Introduction

In 1983, the University of Pittsburgh performed the first lung transplant on a patient with end-stage lung disease from cystic fibrosis (CF). Since the mid-1980s lung transplantation has steadily increased, with approximately 3,500 transplants performed annually worldwide. CF is currently the third most common indication for bilateral lung transplant, with 5,688 performed between January 1995 and July 2011 [1•]. The International Society for Heart and Lung Transplantation (ISHLT) registry reports survival figures of 79 % at one year, 64 % at three years, 53 % at five years, and 30 % at 10 years. CF patients consistently have the highest reported long-term survival after lung transplant (Fig. 1).

Fig. 1
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Adult lung transplants (J Heart Lung Transplant. 2012 Oct; 31(10):1045–1095)

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Cystic fibrosis is an autosomal recessive genetic disorder caused by a mutation in the cystic fibrosis transmembrane conductance regulator (CFTR) gene, which encodes and produces a defective chloride channel resulting in multi-organ disease [2]. With advances in medical therapy, the median predicted survival age for people with CF has risen steadily over the last 25 years. In 2011, the median survival age was 36.8 years [3]. Despite therapeutic advances respiratory failure accounts for most morbidity and mortality, and lung transplant is the only treatment option to improve survival. Although, among all lung diseases requiring transplants, median survival is longest for CF patients, post-transplant complications are the second most common cause of mortality [3].

Referral and Evaluation

CF is a complex disease which causes multiple comorbidity, including chronic respiratory failure from infections, liver dysfunction, pancreatic insufficiency resulting in diabetes, chronic sinusitis, and chronic malnourishment. Assessing the appropriate timing for lung transplant referral and for the transplant itself is a continual challenge for both CF and transplant physicians. As well as medical comorbidity, psychosocial difficulties greatly affect overall outcomes in the pre and post-transplant periods.

The current international guideline recommendations for referral are a forced expiratory volume in one second (FEV1) less than 30 % of the predicted value or rapidly progressive respiratory deterioration (e.g. increasing frequency of exacerbation requiring antibiotic therapy, recurrent hemoptysis not controlled by embolization, refractory and/or recurrent pneumothorax) with an FEV1 greater than 30 % of the predicted value (Table 1). Absolute contraindications are criteria assessed as having a high probability of contributing to increased risk of morbidity and mortality post-lung transplant (Table 2). Relative contraindications include osteoporosis, malnutrition, severely limited functional status with poor rehabilitation potential, poorly managed medical problems (e.g. gastroesophageal reflux and diabetes), mechanical ventilation, and psychosocial dysfunction (e.g. medical non-compliance) [4]. To maintain eligibility as an active lung-transplant candidate, patients must demonstrate ongoing adequate management of any preoperative psychosocial difficulties. Guideline recommendations for transplant are oxygen-dependent respiratory failure, hypercapnia, and pulmonary hypertension [4].

Table 1 Guidelines for referral (Ref. [4])
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Table 2 Absolute contraindications (Ref. [4])
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Kerem et al. showed, via regression analysis, by use of models with single covariates, that FVC below 40 % predicted value, FEV1 below 30 % predicted value, PaO2 less than 55 mm Hg, PaCO2 greater than 50 mm Hg, and weight–height percentage (weight as a percentage of the ideal weight for height and sex), were stronger predictors of greater than 50 % mortality within two years of transplant than any other factor except age and gender. However, use of the same covariates in multiple-variable models found the strongest predictors of increased mortality to be age (less than 18 years of age), sex (female), and FEV1; this three-variable model was most useful for predicting high mortality [5]. Mayer-Hamblett et al. showed, by use of univariate logistic regression, that significant predictors of two-year mortality included number of hospitalizations for acute exacerbation, number of home intravenous antibiotics courses, respiratory colonization with B. cepacia and P. aeruginosa, weight and height percentile, FEV1 % predicted value, and age. Colonization with both B. cepacia and P. aeruginosa was associated with the greatest probability of dying within two years (odds ratio (OR): 4.1; 95 % CI: 2.4, 6.9) in comparison with CF patients not colonized with either organism [6].

