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doi:10.1378/chest.06-1163
(Chest. 2007; 131:1224-1231)
© 2007 American College of Chest Physicians
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Special Considerations for Patients With Cystic Fibrosis Undergoing Lung Transplantation*

Denis Hadjiliadis, MD, MHS, FCCP

* From the Division of Allergy, Pulmonary and Critical Care, University of Pennsylvania, Philadelphia, PA.

Correspondence to: Denis Hadjiliadis MD, MHS, FCCP, Assistant Professor of Medicine, Allergy, Pulmonary and Critical Care, University of Pennsylvania, Associate Medical Director, Lung Transplantation Program, 835W Gates Building, Hospital of the University of Pennsylvania, 3600 Spruce St, Philadelphia, PA, 19104; e-mail: Denis.Hadjiliadis{at}uphs.upenn.edu

Abstract

This article reviews lung transplantation in patients with cystic fibrosis (CF). Lung transplantation is commonly utilized for patients with end-stage CF. There are several characteristics of CF that present unique challenges before and after lung transplantation. There is new information available that can be utilized to predict outcomes in patients with end-stage CF, and therefore can help in decisions of referral and listing for lung transplantation. The new lung allocation score, which allocates organs to patients who are on the lung transplant waiting list in the United States, presents new challenges and opportunities for patients with end-stage CF. In addition, the effect of the presence of microbiological flora prior to lung transplantation has been better linked to outcomes after lung transplantation. It is now known that, other than those patients harboring Burkholderia cepacia in their lungs before transplantation, most CF patients can undergo transplantation successfully. Nutrition remains an important issue among CF patients, and diabetes is a common problem after lung transplantation. In contrast, liver disease does not usually present major problems but, if it is severe, can necessitate liver and lung transplantation. Mechanical ventilation prior to transplantation might not be an absolute contraindication for CF patients. CF lung transplant recipients have good outcomes after lung transplantation compared with those of other lung transplant recipients. Quality of life is dramatically improved. However, they are still prone to common complications that all lung transplant recipients are prone to, including primary graft dysfunction, acute and chronic rejection, a variety of infections and malignancies, and renal failure.

Key Words: Burkholderia cepacia • cystic fibrosis • diabetes mellitus • lung transplantation • Pseudomonas aeruginosa

Lung transplantation is an appropriate therapy for end-stage lung disease. Since the first lung transplant of the modern era in 1983, the number of lung transplants performed has increased to approximately 1,700 per year worldwide.1 Cystic fibrosis (CF) is the third most common indication for which lung transplantation is performed and the most common indication for double lung transplantation.1 Two thirds of these transplants are performed in the United States.2 Data from the Cystic Fibrosis Registry show that death due to complications of lung transplantation is the second most common cause of death in CF patients.3 As more transplants are performed and the number of long-term survivors increases, several issues important to patients with CF undergoing lung transplantation have become evident.

Timing of Lung Transplantation

Several studies456789 from the past few years have attempted to assess the risk of death in cohorts of CF patients based on several baseline characteristics. According to these studies, several factors, in addition to FEV1, have been shown as important predictors. According to the largest studies,4 using data from the Cystic Fibrosis Registry, pulmonary function, number of exacerbations, age, gender, weight, presence of diabetes, pancreatic insufficiency, and type of bacterial colonization are all important parameters in predicting 5-year survival. Another study7 found similar predictors, but for 2-year survival FEV1 alone performed almost as well. The disadvantages of these studies are the inclusion of all patients with CF, regardless of whether they were transplant candidates or not. Smaller studies56 have assessed only patients listed on the lung transplant list or single-center patients, but they lacked the power to adequately assess many factors. A recent study9 used a multicenter approach to identify predictors of death for patients on the waiting list. Lung function, PaCO2, and referral from an accredited CF center were all important predictors of outcome. In addition, patients who had been referred in later years had decreased risk of death. The study included adult and pediatric patients in two different countries with different listing systems; therefore, it is difficult to assess how the findings apply in each specific situation. Finally, a recent study10 found that patients with severe exacerbations requiring ICU care have a very poor prognosis.

Another recent controversial study11 found that pediatric patients and patients colonized with Burkholderia cepacia never derive a survival advantage with lung transplantation, although the number of patients in these categories undergoing lung transplantation was small. In addition, the study was based on registry data, which are a compilation of data from many centers performing a small number of transplants for pediatric and B cepacia patients. Only a few centers perform a significant number of transplants on the above group of patients, and they could provide better information on their outcomes.

