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General Considerations in Candidate Selection and Timing of Transplantation
The goal of LTx is to improve survival and quality of life. Usually to prolong survival by LTx natural expected survival without LTx should be lower than 50%. LTx is a high-risk surgical procedure with a 3-month mortality of ~10 to 20% depending on the condition of the patient. General contraindications for candidate selection should be respected facing the situation of donor shortage (Table 1).
Age
ISHLT recommends an upper age limit for transplantation of 65 years, though there are variations between centers and countries reflecting local views. The age criterion is influenced by data showing a progressive increase in mortality for procedures in patients over the age of 55 years. Meanwhile, in the United States the proportion of recipients of 65 years and older has grown to 15%. Patients who develop end-stage pulmonary disease failing on medical therapy may be considered for transplantation if they conform to other criteria listed here. Lung transplantation should be used with caution in patients above the age of 60 years and should not be used for patients older than 70 years.
In a recent UNOS data review among 8,363 adult patients who underwent LTx between 1999 and 2006, 57 were above the age of 70. One-year survival was 58% and substantially lower when compared with the reference of those less than 70 years.
Weight
Obesity is considered a relative contraindication to lung transplantation. A retrospective study involving 5,978 adult lung transplant recipients with the diagnosis of cystic fibrosis, chronic obstructive pulmonary disease, and diffuse parenchymal lung disease were examined between 1995 and 2003. Compared with normal-weight recipients, the multivariable-adjusted rates of death were 15% higher for overweight recipients and 22% higher for obese recipients early on, and these relationships persisted in analysis of 5-year survival.
Other Potential Contraindications
The presence of uncontrolled systemic disease in addition to respiratory failure precludes LTx. Any cancer except form nonmelanotic skin cancer should be in remission for at least 2 years before the person is listed as a possible transplant candidate. Smoking and illicit drug abuse are not acceptable in LTx candidates; abstinence for at least 6 months is required and should be documented by blood or urine tests (e.g., cotinine).
Good renal function is essential in view of calcineurin-inhibitor toxicity and a creatinine clearance of more than 40 mL/min/1.73 m is required. In severe PH, developing kidney failure usually indicates prerenal kidney failure due to low cardiac output. Nevertheless, independent kidney disease should be ruled out in this situation. Only minor abnormalities of liver function are acceptable with no abnormalities of coagulation. A raised hepatic alkaline phosphates with minimal elevation of transaminases requires investigation but does not preclude assessment. PH is seen occasionally in patients with cirrhosis; hence, it is important to exclude the presence of this in patients with PH and abnormal liver function tests. Severe hepatic congestion may occur in patients with terminal PH. Elevated bilirubin, and especially a rise in bilirubin by 50%, usually indicates progressive disease and does not preclude LTx by itself.
Special Considerations in Idiopathic Pulmonary Fibrosis
Although LTx is viewed as an acceptable option for patients with end-stage IPF, the survival benefit of this approach is still debated. A small, single-center study has examined the survival benefit of LTx in IPF. During a 12-year period 46 IPF patients accepted for LTx and using Cox proportional-hazards modeling were compared with patients on a waiting list (e.g., control group). Twenty-eight patients underwent lung transplantation, 16 patients died while waiting, and 2 patients remained on the active waiting list. Survival after LTx was 79% and 39% at 1 and 5 years, respectively. Multivariate analysis showed that LTx reduced the risk of death by 75% after adjustment on potential confounding variables. In another single-center, retrospective analysis 31% of 129 patients (mean age 63 years) were transplanted and 27 died without transplant during a mean follow-up of 1.1 year. Delayed referral was associated with an increased risk of death.
The median 5-year survival rate of unselected patients with IPF is around 30%. There is no cure for IPF, and treatment options are limited. Currently available pharmacological therapies have limited efficacy, and none have been associated with improved survival. LTx is so far the only treatment with a better survival for carefully selected patients. Overall wait list mortality of patients with IPF is 31 to 49%.
Available longitudinal studies do not allow a clear assessment of median survival in unselected IPF patients. However, a retrospective longitudinal study involving 238 patients suggested a median survival time of 2.9 years from the time of diagnosis and 6.8 years from the estimated onset of the illness. Conversely, recent data from clinical trials demonstrate several possible natural histories for patients with IPF. Most patients demonstrate a slow, gradual progression over many years. Some patients remain stable, whereas others have an accelerated decline. Some patients may experience episodes of acute respiratory worsening. Features associated with decreased survival are increased level of dyspnea, a diffusion capacity of lower than 40% predicted, desaturation < 89% during a 6-minute walk test (6MWT), extensive honeycombing on high-resolution computed tomographic (HRCT) scans and presence of PH. Longitudinal changes including a decrease in forced vital capacity (FVC) by > 10% absolute value, worsening of fibrosis on HRCT, and decrease in diffusion capacity by > 15% absolute value were negative prognostic indicators.
