to injury from inhaled material and infection may contribute to the higher rejection rate. The transplanted lungs do not have normal mucociliary clearance, innervation or lymphatic drainage so that removal of secretions, micro-organisms and foreign material is impaired (Studer et al, 2004).
Bcc infection is associated with a worse outcome. One and five year survival has been documented as 60% and 36% compared to 86% and 64% in non-Bcc infected patients (Egan et al, 2002). This high risk seems to relate to B. cenocepacia (genomovar III), infection exclusively (De Soyza et al, 2004). The greatest danger to Bcc infected patients seems to be in the perioperative period. Beyond six months from the transplant the actuarial survival curves of Bcc infected patients and other patients with CF run parallel. MRSA infection does not have any significant negative impact after lung transplant in patients with CF and should not be considered a contraindication to surgery (Chaparro et al, 2004). Nor is post transplant outcome related to the degree of P. aeruginosa antibiotic resistance (Melley et al, 2003).
Limited donor lung supply and living related donor transplants
Unfortunately in the UK only about 40% to 50% of patients who are suitable will receive a transplant because of a shortage of donor organs. The pool of donor organs may be increased by using donor lungs hitherto rejected because they have not met the rigid quality control criteria imposed by transplant centres. Research is active into exactly which criteria should be applied to the donor lungs to decide whether they are acceptable or unacceptable for transplant. Less stringent criteria will, of course, allow more transplants to take place but the transplant team must be sure that the donor lungs will function adequately in the recipient.
The shortage of donor organs has increased the interest in the use of living related donors – the donors usually being the parents. It is thought that about 25% of patients with CF have family members willing and able to donate organs (Hodson, 2000). If 25% of patients could be treated in this way, a significant number of cadaveric donors would be released for other patients on the waiting list. Living unrelated donors have also been used, e.g. the husband. A left lower lung lobe is taken from one donor and a right lower lung lobe from a second donor. These become the patient’s new left and right lungs. The donor loses approximately 15% of lung function, but can still do everything necessary for normal daily living, and the recipient has a new set of lungs. One, three and five year actuarial survival is reported at 70%, 54% and 45% respectively in all patients receiving a living lobar lung transplant (84% with CF), (Starnes et al, 2004), less than for cadaveric transplants. Mean FEV1 percent predicted levels achieved are however, very similar (Cohen & Starnes, 2001; Sweet et al, 2000) and freedom from OB is much better (95% at three years), possibly reflecting the close family relationship between most donors and recipient pairs.
The technique of living donor lung transplantation however, raises many unresolved ethical issues. Donors have a theoretical 1% risk of not surviving themselves (Starnes et al, 1994). The procedure is also logistically difficult requiring three theatres and three surgical teams. The advantage is that it can be planned in advance. As only a lobe is transplanted rather than the whole lung, there will be unoccupied space in the lung cavity of the recipient and this space is at an increased risk of becoming infected. Some transplant centres do not therefore consider patients with Bcc or pan resistant P. aeruginosa as appropriate candidates for this type of lung transplant.
We would like all of our patients on a transplant waiting list to know about the possibility of this procedure and the doctors on the unit would be very happy to talk to any family who wishes to consider it or know more about it.
Lung transplant may not be for all patients
We should always remember that transplant is not a viable option for every patient. In some cases the possibility of a transplant may raise false hopes and prolong the suffering of a patient who eventually dies before donor organs become available. Some patients and parents just do not see transplant as something for them. This view must be respected and no one should be encouraged to follow a course of treatment about which they have serious doubts.
• Lung transplant is a viable option for patients in end stage lung disease
• Burkholderia cenocepacia infection is associated with a worse prognosis but does not preclude referral
• MRSA infection is not a contraindication
• Living related lobar transplantation may be a surgical option
• Obliterative bronchiolitis is the major post-operative complication
• Transplantation may not be the preferred option for all patients and families
• Patients should be referred when FEV1 percent predicted falls below 30% or when they show a rapid fall in lung function
• Other variables may be taken into account
Augarten A, Akons H, Aviram M, et al. Prediction of mortality and timing of referral for lung transplantation in cystic fibrosis patients. Pediatr Transplant 2001; 5: 339-342. [PubMed]
Bech B, Pressler T, Iversen M, et al. Long term outcome of lung transplantation for cystic fibrosis – Danish results. Eur J Cardiothorac Surg 2004; 26: 1180-1186. [PubMed]
Belkin RA, Henig NR, Singer LG, et al. Risk factors for death in cystic fibrosis patients awaiting lung transplantation. Am J Respir Crit Care Med 2006; 173: 659-666. [PubMed]
Chaparro C, Cabello H, Gutierrez C, et al. MRSA infection in CF patients and lung transplantation. Toronto, Canada. Pediatr Pulmonol 2004; Suppl 27; 318.
