L u n g Tr a n s p l a n t a t i o n f o r C y s t i c F i b ro s i s Matthew R. Morrell, MDa, Joseph M. Pilewski, MDa,b,* KEYWORDS Lung transplantation Cystic fibrosis Advanced lung disease Respiratory failure Burkholderia cepacia Nontuberculous mycobacteria
KEY POINTS Lung transplantation is a good option for many patients with advanced lung disease due to cystic fibrosis (CF), including patients with comorbidities, resistant pathogens, prior thoracic procedures, and liver disease. Early referral is critical for patient education and intervention for comorbidities, such as malnutrition, poorly controlled diabetes, and atypical infections that may increase the risk of posttransplant complications. Criteria for lung transplant for patients with CF vary significantly among transplant centers; thus, referral to multiple centers may be necessary to maximize opportunities for individual patients. Patients with CF and respiratory failure requiring mechanical support with ventilation and/or extracorporeal membrane oxygenation may remain viable candidates for transplant with outcomes comparable with other patients with CF.
Lung transplantation is a viable option for many patients with end-stage lung disease. Since inception, more than 47,000 adult lung transplantations have been performed worldwide, according to the most recent International Society of Heart and Lung Transplantation report.1 Despite the development of newer cystic fibrosis (CF) therapies and improved delivery of care, which has resulted in improved median survival for patients with CF,2 lung transplantation provides an additional management option for patients with end-stage pulmonary disease from CF. In 1983 the first lung transplant for CF was performed, and CF now accounts for almost 17% of all pretransplant diagnoses.1,3 Despite refinements in lung allocation practices, a
proportion of patients with CF die while waiting for 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%.4 Other variables associated with a high risk of death from CF are hypoxia, hypercapnia, pulmonary hypertension, reduced 6minute walk distance, and female sex.4,5 From these variables, a few predictive models of survival in patients with CF have been developed; however, predicting survival for patients with CF is imprecise at best.6–8 The goal of lung transplantation in patients with CF is to not only extend survival but also to improve quality of life. In comparison with other patients with end-stage lung disease, individuals with CF
Disclosure statement: The authors have nothing to disclose relevant to this article. a Lung Transplant Program, University of Pittsburgh Medical Center, NW628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA; b Adult Cystic Fibrosis Program, Children’s Hospital of Pittsburgh of UPMC and University of Pittsburgh Medical Center, NW628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 37 (2016) 127–138 http://dx.doi.org/10.1016/j.ccm.2015.11.008 0272-5231/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
BACKGROUND
128
Morrell & Pilewski face unique challenges when considering lung transplantation, yet the median survival for individuals with CF after transplant exceeds those of individuals who underwent a transplant for other end-stage lung diseases.1
Box 2 Studies performed during lung transplant evaluation for CF Chest radiograph Computed tomography of the chest
GUIDELINES FOR REFERRAL AND EVALUATION
Complete pulmonary function tests
Listing for lung transplantation should be considered at a time when survival from respiratoryrelated complications from CF is considered to be less than survival after lung transplantation. To date, there are no prospective, randomized, well-powered studies that define the optimal timing of transplant referral and listing. Early referral to a lung transplant center, before the anticipated need for listing, is highly encouraged to initiate patient and family education and to identify and correct potential barriers to lung transplantation (eg, malnutrition, substance abuse, poor psychosocial support). The decision to list patients with CF is complex and should take into account the rate of decline in pulmonary function, frequency of exacerbations, and the development of baseline hypercapnia and pulmonary hypertension. Current recommendations from the International Society of Heart and Lung Transplantation are based on small studies and expert opinion consensus (Box 1). To determine the severity of disease and appropriateness for lung transplantation, several studies are performed during the evaluation process (Box 2).