Although there is evidence of poorer transplant outcomes [4] for patients with respiratory failure who use mechanical ventilation, many centers have reported successful transplant outcomes for these patients. Bartz et al. compared outcomes for eight CF patients who underwent mechanical ventilation for 62 ± 20 days (range 3–153 days) before bilateral lung transplant with those for 24 CF patients who were not mechanically ventilated before transplant. CF patients ventilated pre-lung-transplant had significantly prolonged extubation time after transplant (11 vs. 4 days); however, no statistical difference between the two groups was found with regard to days until hospital discharge, FEV1 % predicted value one year after transplant, or post-transplant survival [7]. Massard et al. evaluated 54 CF patients who underwent bilateral lung transplant, 10 of whom were mechanically ventilated for 14.5 ± 4.5 days (range 3–42 days) before transplant. Actuarial survival at one year was 70 % for the latter group, and was no different from that for the patients not mechanically ventilated [8]. Proper selection of such patients is necessary to achieve acceptable outcomes.

Lung Allocation Score

In 2005 the Organ Procurement and Transplantation Network implemented the lung allocation score (LAS), changing the system from one primarily based on waiting list time to one allocating donor lungs on the basis of a score calculated from multiple variables. The LAS was derived from a prediction of benefit, calculated using expected one-year post-transplant survival days and expected one-year waiting-list-time survival days. The principle objective of the LAS was to reduce the number of deaths among potential and actual lung-transplant candidates aged 12 years or older [9]. Since implementation of the LAS, there has been a reduction in waiting-list mortality without a significant effect on post-transplant survival, particularly for low-LAS groups.

Thabut et al. reviewed data from the United Network for Organ Sharing (UNOS) registry and identified 704 adult CF patients on a waiting list for lung transplant from 2005 to 2009. The main objective of the study was to assess the survival benefit of lung transplant for CF patients since LAS implementation. The cumulative incidence of lung transplant was 39.3 % (95 % CI: 35.6–42.9 %) at three months and 64.7 % (61–68.4 %) at 12 months, whereas the incidence of death during the same period for patients still on the waiting list was 8.5 % (6.4–10.6 %) at three months and 12.9 (10.3–15.5 %) at 12 months. Post-transplant survival was 96.5 % (94.7–98.2 %) at three months, 88.4 % (85.1–91.8 %) at 12 months, and 67.8 % (59.6–76.8 %) at three years. Lung transplant was associated with a 69 % reduction in risk of death (51–80 %) [10•]. For comparison, the percentage of waiting-list CF patients (n = 708) dying between January 1, 1997 and December 31, 1998 was 28 % [9].

Infections

Most CF patients are colonized by or chronically infected with respiratory pathogens (e.g. Pseudomonas aeruginosa, Methicillin-resistant Staphylococcus aureus, Burkholderia cepacia, Stenotrophomonas maltophilia). Despite initial studies reporting poor post-lung-transplant outcomes for patients with multi-drug-resistant Pseudomonas aeruginosa compared with non-infected individuals [11], subsequent studies found that post-lung-transplant survival was not affected [12–15]. However, there may be an association between the development of bronchiolitis obliterans syndrome (BOS) and infection, and possibly even colonization, by Pseudomonas aeruginosa [16, 17, 18••].

Burkholderia cepacia complex species affect approximately 3–5 % of CF patients. B. cenocepacia (formerly known as “genomovar III”) is strongly associated with increased one year post-lung-transplant mortality, with survival of infected patients being approximately 15–20 % lower at all time after lung transplant compared with that of other CF patients [19–21]. Even with adjustments to immunosuppressant drugs and aggressive antibiotic regimens, patients usually die of sepsis “cepacia syndrome” within the first few months. Many lung transplant centers regard B. cenocepacia as an absolute contraindication for lung transplant, although some centers have published case reports of successful outcomes [20–23]. Other Burkholderia cepacia complex species, excluding B. cenocepacia, have resulted in outcomes comparable with the ISHLT registry data.