Recently, several scoring systems to predict prognosis were proposed. The problem with these prognostic studies is their retrospective nature, and the cohorts studied are usually not typical transplant candidates. Most patients are older than 65 years and many have comorbidities that independently affect survival.
International guidelines recommend that candidates with pulmonary fibrosis (the histological or radiographic evidence of UIP irrespective of FVC) be referred as early as possible. The same group of experts suggest the following as criteria for listing patients when the diffusion capacity is less than 39% predicted: a 10% or greater decrement in FVC during 6 months of follow-up, a decrease in pulse oximetry below 88% during a 6MWT, and extensive honeycombing on HRCT (fibrosis score of > 2). In NSIP patients suggested listing criteria were a diffusion capacity of less than 35% predicted, a 10% or greater decrement in FVC, or a 15% decrease in diffusion capacity during 6 months of follow-up. Table 1 and Table 2 summarize suggested new and established IPF-specific recommendations of contraindications and indications, respectively.
There is now increased recognition that the underlying histology of lung fibrosis associated with connective tissue disease (CTD) may vary from that of IPF, particularly in those individuals with scleroderma-associated pulmonary fibrosis. A total of 324 cases of CTD-PF (65% rheumatoid arthritis, 14% systemic sclerosis, 19% miscellaneous) and 2,209 cases of primary IPF were followed up over a period of 2.3 years on average. The median survival for cases with IPF (median 3.1 years) was significantly lower than that for cases with CTD-PF (median 6.6 years for rheumatoid arthritis, 8.8 years for systemic sclerosis, 5.6 years for other). After adjusting for age, sex, and year of diagnosis, cases with CTD-PF had a better prognosis compared with those with IPF-CS.
The importance of desaturation in IPF patients was emphasized in a single- center retrospective when oxygen saturation (SpO2) was lower than 89% on 6MWT, 5-year survival was 20% compared with 60% without desaturation. Similarly, a resting oxygen demand before 6MWT was examined in 104 adults with IPF enrolled in a prospective cohort study and a validation cohort of 151 adults with a variety of interstitial lung diseases. The lowest oxygen flow rate required to maintain a saturation of 96% while standing was associated with a greater mortality rate independent of FVC and 6MWT results in IPF. A single-center study with prospective validation in 228 and 330 patients identified older age, female gender, a FVC below 50%, and diffusion capacity < 50% as negative prognostic indicators. Three stages (stages I, II, and III) were identified based on this index with 1-year mortality of 6%, 16%, and 39%, respectively. Similarly, 70 patients newly diagnosed with IPF were prospectively followed after building a risk stratification score from a retrospective cohort of 68 patients. Medical Research Council (MRC)-based dyspnea, 6MWT < 72% predicted (or 350 m), and composite physiological index > 41 predicted 3-year mortality with high specificity. No patient survived who fulfilled all criteria.
The development of PH can complicate IPF. In a retrospective analysis of 79 patients, 32% demonstrated a mean pulmonary artery pressure (PAP) of more than 25 mm Hg. Those patients with PAH had a lower mean diffusing capacity and a lower 6MWT and were more likely to require supplemental oxygen. One-year mortality rates were higher in those with PH (28 vs. 6%). It was suggested that non-IPF interstitial lung disease should be evaluated for LTx if disease progression is documented in advanced patients (FVC < 50%) by hypoxemia (pO2 < 55 mm Hg) at rest as well as an occurrence of "out of proportion" PH. "Out of proportion" PH was recently proposed as at least two out of three criteria from mean PAP > 35 mm Hg, mean PAP ≥ 25, and CI < 2.0 L/min/m or pulmonary vascular resistance > 480 dyn × s × cm.
Special Consideration in Selection of Pulmonary Artery Hypertension Patients
The timing of referral for patients with PH remains difficult, though there is consensus that patients with pulmonary veno-occlusive disease (group 1') and pulmonary capillary hemangiomyomatosis (e.g., typically do not respond to medical therapy) should be referred for transplantation consideration at diagnosis providing they appear suitable for consideration on general criteria.