The average waiting time for patients with CF between 1997 and 2002 was similar to that for patients with other diseases and was > 2 years, with approximately 20% of patients undergoing transplantation within 1 year and 40% within 2 years.12 From 2000 to 2004, the number of CF patients on the waiting was approximately 400. During these years, between 141 and 191 CF patients were transplanted each year, and 78 to 110 CF patients died while waiting on the list.12 CF patients have the best short-term and long-term survival times compared to patients with other diagnoses. The 1-month, 1-year, 3-year, 5-year, and 10-year survival rates are 92.4%, 80.6%, 65.2%, 53.8%, and 32.1%, respectively, and are statistically better than rates for patients with other diagnoses.1 The survival of CF patients after undergoing lung transplantation compared with other lung transplant recipients can be seen in Figure 1 . Any decision on listing for lung transplantation has to take into account survival with and without transplantation.


Figure 1
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  		Figure 1. Survival of lung transplant recipients with CF compared with that of other lung transplant recipients.

 
Another factor on the timing of referral for lung transplantation is the new organ allocation system that has been in effect in the United States since May 2005. According to the new system, all patients awaiting lung transplantation receive a lung allocation score (LAS), which is based on the patient’s predicted transplant benefit and risk of death without a transplant after blood group and size are taken into account.13 As a result, patients with the highest risk of death and potential benefit are given priority. The variables of the prediction model can be seen in Table 1 . The model has been constructed by using information from the United Network of Organ Sharing (UNOS) from patients who have been listed for lung transplantation and from those who have undergone lung transplantation. Its prediction window is 1 year. However, this model has not yet been prospectively validated and did not include many other CF-specific factors (eg, bacterial colonization).13 At this time, CF patients, as a group, do not appear to be given increased or reduced priority based on the new system, although there is the opportunity for sicker patients to receive higher priority.14 In addition, according to UNOS, the number of deaths of CF patients on the waiting list in 2005 was reduced, without changing the number of patients receiving a transplant (CF patients undergoing transplantation, 190; CF patients died on the waiting list, 67).12


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  		Table 1. Variables Used To Calculate LAS Score and Allocate Lungs for Patients on the Waiting List in the United States*

 
Patients with a high risk of death in 2 to 3 years should be considered for referral for lung transplantation. Patients should not have other significant medical and psychosocial problems.15 Absolute and relative contraindications to lung transplantation can be seen in Table 2 , although updated guidelines are in the process of being developed, since new evidence has altered practice at many centers. Quality of life should also be taken into account when considering lung transplantation, although it cannot be the sole determinant for consideration for lung transplantation. In the United States, early referral for high-risk patients should be considered, since it is unknown how the new LAS system will affect the length of time spent on the waiting list. All of the above studies should serve as a guideline for referral and listing for lung transplantation, while taking into account unique patient and center characteristics. In addition, patients have to be healthy enough to be able to survive the transplant operation.


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  		Table 2. Absolute and Relative Contraindications to Lung Transplantation According to the International Society for Heart and Lung Transplantation, the American Thoracic Society, the European Respiratory Society, and the American Society of Transplant Physicians*

 
The seemingly conflicting results of the predictors of survival in CF patients can be explained by the use of different databases to derive the models and by the differing time frames the prediction was aimed at. In general, lung function, body mass index, age, and comorbid conditions appear to be common risk factors in all models, so lung transplantation should be thought of in their presence. It is difficult to make firm recommendations for patients with B cepacia or for pediatric patients, but select patients at experienced centers can be considered for lung transplantation.

Bacterial Colonization/Infection

The majority of CF patients are colonized/infected with Pseudomonas aeruginosa by the time they are considered for lung transplantation. In most cases, there are mucoid and nonmucoid strains of the organism in the lungs of the transplant recipient.16 The impact of the resistance pattern of the Pseudomonas strains before lung transplantation appears to be minimal on survival after lung transplantation. Three smaller studies171819 have provided conflicting results, while a larger study20 has shown a significant, but clinically small, effect. The isolation of pretransplant organisms after transplantation is common; however, its impact appears to be less important in the setting of normal lung function.