Other common infectious colonizers and/or infectious agents associated with CF are Aspergillus and non-tuberculous mycobacterial (NTM) species. Approximately 20 % of CF patients are colonized with Aspergillus species pre-lung transplant. The presence of Aspergillus species has not been found to affect lung transplant outcomes; however, data suggest an increased risk of BOS and of airway complications (e.g. bronchial anastomosis infection) [24–27]. Non-tuberculous mycobacterial species are isolated from 10–15 % of CF patients, the most common being Mycobacterium avium complex [28, 29]. NTM have been increasingly identified in the post-lung-transplant population, with prevalence of 13.7 % in CF patients compared with 3.8–9 % in other lung transplant patients [30, 31, 32•]. The presence of NTM species has not been found to affect lung transplant outcomes [31, 32•, 33••]; however, Mycobacterium abscessus can pose substantial challenges post-lung transplant. M. abscessus’ disseminated nature often contributes to diseases involving skin, soft tissues, and foreign bodies. It is not uncommon for M. abscessus to affect the thoracic cavity, resulting in empyema, mediastinitis, and lung abscess. M. abscessus contributes to substantially more morbidity and mortality post-lung transplant than other NTM species [31, 32•]. However, isolation of M. abscessus during the pre-transplant evaluation process is not a contraindication for lung transplant. Eradication using a standard triple-drug regimen as recommended by American Thoracic Society guidelines should be attempted before transplant [34, 35]. Some transplant centers require smear negativity before lung transplant. Case studies of successful outcomes were reported for patients colonized with M. abscessus [36]. Aggressive treatment with anti-mycobacterial drugs for one year post-lung transplant is recommended. However, caution is required because of drug–drug interactions between anti-mycobacterial drugs (e.g. rifampin) and immunosuppressive agents (e.g. calcineurin inhibitors).

Diabetes

The incidence of CF-related diabetes (CFRD) has increased as more patients live longer, and it now affects approximately 19 % of adolescents and 40–50 % of adults [37]. Propensity to develop CFRD depends on gender: Sims et al. showed female patients to have a greater likelihood of having CFRD than male counterparts (OR: 12.38; CI: 2.6–59.0; P = 0.002) [38]. Complications associated with CFRD include microvascular (but not macrovascular) disease, reduced lung function, and increased mortality [37, 40•, 41]. Microvascular complications are primarily related to neuropathy, microalbuminuria, and retinopathy, although to a lesser extent than seen in other diabetes populations [39]. CFRD related to post-lung-transplant outcomes is limited. Studies to date have not shown an associated increased risk of mortality [42, 43••, 44]. For patients who are not diabetic pre-lung transplant, CF is an independent risk factor for developing CFRD post-lung transplant [42, 45]. Although CFRD is not a contraindication for lung transplant, uncontrolled CFRD may be.

Gastroenterology

GI-tract manifestations of CF are an increasing cause of morbidity for post-lung transplant CF patients. Manifestations commonly seen in adult patients include gastroesophageal reflux (GERD), pancreatic insufficiency, biliary disease (e.g. cholelithiasis, biliary cirrhosis), and distal intestinal obstruction syndrome (DIOS). Colon cancer, although a significant contributor to morbidity and mortality, is a less common complication.

GERD has a prevalence of approximately 75 % to 90 % in CF patients [46, 47]; in comparison, GERD is prevalent in approximately 50 % to 75 % of lung transplant patients suffering from other causes of end-stage lung disease [48, 49]. It is hypothesized that increased risk of post-lung transplant GERD could be associated with vagal nerve injury (intra-operatively), immunosuppressive therapy, and pre-transplant diagnosis of GERD. Studies have confirmed a strong correlation between GERD and bronchiolitis obliterans syndrome (BOS). King et al. found non-acid reflux pepsin and bile salts, measured by use of esophageal impedance, to be associated with development of BOS [50]. Other studies have revealed an association between BOS and the presence of bile acids and peptins in bronchoalvealor lavage specimens [51, 52]. Proton-pump inhibitors have been revealed to reduce the acidity of gastric contents; however, they do not reduce non-acid reflux. Palmer et al. and others showed that Nissen fundoplication, a surgical intervention, halted lung allograft dysfunction caused by acid reflux [53, 54, 55•, 56]. Given the high incidence of GERD in CF patients, early recognition and implementation of therapy is prudent to support successful long-term survival.