Quantitative ventilation/perfusion scan
6-minute walk Barium swallow Electrocardiogram Transthoracic echocardiogram Right 1/
left heart catheterization
Bone densitometry Age-appropriate examinations
health
maintenance
Complete blood count Renal function panel Hepatic function panel Arterial blood gas Sputum culture, including fungal and AFB 24-hour urine for creatinine clearance Thrombosis risk panel HLA molecular typing HLA antibody screen Blood group type Hemoglobin A1C Urinalysis PPD/Quantiferon Gold TB test Serologies
Box 1 Criteria for listing for lung transplantation in patients with CF
HIV Hepatitis B Hepatitis C
FEV1 less than 30% predicted or rapidly declining lung function
Syphilis
Frequent exacerbations requiring antimicrobial therapy
Varicella-zoster virus
Recent exacerbation requiring mechanical ventilation Increasing oxygen requirements Recurrent hemoptysis despite embolization procedures Refractory or recurrent pneumothorax Baseline hypercapnia (PCO2 >50 mm Hg) Pulmonary hypertension Ongoing weight loss despite aggressive nutritional supplementation
Herpes simplex virus Cytomegalovirus Epstein-Barr virus Toxoplasmosis Abbreviations: AFB, acid fast bacilli; HIV, human immunodeficiency virus; PPD, purified protein derivative; TB, tuberculosis.
SELECTION OF CANDIDATES FOR LUNG TRANSPLANTATION Lung transplantation should be considered for patients whose clinical status has progressively
Lung Transplantation for Cystic Fibrosis declined despite maximal medical therapy. Candidates should have a high risk of death from lung disease (>50%) within 2 years without lung transplantation and a high likelihood of 5-year posttransplant survival in the setting of acceptable graft function.9 The ideal candidate should be free of significant extrapulmonary comorbidities; however, the other systemic manifestations of CF rarely preclude lung transplantation. 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. In general, patients with CF should be free from the following: malignancy within the past 2 years; significant and untreatable heart, renal, or hepatic dysfunction; significant chest wall deformity; uncorrectable bleeding diathesis; and psychiatric conditions that may impede adherence to a complex medical regimen. Candidates should be historically compliant with medical therapies, have good insight and a reliable social support system, have a good potential for physical rehabilitation, and be free of any recent substance abuse or dependence.9
TYPE OF TRANSPLANTATION Although the first lung transplantation for CF was actually a combined heart and lung transplantation, bilateral sequential lung transplantation became the preferred procedure in the early 1990s.10,11 This procedure originally involved transection of the sternum in a clamshell procedure to fully expose the chest cavity. However, bilateral anterior thoracotomies are now preferred at some centers as a sternal-sparing procedure to avoid surgical complications, such as nonunion of the sternum and sternal osteomyelitis.12,13 However, for cases in which surgical challenges are expected, the clamshell procedure remains ideal to fully expose all intrathoracic structures. To combat the high mortality among patients with CF awaiting lung transplantation, and limited donor lung availability, living-donor lobar lung transplantation was implemented as an alternative to conventional cadaveric lung transplantation.14 With this procedure, single lobes are removed from one or more living donors and implanted in the recipient. Despite reports of comparable shortand long-term outcomes compared with conventional lung transplantation, this procedure is rarely performed now because of occasional donor complications and the recent changes in the urgency/ benefit allocation system for cadaveric lung transplantation in the United States.15,16 Cadaveric lobar lung transplantation carries the benefit of reducing wait-list mortality for patients with small stature without imposing any risk to a living donor.
In this procedure, individual lobes from deceased donors with larger chest cavities are implanted in recipients with smaller chest cavities. In this decade, cadaveric lobar lung transplantation has been safely performed in patients with CF with encouraging short- and long-term outcomes.17,18
COMORBIDITIES IN CYSTIC FIBROSIS AND IMPACT ON TRANSPLANT CANDIDACY AND OUTCOMES An important consideration for lung transplantation is the impact of pretransplant comorbidities on outcomes. Several reports of single-center outcomes for patients with CF have been published; however, to date, there are no predictive models that allow estimation of risk associated with multiple comorbidities. CF-specific comorbidities and their individual impact on survival are listed in Table 1. Candidacy for lung transplant is based largely on center experience and level of risk aversion, which varies widely among transplant programs. Typically higher-volume transplant centers will often offer transplant listing to patients previously declined at less experienced centers. For this reason, it is imperative that CF clinicians explore referral to multiple transplant centers if the local center declines.