In contrast, colonization with B cepacia complex appears to have a major impact on posttransplant outcomes. The survival rate is approximately 15 to 20% lower at all time points after lung transplantation compared with that of other CF patients.2122 Most of the patients die of sepsis from B cepacia in the early posttransplant period, although late sepsis has been observed after periods of intense immunosuppression. Efforts to alter immunosuppression, or to use aggressive sterilizing techniques or multiple combinations of antibiotics have made little impact on long-term survival (Cecilia Chaparro, MD; personal communication; November 2006). The results are even more impressive considering that many of these transplants were performed at very experienced centers.

At this time, the majority of B cepacia patients who have required transplantation have harbored B cepacia genomovar III (cenocepacia).2223 The small number of nongenomovar III patients makes it difficult to assess the difference in the effect of these bacteria on posttransplant survival. Data from the CF, nontransplant literature suggest that the impact of other B cepacia genomovars is less dramatic than that of genomovar III.24

The presence of Staphylococcus aureus, methicillin-sensitive or methicillin-resistant, appears to have no significant impact on outcomes after lung transplantation (although more IV therapy is needed for patients with resistant strains).25 The effect of other bacteria remains unknown. There are not enough data on the impact of Stenotrophomonas maltophilia or Achromobacter xylosoxidans on posttransplant survival. However, these bacteria do not seem to adversely affect outcome compared with Pseudomonas in CF patients outside the setting of transplantation.25 The current evidence suggests that colonization with bacteria other than B cepacia should not be a contraindication to lung transplantation. Patients colonized/infected with B cepacia can be considered for transplantation at specialized centers, when their expected survival without a transplant is very poor.

Colonization/Infection With Fungi and Mycobacteria

There is less information available on the significance of colonization/infection with fungi prior to lung transplantation. Aspergillus species are isolated before transplantation in 10 to 25% of patients with CF.1525 Their presence does not appear to predict the isolation of fungal species after transplantation and it does not predict outcome.2627 Aspergillus is frequently isolated in patients with anastomotic problems after transplantation, whether they have CF or not.28

A rarer form of Aspergillus colonization pretransplant can be in the form of intracavitary aspergillosis. There is little information on the effect of such a disease posttransplant; however, in patients with other diseases, cavitary aspergillomas that abide the pleura can lead to decreased posttransplant survival. Aggressive pretransplant and posttransplant therapy can lead to successful transplantation.29

Nontuberculous mycobacteria are isolated in 10 to 15% of CF patients prior to lung transplantation.30 The most common mycobacterium isolated is Mycobacterium avium complex. Its presence does not lead to poor outcomes before or after lung transplantation.31 However, there have been several reports3233 of Mycobacterium abscessus infection resulting in problems after lung transplantation. M abscessus is part of the rapidly growing mycobacteria, is inherently resistant to many antibiotics, and has a propensity to infect soft tissues; therefore, removal of the native lungs does not guarantee the elimination of the above-mentioned organism. Individualized approaches are needed for patients with M abscessus who require lung transplantation, with efforts to treat infections before undergoing transplantation.

Diabetes Mellitus

The prevalence of diabetes mellitus in patients with CF has been increasing, since more patients are living longer.34 This is a problem for pancreatic-insufficient patients, who comprise 85 to 90% of patients with CF. In a recent study,35 approximately 30% of adult patients undergoing lung transplantation had CF-related diabetes. In addition, diabetes develops in approximately 20% of patients posttransplant, usually in the early postoperative period.35

The presence of diabetes has been associated with worse outcomes in CF patients, irrespective of lung transplantation.34 However, no such data exist for CF patients with diabetes undergoing lung transplantation. The small size of the studies and the presence of other more significant factors determining outcome after lung transplantation are the likely cause of the above findings.

Uncontrolled diabetes can lead to microvascular complications (renal and retinal disease),34 therefore complicating transplantation. Poorly controlled diabetes is a relative contraindication to lung transplantation for the reasons described above. Careful management posttransplant is also important. In addition, CF patients with diabetes should be managed posttransplant without caloric restriction.34 Diabetes in CF patients is not a contraindication to lung transplantation, but patients should be counseled about the risk of developing diabetes after lung transplantation.

