Lung transplantation (LuTx) is established as the ultimate therapeutic option for patients with end stage respiratory insufficiency. However, several diseases are prone to developing both cardiopulmonary and hepatic complications and severe impairment of liver function may jeopardize the outcome of LuTx or may render this procedure impossible. Diseases most frequently associated with lung and liver involvement are cystic fibrosis and α1-proteinase inhibitor deficiency (α1-PID). In addition, patients with cirrhosis and portopulmonary hypertension (PPHT) may not be amenable to isolated liver transplantation because of unacceptably high mortality rates during the perioperative period (1, 2).
Patients with combined lung and liver disease have a high degree of morbidity. They are often in a poor nutritional state and muscular wasting is common. This is especially true for patients with cystic fibrosis where the high frequency of pulmonary infection, often caused by bacterial strains displaying multiple antibiotic resistances poses additional challenges. Therefore, combined lung and liver transplantation (Lu-LTx) in these patients continues to be a matter of debate in transplantation medicine, not least in view of the considerable shortage of donor organs (3, 4).
To date, very few cases of combined Lu-LTx have been performed, most of them in young adults with cystic fibrosis (5–7). From 1999 to 2003, only four combined heart-lung and liver transplantations and seven Lu-LTx were performed in the United States (8). The largest single-center experience, published in 1995 by Couetil et al,. comprised 10 patients with cystic fibrosis with survival rates of 70% after 1 and 3 years (5).
Herein we report our experience in 13 consecutive cases of combined (heart-) Lu-LTx performed between April 1999 and December 2003.
PATIENTS AND METHODS
Patients
We analyzed the data from all patients who underwent combined lung and liver transplantation between April 1999 and December 2003. The postoperative course of the patients was studied retrospectively based on patient files. All patients were routinely examined at the outpatient clinic. Patients were followed until June 30, 2007.
Operative Procedure
The surgical approach started with LuTx in all patients. Sequential bilateral LuTx was carried out in 11 out of 13 patients via anterolateral minithoracotomies to avoid clamshell incisions. In five patients, cardiopulmonary bypass (CPB) was used; the other transplantations were performed without CPB. One patient with severe tricuspid regurgitation due to pulmonary hypertension with dilatation of the right ventricle received an additional DeVega anuloplasty. In one patient with portopulmonary hypertension, a unilateral right lung transplantation (Tx) was performed and one patient presenting with restrictive cardiomyopathy leading to secondary pulmonary hypertension and cirrhose cardiaque received an en-bloc heart-lung and liver transplantation. When starting the program, stabilization of respiratory and circulatory function on the intensive care unit (ICU) was found to be necessary prior to liver transplantation with regard to reperfusion edema. With expanding experience using low-potassium-dextran- solution (Perfadex), reperfusion edema did not seem to be a clinically relevant problem anymore. Thus, while the first seven patients were transferred to ICU upon completion of the lung Tx for 2 to 4 hours prior to liver Tx, the liver was transplanted immediately after the completion of the lung Tx in the subsequent patients.
For the heart-lung-liver transplantation, CPB was used throughout the entire procedure. All other liver transplantations were carried out without extracorporeal circulation.
In 12 cases, liver transplantation was performed with a full size liver and in one case with a split liver (segments I, V-VIII). Biliary reconstruction was performed either by hepatico-choledochostomy (12 patients) or Roux-en-Y hepatico-jejunostomy (1 patient).
Immunosuppression
Immunosuppression was based on cyclosporine A (CsA, Sandimmun, Optoral, Novartis Pharma) as part of a triple or quadruple regimen. Target trough levels of CsA were 250–300 ng/ml in the first 6 postoperative months and reduced thereafter. In the first three patients (from April 1999 to December 1999), the combination of CsA, azathioprine, (Aza, Imurek, Glaxo Smith Kline), and prednisolone (Decortin H, Merck) was used. In January 2000, Aza was replaced by mycophenolate mofetil (MMF, CellCept, Roche). Induction therapy with an anti-IL2-receptor antibody (Basiliximab, Simulect, Novartis Pharma) was introduced in June 2001.
Antifungal, Antibiotic, and Antiviral Prophylaxis
Standard prophylaxes consisted of lifelong 800/160 mg trimethoprim/sulfamethoxazole (Cotrim forte, Hexal) administered twice weekly and lifelong oral itraconazol (Sempera, Janssen-Cilag) as well as inhalational and topical amphotericine B (Ampho-Moronal, Bristol-Myers Squibb) in the postoperative period. These prophylactic regimens were adopted from the current practice of the lung transplant program at Hannover Medical School. Additionally, all patients received perioperative antibiotic prophylaxis consisting of ceftazidime (Fortum, Glaxo Smith Kline/Cascan), tobramycin (Gernebcin, Lilly) adjusted to blood levels and flucloxacilline (Staphylex, Glaxo Smith Kline) for a minimum of 10 days. Since 2002, patients with a major risk profile for cytomegalovirus (CMV; donor CMV IgG+/recipient CMV IgG–) received gancyclovir (Cymeven, Roche) intravenously for a minimum of 1 month followed by oral acyclovir (Zovirax, Glaxo Smith Kline) until month 6 postTx. Furthermore patients with a high-risk CMV status or those who developed CMV reactivation/ de novo infection posttransplantation received lifelong prophylaxis with valgancyclovir (Valcyte, Roche).