Prior Thoracic Procedures Historically, prior thoracic procedures were considered to be a major contraindication to lung transplantation. Pneumothoraces are a risk factor for mortality in patients with CF; for the transplant surgeon, less aggressive measures are preferred over chemical or surgical pleurodesis.19 Many patients can be managed with prolonged chest tube drainage, often with a indwelling pleural catheter, to minimize the short- and long-term risk of pleurodesis. Nevertheless, although few studies have detailed the impact of pleural procedures on transplant outcomes, many centers have found that prior pleural procedures increase the complexity of recipient pneumonectomy and increase pleural bleeding. In one large single-center report, Meachery and colleagues20 reported on outcomes for 176 patients with CF who underwent lung or heart-lung transplantation from 1989 to 2007. For the 12% who had prior pneumothorax (including 6 patients with pleurodesis), outcomes were no worse in patients with prior pneumothoraces and pleurodesis compared with the larger cohort. Thus, patients with prior pneumothoraces, including those treated by pleurodesis, can, in the care of an experienced transplant team, have comparable outcomes.
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Table 1 Controversial comorbidities in CF and their impact on transplant outcomes Comorbidity
Impact on Outcomes
Multiple-drug resistant Pseudomonas aeruginosa Gram-negative CF pathogens other than Burkholderia gladioli and Burkholderia cenocepacia Burkholderia cenocepacia
None
Mycobacterium abscessus Aspergillus fumigatus Cirrhosis Malnutrition Mechanical support with invasive ventilation or ECMO
None
Approximately 40% decrease in 1 y survival; minimal effect on 5-y survival Increase in perioperative morbidity; no appreciable effect on mortality None None with Child-Pugh A and perhaps B Debated but worst case estimate 10% lower survival at 3 and 5 y with BMI
KEY POINTS Lung transplantation is a good option for many patients with advanced lung disease due to cystic fibrosis (CF), including patients with comorbidities, resistant pathogens, prior thoracic procedures, and liver disease. Early referral is critical for patient education and intervention for comorbidities, such as malnutrition, poorly controlled diabetes, and atypical infections that may increase the risk of posttransplant complications. Criteria for lung transplant for patients with CF vary significantly among transplant centers; thus, referral to multiple centers may be necessary to maximize opportunities for individual patients. Patients with CF and respiratory failure requiring mechanical support with ventilation and/or extracorporeal membrane oxygenation may remain viable candidates for transplant with outcomes comparable with other patients with CF.
Lung transplantation is a viable option for many patients with end-stage lung disease. Since inception, more than 47,000 adult lung transplantations have been performed worldwide, according to the most recent International Society of Heart and Lung Transplantation report.1 Despite the development of newer cystic fibrosis (CF) therapies and improved delivery of care, which has resulted in improved median survival for patients with CF,2 lung transplantation provides an additional management option for patients with end-stage pulmonary disease from CF. In 1983 the first lung transplant for CF was performed, and CF now accounts for almost 17% of all pretransplant diagnoses.1,3 Despite refinements in lung allocation practices, a