GI and Hepatic Issues

CF patients with pancreatic insufficiency require enzyme supplementation in order to absorb nutrients. There is no compelling evidence, but most experts have suggested that pancreatic enzymes should be given along with immunosuppressive medications in order to improve absorption.36 Therapy with pancreatic enzymes should be started as soon as possible after the transplant operation. It can be more difficult to achieve therapeutic levels for CF patients with either cyclosporine A or tacrolimus.37 Sublingual tacrolimus has also been used successfully in select patients.38

Patients with pancreatic sufficiency who have CF occasionally experience episodes of acute pancreatitis. These episodes are usually treated with narcotic analgesics, the use of pancreatic enzymes, and the avoidance of fatty foods.39 They are usually not as severe as those with alcoholic or gallstone pancreatitis. Despite the fact that a commonly used posttransplant medication, azathioprine, is associated with pancreatitis, it has not been a significant problem posttransplant.

Another complication posttransplant for patients with CF is distal intestinal obstruction syndrome (DIOS). It occurs in some of the patients with pancreatic insufficiency and is commonly treated with polystyrene resin ingestion. Early after transplantation, DIOS can be a frequent and difficult problem to treat.40 The use of narcotics for postoperative pain and poor oral fluid intake can precipitate the problem and occasionally can require surgical therapy.40 For all patients with CF, and particularly those with a history of DIOS, special efforts should be made to avoid and/or treat the disease early.

Liver enzyme abnormalities are common in CF patients.41 However, true decompensated cirrhosis occurs in only 2 to 5% of patients.15 Liver biopsy in patients with CF can lead to both false-positive and false-negative results, since the disease can be quite patchy.42 Evidence suggests that synthetic function and portal hypertension can have more significant implications on liver function and outcomes.42 For patients with severe liver disease, lung-liver transplantation can be considered.43 Long-term survival for these patients appears comparable to that in lung transplant recipients.

Sinusitis

Sinusitis is very common in patients with CF. They are frequently colonized/infected with organisms similar to those in their lungs. Fear of spreading the infection to the new lungs in the setting of immunosuppression has prompted many centers to attempt preemptive operations and drainage of the sinuses.44 However, outcomes did not change, and at this time routine surgical drainage of the sinuses prior to lung transplantation cannot be recommended. A more recent study45 has suggested that surgical therapy after transplantation leads to decreased rates of colonization of the lower respiratory tract.

Nutrition

Malnutrition is an independent predictor of poor outcomes in CF patients. Studies4647 have shown that poor nutritional status leads to worse outcomes after lung transplantation and while the patient is on the transplant waiting list. Efforts to improve nutrition by using supplementation via nasogastric/nasojejunal or with percutaneous gastrostomy/jejunostomy tube insertion are usually undertaken. No absolute level of malnutrition precludes patients from undergoing lung transplantation, but usually weight < 80% of ideal or a body mass index of < 17 are considered to be a contraindication to lung transplantation. Weight gain after lung transplantation is frequent and is usually associated with improved outcomes, likely reflecting decreased energy expended for breathing, prednisone supplementation, and good health status.48

Other Issues

Osteoporosis is common in patients with end-stage lung disease.49 CF patients are particularly vulnerable to osteoporosis because of vitamin D absorption issues, in addition to chronic lung disease. Osteoporosis tends to worsen after lung transplantation because of steroid and calcineurin inhibitor use.50 Aggressive calcium and vitamin D supplementation with concomitant use of bisphosphonates can lead to maintenance of or improvement in bone density.51 Severe, symptomatic osteoporosis is a relative contraindication to lung transplantation, although in most cases careful management makes lung transplantation feasible.15

Lung transplantation for ventilator-dependent patients has been associated with a high risk of death.1 However, some reports52 have suggested that selected patients with CF can successfully undergo transplantation while receiving mechanical ventilation with excellent results. Young age and the rehabilitation potential of patients with CF might make transplantation while the patient is receiving mechanical ventilation a viable option; however, an individualized approach and careful decision making for each patient is needed.

Finally, there are other issues that are not specific to CF patients that need to be taken into consideration while assessing patients for lung transplantation. Poor exercise capacity is thought to be a contraindication to lung transplantation, but evidence assessing the level of fitness needed to successfully undergo lung transplantation remains unknown.15 Uncontrolled systemic infections, malignancy without curative therapy, and drug, alcohol, and tobacco abuse are absolute contraindications in most lung transplant centers.15 Other important factors in determining eligibility for lung transplantation include appropriate social support and the absence of decompensated psychiatric disease, which could lead to noncompliance with therapy. Unfortunately, there are no studies supporting these recommendations.