There have been considerable changes in the approach to the assessment and listing of patients with severe PAH since the development of targeted medical therapy. The development of new drugs and combination medical therapy with prostaglandins, endothelin receptor antagonists, and phosphodiesterase inhibitors has clearly impacted the timing of transplant listing. Moreover, two studies have demonstrated that 60 to 70% of patients who had previously been listed for transplantation on pre-epoprostenol criteria can be delisted because of clinical improvement.
It is in this setting that PH and transplant centers must decide whom to refer for listing and the timing of such a referral. One study surveyed current practices in a wide variety of transplant centers throughout North America, Europe, and Australia. Forty percent of centers felt all FC III patients should be referred to transplant centers. By contrast, 57% of centers limited referral to those FC III and IV patients who had failed to show benefit after an average of 3 months of epoprostenol therapy. A recent single-center report has demonstrated the value of assessment after 3 months of epoprostenol therapy. An improvement in FC to class II and a decrease in pulmonary vascular resistance of 30% or more is associated with a survival of 90% at 5 years.
Forty percent of centers use one or more hemodynamic criteria for listing. These include a mean right atrial pressure of more than 15 mm Hg, a pulmonary vascular resistance of more than 4 Wood units, a mixed venous oxygen saturation of less than 63%, and a cardiac index of less than 2 L/min. No isolated measurement on echocardiogram has emerged as an outstanding predictor. The evidence suggests, however, that exercise testing can be more helpful. A 6MWT of more than 300 m is associated with a good prognosis, and this simple exercise test is both reproducible and correlates reasonably well with hemodynamics. It is also very sensitive in the detection of improvements related to therapy. Cardiopulmonary exercise testing is utilized by some centers with a mean oxygen consumption of less than 10 mL/kg/min used as an indicator for listing.
Overall, the results show that major PH and transplant centers vary considerably regarding patterns of referral, listing, and transplantation of patients, and it is only with continued carefully collected registry data that guidelines for best practice will be refined. One important issue for FC IV failing to respond to intravenous prostanoid over 3 months relates to the potential delay in listing for transplantation and the effect this has on the patient's overall chances of receiving a graft. Patients who remain in a stable clinical state at FC III will also prove a potentially difficult group, and it is suggested that careful note is taken of the patients' informed views in this situation.
Patients who are experiencing problems with exertional syncope but who otherwise seem to have a good quality of life may be considered for atrial septostomy in addition to receiving prostanoid therapy. Finally, potentially life-threatening hemoptysis should also be considered an indication for listing for transplant patients. A suggested guideline for transplant listing in PAH is shown in Table 2.
International guidelines suggest for candidates with PAH as criteria for referral: FC III or IV and rapidly progressive disease. The same group of experts suggest the following criteria for admitting PAH patients to the wait list: FC III or IV that persists on maximal medical therapy, 6MWT that falls below 350 m and fails to improve with intravenous epoprostenol or equivalent, a cardiac index that is less than 2 L/min/m, or right atrial pressure that exceeds 15 mm Hg.
Data from 2,716 patients with PAH enrolled consecutively in the U.S. Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) were analyzed to assess predictors of 1-year survival. Key predictors of survival based on the patient's most recent evaluation were derived from a multivariable, weighted risk formula for clinical use. One-year survival from the date of enrollment was 91.0%. Variables independently associated with increased mortality included increased pulmonary vascular resistance, PAH associated with portal hypertension, FC IV, men above 60 years, and family history of PAH. Renal insufficiency, PAH associated with connective tissue disease, FC III, elevated mean right atrial pressure, decreased resting systolic blood pressure and elevated heart rate, decreased 6MWT distance, increased brain natriuretic peptide, decreased percent predicted carbon monoxide diffusing capacity, and presence of a pericardial effusion on echocardiogram as covariates predicted mortality. A problem is that the registries do not represent incident case series, and survival in registry patients might be different from that in selected lung transplant candidates with the same disease.
Allocation
Allocation criteria may be geographic (regional, national, international), urgency (e.g., by an audit), individual or objective decision (e.g., by a score system), and based on waiting time. At the international level, we frequently see the combination of several criteria. The so-called center decision with regional distribution is most common in Europe as well as a distribution according to waiting period or urgent case definition.