proportion of patients with CF die while waiting for 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%.4 Other variables associated with a high risk of death from CF are hypoxia, hypercapnia, pulmonary hypertension, reduced 6minute walk distance, and female sex.4,5 From these variables, a few predictive models of survival in patients with CF have been developed; however, predicting survival for patients with CF is imprecise at best.6–8 The goal of lung transplantation in patients with CF is to not only extend survival but also to improve quality of life. In comparison with other patients with end-stage lung disease, individuals with CF
Disclosure statement: The authors have nothing to disclose relevant to this article. a Lung Transplant Program, University of Pittsburgh Medical Center, NW628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA; b Adult Cystic Fibrosis Program, Children’s Hospital of Pittsburgh of UPMC and University of Pittsburgh Medical Center, NW628 MUH, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA * Corresponding author. E-mail address: [email protected] Clin Chest Med 37 (2016) 127–138 http://dx.doi.org/10.1016/j.ccm.2015.11.008 0272-5231/16/$ – see front matter Ó 2016 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
BACKGROUND
128
Morrell & Pilewski face unique challenges when considering lung transplantation, yet the median survival for individuals with CF after transplant exceeds those of individuals who underwent a transplant for other end-stage lung diseases.1
Box 2 Studies performed during lung transplant evaluation for CF Chest radiograph Computed tomography of the chest
GUIDELINES FOR REFERRAL AND EVALUATION
Complete pulmonary function tests
Listing for lung transplantation should be considered at a time when survival from respiratoryrelated complications from CF is considered to be less than survival after lung transplantation. To date, there are no prospective, randomized, well-powered studies that define the optimal timing of transplant referral and listing. Early referral to a lung transplant center, before the anticipated need for listing, is highly encouraged to initiate patient and family education and to identify and correct potential barriers to lung transplantation (eg, malnutrition, substance abuse, poor psychosocial support). The decision to list patients with CF is complex and should take into account the rate of decline in pulmonary function, frequency of exacerbations, and the development of baseline hypercapnia and pulmonary hypertension. Current recommendations from the International Society of Heart and Lung Transplantation are based on small studies and expert opinion consensus (Box 1). To determine the severity of disease and appropriateness for lung transplantation, several studies are performed during the evaluation process (Box 2).
Quantitative ventilation/perfusion scan
6-minute walk Barium swallow Electrocardiogram Transthoracic echocardiogram Right 1/
left heart catheterization
Bone densitometry Age-appropriate examinations
health
maintenance
Complete blood count Renal function panel Hepatic function panel Arterial blood gas Sputum culture, including fungal and AFB 24-hour urine for creatinine clearance Thrombosis risk panel HLA molecular typing HLA antibody screen Blood group type Hemoglobin A1C Urinalysis PPD/Quantiferon Gold TB test Serologies
Box 1 Criteria for listing for lung transplantation in patients with CF
HIV Hepatitis B Hepatitis C
FEV1 less than 30% predicted or rapidly declining lung function
Syphilis
Frequent exacerbations requiring antimicrobial therapy
Varicella-zoster virus
Recent exacerbation requiring mechanical ventilation Increasing oxygen requirements Recurrent hemoptysis despite embolization procedures Refractory or recurrent pneumothorax Baseline hypercapnia (PCO2 >50 mm Hg) Pulmonary hypertension Ongoing weight loss despite aggressive nutritional supplementation
Herpes simplex virus Cytomegalovirus Epstein-Barr virus Toxoplasmosis Abbreviations: AFB, acid fast bacilli; HIV, human immunodeficiency virus; PPD, purified protein derivative; TB, tuberculosis.