Pancreatic insufficiency and malnutrition contribute to morbidity and mortality for CF patients. Pancreatic insufficiency affects absorption of immunosuppressive therapy (e.g. calcineurin inhibitors). Although no compelling evidence supports routine use of supplemental pancreatic enzymes, expert opinion recommends co-administration to maintain adequate enzyme levels. Malnutrition affects post-lung transplant survival of CF patients. Madill et al. revealed that a body mass index <17 kg m−2 was associated with a 3.7 odds ratio for risk of death within 90 days of lung transplant [57]. In contrast, Lederer et al. showed increased late mortality for underweight transplant recipients with CF, which was attributed to chronic allograft dysfunction [58]. Underweight patients and chronically ill patients have low serum albumin, and hypoalbuminemia (serum albumin <3.5 mg dL−1) is a marker of inflammation. Using albumin concentration as a continuous predictor, Zisman et al. showed that patients with idiopathic interstitial pneumonia who were on the waiting list for lung transplants had a mortality hazard ratio of 1.79 associated with each 0.5 mg dL−1 reduction in serum albumin concentration [59]. Similarly, Baldwin et al. found that, compared with other diseases including chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis, post-lung-transplant CF patients with hypoalbuminemia had the strongest association with significantly reduced one-year and overall survival [60••]. Overall, although being underweight (or severely malnourished) is not an absolute contraindication, aggressive measures should be taken to improve nutritional status before lung transplant.

Distal intestinal obstruction syndrome (DIOS) affects approximately 10–20 % of CF patients post-lung transplant, almost exclusively affecting patients with pancreatic insufficiency [61, 62]. Precipitating factors include narcotic use, poor oral intake and/or dehydration shortly after transplant. To avoid the need for surgical intervention, active measures, including aggressive bowel regimens, should be instituted before onset.

Pre-transplant CF-related liver disease is the third most common cause of mortality of CF patients. However, serious liver disease associated with liver cirrhosis and portal hypertension resulting in synthetic dysfunction is prevalent in 10 % of CF patients only [63]. Despite evidence of CF-associated liver cirrhosis with preserved synthetic function, Nash et al. reported that carefully selected CF patients can tolerate lung transplant, with outcomes comparable with those for CF patients without CF-related liver disease [64•]. Regarding combined lung–liver transplant, Desai et al. reported outcomes comparable with those for isolated lung transplant [65]. Actuarial survival for combined lung–liver transplant for one, three, and five years was 72 %, 61.4 %, and 61.4 %, respectively. Similar outcomes were reported by other institutions [66]. Combined transplant outcomes are probably comparable with those for isolated lung transplant because of increased scrutiny of recipient selection criteria and young recipient age.

Sinus Disease

Sinusitis affects most CF patients. Organisms identified within the sinus tract are identical with those of the lower respiratory tract. Leung et al. performed a retrospective chart review of all CF patients who underwent heart–lung and lung transplant at Stanford Medical Center between 1988 and 2005, assuming that pre-lung-transplant surgical sinus intervention would lead to reduced bacterial seeding of the transplanted lungs. For 87 % of patients re-colonization with Pseudomonas occurred, and an overall survival benefit was not evident [67].

Malignancy

Risk of developing malignancy is increasing as the survival of post-lung transplant patients continues to improve. The ISHLT registry reports cumulative malignancy risk for one-year, three-year, and five-year survivors to be 3.5 %, 14.1 %, and 27.2 %, respectively [1•]. In a retrospective cohort study of 93 lung transplant recipients with CF, Saueressig et al. revealed an 8.6 % risk of developing post-transplant lymphoproliferative disease during a median time of six months (range 3–19 months) for seronegative CF patients with Epstein–Barr virus and human herpes virus (types 1, 2, 3, 6, and 8) [68••]. Colorectal cancer is the third most common malignancy diagnosed in the general population of the US. In a recent study, Maisonneuve et al. prospectively obtained data covering a 20-year period from the US Cystic Fibrosis Foundation Patient registry. Post-lung transplant, they found an unexpectedly high risk of digestive tract cancers (19 observed vs. 1.1 expected; 95 % CI: 10.7–26.5), particularly cancer of the colon (11 observed vs. 0.4 expected; 95 % CI: 15.8–52.2). One hypothesis suggests the combination of underlying bowel cancer risk and immunosuppressant therapy after lung transplant leads to a higher incidence for this population [69••, 70••].

Conclusions

The leading cause of death of CF patients is respiratory failure. Until improved medical therapy brings about a substantial reduction in respiratory failure, lung transplant remains a treatment option for CF patients. Despite the multiple co-morbidities associated with increased morbidity and mortality in CF, long-term outcomes for CF patients continue to be superior to those for patients with other lung diseases amenable to transplant. Possible areas for future research to improve transplant outcomes include surgical technique, organ procurement and preservation, and post-operative management in the intensive care unit.