In May 2005, lung allocation for transplantation in the United States and Germany in December 2011 changed from a system based on waiting time to a system based on the lung allocation score (LAS) for patients of 12 years and older. The LAS is a numerical value used to assign relative priority for distributing donated lungs for transplantation. The lung allocation score takes into account various measures of a patient's health to direct donated organs toward the patients who would best benefit from a lung transplant. The score is calculated using various measures of a patient's health that estimate survival probability and projected duration of 1-year survival with or without a lung transplant. LAS scores range from 0 to 100, and patients with higher scores, reflecting greater predicted survival benefit, get priority. In contrast to the other diagnosis groups, in PAH patients PA pressure proved not to predict wait list survival. One-year wait list mortality of IPF patients has decreased from 21 to 11% since introduction of the LAS in the United States, while the mortality for PAH patients on the wait list remained unchanged. In the REVEAL registry, 2,327 patients with PAH enrolled had all required variables available to compute the LAS and were included in a recent analysis. Univariable and multivariable analyses were conducted to compare waitlist survival predicted by the LAS formula with that observed in the REVEAL cohort. The authors identified two variables independently associated with increased mortality compared with that predicted by the LAS in multivariable analysis using a Cox proportional hazards model. The first was mean right atrial pressure (mRAP) more than or equal to 14 mm Hg and the second was a 6MWT distance (6MWD) less than or equal to 300 m. A modified LAS system for PAH was proposed with addition of mRAP that is greater than 15 mm Hg and 6MWD (currently entered as less than or greater than 47 m) to the LAS. Results from analysis of the REVEAL registry cannot transfer exactly to the transplant situation, because transplant candidates may differ in terms of age and comorbidities, and the REVEAL registry does not cover posttransplant survival. Based on UNOS registry analysis, in the United States the change (increase) in bilirubin of at least 50% occurring in a 6-month period was added to the LAS for patients with PH.
Bridging to Transplantation
Patients with IPF and PAH who are failing on medical therapy may develop respiratory failure or severe right heart failure while they are actively listed for transplantation. LTx of patients on mechanical ventilation is controversial because of impaired survival. In a recent retrospective analysis of all ventilated LTx candidates in a single center, factors associated with survival were evaluated. In the 100 intubated patients included (24% IPF), 60 had additional extracorporeal support. Sixty patients were transplanted; 5 were weaned from mechanical ventilation and 38 died while on the wait list. One-year survival rates were 57, 36, and 5% for transplanted patients, all candidates, and nontransplanted candidates, respectively. Escalating therapy and an abnormal procalcitonin level were associated with a poor outcome. The use of an oxygenating membrane device in a bypass circuit from the pulmonary artery to the left atrium (e.g., extracorporeal membrane oxygenation) in awake patients with PAH and IPF has been described.
Lung Transplant Results for Pulmonary Artery Hypertension and Idiopathic Pulmonary Fibrosis
The most recent survival data for the ISHLT Registry suggest a 5-year survival for recipients with PAH of ~50% following HLTx or DLTx. However, PAH is one of the major risk factors for both early and late mortality with an odds ratio of 1.52 due to the increased risk of postoperative PGD.
Unadjusted 3-month mortality after transplantation is highest in idiopathic pulmonary arterial hypertension (IPAH, 24%), lower in IPF (15%), and lowest in chronic obstructive pulmonary disease (COPD, 9%), most likely due to differences in early complications such as PGD. In contrast to overall survival rates, 5-year survival among patients surviving at least 1 year was significantly better in recipients with IPAH (72%) than in those with COPD (62%) and IPF (61%). The ISHLT Registry shows a 1-year survival of 70 and 73% with a 5-year survival of ~50 and 45% following LTx for PAH and IPF, respectively. Recipients can expect to attain their normal predicted forced expiratory volume in the first second of expiration (FEVI) and vital capacity by 1 year in the absence of complications if they receive two new lungs, although the diffusing capacity usually remains reduced. All patients should expect restoration of normal lifestyle with little or no functional restriction during normal activities of daily living. Exercise data comparing the 6MWD and maximum oxygen consumption during an incremental symptom-limited exercise test show that recipients of successful transplants, irrespective of the operation, return to a normal 6MWD of 600 m or greater. The maximum oxygen consumption is significantly greater in HLTx and DLTx compared with SLTx alone. However, maximum oxygen consumption during a symptom-limited test remains at around 50% predicted for a given subject in the first year, in part due to decompositions because of the pretransplant disability. Nevertheless, the functional results allow restoration of a comfortable lifestyle. There has been great interest in the study of lungs after successful lung transplantation to see if the acquired lung disease will recur in the allografts. To date, there is no evidence of idiopathic PH or IPF returning in lung grafts.
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