SELECTION OF CANDIDATES FOR LUNG TRANSPLANTATION Lung transplantation should be considered for patients whose clinical status has progressively
Lung Transplantation for Cystic Fibrosis declined despite maximal medical therapy. Candidates should have a high risk of death from lung disease (>50%) within 2 years without lung transplantation and a high likelihood of 5-year posttransplant survival in the setting of acceptable graft function.9 The ideal candidate should be free of significant extrapulmonary comorbidities; however, the other systemic manifestations of CF rarely preclude lung transplantation. 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. In general, patients with CF should be free from the following: malignancy within the past 2 years; significant and untreatable heart, renal, or hepatic dysfunction; significant chest wall deformity; uncorrectable bleeding diathesis; and psychiatric conditions that may impede adherence to a complex medical regimen. Candidates should be historically compliant with medical therapies, have good insight and a reliable social support system, have a good potential for physical rehabilitation, and be free of any recent substance abuse or dependence.9
TYPE OF TRANSPLANTATION Although the first lung transplantation for CF was actually a combined heart and lung transplantation, bilateral sequential lung transplantation became the preferred procedure in the early 1990s.10,11 This procedure originally involved transection of the sternum in a clamshell procedure to fully expose the chest cavity. However, bilateral anterior thoracotomies are now preferred at some centers as a sternal-sparing procedure to avoid surgical complications, such as nonunion of the sternum and sternal osteomyelitis.12,13 However, for cases in which surgical challenges are expected, the clamshell procedure remains ideal to fully expose all intrathoracic structures. To combat the high mortality among patients with CF awaiting lung transplantation, and limited donor lung availability, living-donor lobar lung transplantation was implemented as an alternative to conventional cadaveric lung transplantation.14 With this procedure, single lobes are removed from one or more living donors and implanted in the recipient. Despite reports of comparable shortand long-term outcomes compared with conventional lung transplantation, this procedure is rarely performed now because of occasional donor complications and the recent changes in the urgency/ benefit allocation system for cadaveric lung transplantation in the United States.15,16 Cadaveric lobar lung transplantation carries the benefit of reducing wait-list mortality for patients with small stature without imposing any risk to a living donor.
In this procedure, individual lobes from deceased donors with larger chest cavities are implanted in recipients with smaller chest cavities. In this decade, cadaveric lobar lung transplantation has been safely performed in patients with CF with encouraging short- and long-term outcomes.17,18
COMORBIDITIES IN CYSTIC FIBROSIS AND IMPACT ON TRANSPLANT CANDIDACY AND OUTCOMES An important consideration for lung transplantation is the impact of pretransplant comorbidities on outcomes. Several reports of single-center outcomes for patients with CF have been published; however, to date, there are no predictive models that allow estimation of risk associated with multiple comorbidities. CF-specific comorbidities and their individual impact on survival are listed in Table 1. Candidacy for lung transplant is based largely on center experience and level of risk aversion, which varies widely among transplant programs. Typically higher-volume transplant centers will often offer transplant listing to patients previously declined at less experienced centers. For this reason, it is imperative that CF clinicians explore referral to multiple transplant centers if the local center declines.
Prior Thoracic Procedures Historically, prior thoracic procedures were considered to be a major contraindication to lung transplantation. Pneumothoraces are a risk factor for mortality in patients with CF; for the transplant surgeon, less aggressive measures are preferred over chemical or surgical pleurodesis.19 Many patients can be managed with prolonged chest tube drainage, often with a indwelling pleural catheter, to minimize the short- and long-term risk of pleurodesis. Nevertheless, although few studies have detailed the impact of pleural procedures on transplant outcomes, many centers have found that prior pleural procedures increase the complexity of recipient pneumonectomy and increase pleural bleeding. In one large single-center report, Meachery and colleagues20 reported on outcomes for 176 patients with CF who underwent lung or heart-lung transplantation from 1989 to 2007. For the 12% who had prior pneumothorax (including 6 patients with pleurodesis), outcomes were no worse in patients with prior pneumothoraces and pleurodesis compared with the larger cohort. Thus, patients with prior pneumothoraces, including those treated by pleurodesis, can, in the care of an experienced transplant team, have comparable outcomes.
129
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Table 1 Controversial comorbidities in CF and their impact on transplant outcomes Comorbidity
Impact on Outcomes
Multiple-drug resistant Pseudomonas aeruginosa Gram-negative CF pathogens other than Burkholderia gladioli and Burkholderia cenocepacia Burkholderia cenocepacia
None
Mycobacterium abscessus Aspergillus fumigatus Cirrhosis Malnutrition Mechanical support with invasive ventilation or ECMO
None
Approximately 40% decrease in 1 y survival; minimal effect on 5-y survival Increase in perioperative morbidity; no appreciable effect on mortality None None with Child-Pugh A and perhaps B Debated but worst case estimate 10% lower survival at 3 and 5 y with BMI