Living Donor Lung Transplantation

The shortage of donor organs and the previous UNOS lung allocation system (which gave priority to patients based on time spent on the waiting list) led to a significant number of deaths of patients who were on the list.2 Living-donor lung transplantation was undertaken for selected patients in order to circumvent the above situation. In that operation, two lower lobes are obtained from taller healthy donors and are placed in the chest cavity of a smaller recipient.53

The operation has been performed successfully in a few hundred patients with outcomes that are comparable to those with cadaveric lung transplantation in experienced centers.53 No donor deaths have been reported, but there have been serious complications. Careful consideration of psychological and social factors needs to be given, since this is an operation that puts three persons at risk. The new LAS system that was implemented in May 2005 has led to the allocation of organs based on transplant benefit and the risk of death while on the waiting list. It is possible that the need for living-donor lung transplantation will be significantly reduced with LAS implementation.

Complications of Lung Transplantation

There are several transplant-specific complications that occur in transplant recipients, irrespective of pretransplant diagnosis. These will only be mentioned briefly in the article, and the list is not inclusive. CF patients are at risk, like all other transplant recipients; however, they need to be counseled about the possibility of these complications.

In the early postoperative period, primary graft dysfunction occurs in approximately 10% of patients, with patients presenting with multilobar infiltrates and poor oxygenation, and is associated with poor early and late outcomes.54 Acute rejection occurs mainly in the first 6 months after transplantation and is found in up to 70% of patients. Chronic rejection is common after the first year posttransplant, is characterized by obliterative bronchiolitis, and is found in up to 65% of 5-year survivors. It leads to a decrease in pulmonary function with an obstructive pattern.54 There are many infectious complications. Bacterial infections in CF patients after transplantation are frequently caused by the presence of organisms pretransplant, likely from the sinuses. Aspergillus and other saprophytic fungi can cause invasive parenchymal or anastomotic infections.54 Viral infections with cytomegalovirus (CMV) are common especially in CMV mismatched patients. CMV presents with systemic or organ-specific symptoms.54 Finally, respiratory viral infections can lead to the development of respiratory failure or to the development of chronic rejection.55

Other complications include the development of renal failure, which occurs in up to 40% of 5-year survivors,1 hypercholesterolemia, and hypertension. In addition, malignancy occurs with increased frequency. For CF patients, posttransplant lymphoma is the most common malignancy, occurring in approximately 5% of patients posttransplant, but in as many as 20% of Epstein-Barr virus (EBV)-seronegative patients who receive EBV-positive organs.15657 CF patients, because of their young age, are EBV-seronegative more frequently than other lung transplant recipients. Another complication after lung transplantation is the development or worsening of gastroesophageal reflux, which is common pretransplant in patients with end-stage lung disease.58 Its presence is associated with chronic allograft dysfunction/chronic rejection.59

Expected Outcomes

CF patients achieve normal lung function after lung transplantation.60 The improvement continues in the first posttransplant year, but lung function declines as chronic rejection starts to occur. In addition, normalization of the blood gases is expected early after transplantation, usually before hospital discharge.

Exercise tolerance significantly improves after lung transplantation. CF patients achieve improvement in their New York Heart Association (NYHA) class and their 6-min walk distances quickly after lung transplantation.60 However, maximum exercise capacity appears to be reduced, likely due to skeletal muscle dysfunction.61

Quality of life also improves after lung transplantation.50 There are not enough data assessing quality of life in a prospective and longitudinal fashion; however, cross-sectional data have shown maximal improvements early after transplantation with some deterioration after the development of chronic rejection.50

Conclusions

Lung transplantation occurs in an increasing number of CF patients. There are several issues unique to this population requiring special attention and management. However, as a group their outcomes are somewhat better than those of non-CF patients. Progress has been made in understanding the factors that affect outcomes before and after transplantation. Nevertheless, there are several areas where improved understanding of the mechanisms that lead to complications after transplantation could lead to improved outcomes.

Footnotes

Abbreviations: CF = cystic fibrosis; CMV = cytomegalovirus; DIOS = distal intestinal obstruction syndrome; EBV = Epstein-Barr virus; LAS = lung allocation score; NYHA = New York Heart Association; UNOS = United Network of Organ Sharing

The author has reported to the ACCP that no significant conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Received for publication May 4, 2006. Accepted for publication August 10, 2006.

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