Cohen RG, Starnes VA. Living donor lung transplantation. World J Surg 2001; 25: 244-250. [PubMed]
De Soyza A, Morris K, McDowell A, et al. Prevalence and clonality of Burkholderia cepacia complex genomovars in UK patients with cystic fibrosis referred for lung transplantation. Thorax 2004; 59: 526-528. [PubMed]
Doershuk CF, Stern RC, LeRoy W. Timing of referral for lung transplantation for cystic fibrosis: over emphasis on FEV1 may adversely effect overall survival. Chest 1999; 115: 782-787. [PubMed]
Egan TM, Detterbeck FC, Mill MR, et al. Lung transplantation for cystic fibrosis: effective and durable therapy in a high-risk group. Ann Thorac Surg 1998; 66: 337-346. [PubMed]
Egan TM, Detterbeck FC, Mill MR. Long term results of lung transplantation for cystic fibrosis. Eur J Cardiothorac Surg 2002; 22: 602-609. [PubMed]
Ganesh JS, Rogers CA, Bonser RS, et al. Outcome of heart-lung and bilateral sequential lung transplantation for cystic fibrosis: a UK national study. Eur Respir J 2005; 25: 964-969. [PubMed]
Hodson ME. Transplantation using lung lobes from living donors. J Med Ethics 2000; 26: 419-421. [PubMed]
Liou TG, Adler FR, FitzSimmons SC, et al. Predictive 5-year survivorship model of cystic fibrosis. Am J Epidemiol 2001; 153: 345-352. [PubMed]
Liou TG, Cahill BC, Adler FR, et al. Selection of patients with cystic fibrosis for lung transplantation. Curr Opin Pulm Med 2002; 8: 535-541. [PubMed]
Mallory GB, Spray TL. Paediatric lung transplantation. Eur Respir J 2004; 24: 839-845. [PubMed]
Mayer-Hamblett N, Rosenfeld M, Emmerson J, et al. Developing cystic fibrosis lung transplant referral criteria using predictors of two year mortality. Am J Respir Crit Care Med 2002; 166: 1550-1555. [PubMed]
Melley D, Hodson M, Gyi K. The effect of colonisation by multiple drug resistance Pseudomonas aeruginosa on the outcome of lung transplantation in cystic fibrosis patients. J Cyst Fibros 2003; 2(Suppl 1): S37.
Mendeloff EN. Lung transplantation for cystic fibrosis. Sem Thorac Cardiovasc Surg 1998; 10: 202-212. [PubMed]
Minai OA, Budev MM. Referral for lung transplantation, a moving target. Chest 2005; 127: 705-707. [PubMed]
Nathan SD. Lung transplantation: disease-specific considerations for referral. Chest 2005; 127: 1006-1016. [PubMed]
Noone PG, Egan TM. Cystic fibrosis: when to refer for lung transplantation – is the answer clear? Am J Respir Crit Care Med 2002; 166: 1531-1532. [PubMed]
Quattrucci S, Rolla M, Cimino G, et al. Lung transplantation for cystic fibrosis: 6 year follow up. J Cyst Fibros 2005; 4: 107-114. [PubMed]
Robinson W, Waltz DA. FEV1 as a guide to lung transplant referral in young patients with cystic fibrosis. Pediatr Pulmonol 2000; 30: 198-202. [PubMed]
Rosenbluth DB, Wilson K, Ferkol T, et al. Lung function decline in cystic fibrosis patients and timing for lung transplantation referral. Chest 2004; 126: 412-419. [PubMed]
Solomon M, MacLusky IB, Drabble A, et al. Paediatric lung transplantation: a single centre eight year experience. Pediatr Pulmonol 2004; Suppl 27: 319.
Starnes VA, Barr ML, Cohen RG, et al. Living related lung transplantation in cystic fibrosis. Pediatr Pulmonol 1994; Suppl 10: 128-129.
Starnes VA, Bowdish ME, Woo MS, et al. A decade of living lobar lung transplantation: recipient outcomes. J Thorac Cardiovasc Surg 2004; 127: 114-122. [PubMed]
Studer SM, Levy RD, McNeil K, et al. Lung transplant outcomes: a review of survival, graft function, physiology, health-related quality of life and cost-effectiveness. Eur Respir J 2004; 24: 674-685. [PubMed]
Sweet SC, de la Morena MT, Schuller D, et al. Pediatric living donor lobar lung transplantation. Pediatr Pulmonol 2000; Suppl 20: 310.
Vermulen KM, Van der Bij W, Erasmus ME, et al. Improved quality of life after lung transplantation in individuals with cystic fibrosis. Pediatr Pulmonol 2004; 37: 419-426. [PubMed]