Follow-Up
All patients were regularly seen in the outpatient clinics for lung and liver transplantation. Follow-up included routine laboratory tests, regular chest radiographs, pulmonary functions tests and abdominal ultrasound evaluations. A diagnosis of rejection of the liver allograft was based on characteristic changes in hepatic aminotransferases with histological confirmation in all cases. Pulmonary infections were always diagnosed by microbiological examination of bronchoalveolar lavage fluid. Pulmonary allograft rejection was diagnosed by the triad worsening of lung function, exclusion of other problems such as infections or bronchial stenoses, and response to steroid treatment. The diagnosis of the bronchiolitis obliterans syndrome was based on standard criteria (9).
Statistics
For assessment of data and statistical analysis, Microsoft Excel 2002 and SPSS 12.0 for Windows were used. The patient survival was calculated using the Kaplan-Meier method.
RESULTS
Patients
Between April 1999 and December 2003, a total of 13 patients underwent combined Lu-LTx at Hannover Medical School. The median age was 35 years ranging from 19 to 55 years. Tables 1 and 2 provide a detailed overview of the underlying diagnoses and the most pertinent findings. In this particular cohort, the primary indication for transplantation was based upon the severity of the pulmonary disease.
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TABLE 1: Patients with pulmonary hypertension
TABLE 2: Patients without pulmonary hypertension
Five patients suffered from treatment-resistant pulmonary hypertension with markedly elevated mean pulmonary arterial pressures (PAPm; median 53 mmHg, range 50–64 mmHg) and pulmonary vascular resistances (PVR; median 655 dynes, range 450–780 dynes; Table 1). The underlying diseases of the other 8 patients were cystic fibrosis (n=5), α1-PID (n=2) and sarcoidosis (n=1); all accompanied by significant respiratory impairment and profound cachexia (median body mass index (BMI): 18.5, range: 14.5–20.8). The severity of liver cirrhosis ranged from Child B to Child C (Table 2).
Donors
The organs were accepted on the basis of standard criteria. Only ABO-compatible donors with no evidence of malignancy or hepatitis B or C infection were accepted.
Perioperative Data
The surgical two-stage procedure was possible due to short operating times for both lung (median 290 min for a sequential double lung) and liver transplantation (median 203 min) with acceptable cold ischemia times (approximately 5 to 7 hr for the lungs and 10 hr for the livers) and moderate amounts of blood product transfusions (median 10 packed red blood cells, 13 fresh frozen plasma, and 2 platelet concentrates (PC) for the whole procedure). Liver transplantation commenced after completion of LuTx and stabilization of the patient and was performed without venovenous bypass in all cases.
Operative and postoperative data are presented in Table 3. Perioperative mortality defined as death within the first 60 days after transplantation or before patients were discharged from hospital was 15% (n=2). One of these patients died from acute right heart failure after reperfusion of the liver graft on postoperative day (POD) 1. Cardiac arrest resulted from hyperkalemia after flushing the liver, which was preserved with UW-solution (University of Wisconsin-solution). The other perioperative fatality was caused by a bronchial-pulmonary arterial fistula resulting from mycotic infection (POD 55).
TABLE 3: Perioperative data
Surgical Complications
Postoperative surgical complications were divided into thoracic and abdominal complications. Thoracic complications occurred in three patients, of whom two (bleeding from an intercostal artery, air leckage due to bronchial anastomosis dehiscence) were managed successfully with surgical intervention, whereas the third case (bleeding from a pulmonary artery) had a fatal outcome.
Abdominal complications occurred in five patients, and included rectum perforation, a subcapsular liver hematoma and gastrointestinal bleeding. While the rectum perforation and the liver hematoma were treated surgically, gastrointestinal bleeding was successfully treated interventionally by intestinoscopy. In the postoperative course, one patient died 67 days postTx from spontaneous rupture of a splenic artery aneurysm and another patient was readmitted and operated after development of a meconium ileus 10 months after combined transplantation.
Other Complications
Two patients developed stenoses of the bronchial anastomoses that required bronchoscopic interventions with balloon dilatation and stent placement. In one recipient two lung metastases of a choriocarcinoma were detected 5 months after double lung Tx without any evidence of primary cancer of the recipient. Genetic patterns of the tumor did not match recipient′s genotype suggesting inoculation of the tumor by the donor organs. The patient was treated with resection of the right upper and the left lower lobe and reduction of the immunosuppression. No further metastases occurred during the follow up period of 59 months.
Rejections
Acute rejection episodes were observed in 3 patients. One patient (patient 1) showed three rejection episodes involving only the lung allograft on day 21, day 57, and month 5, and two additional rejection episodes of the liver on day 10 and month 8. All these episodes were treated with 500–1,000 mg methylprednisolone i.v. daily for 3 consecutive days and adjustments of the CsA dosage. The other patient (patient 2) developed one rejection episode, involving the lung (day 7) and liver (day 15) and was treated with methylprednisolone and transition from CsA to tacrolimus (Prograf, Fujisawa). Another patient (patient 12) developed a single episode of acute pulmonary rejection 25 months postTx. Two patients developed the bronchiolitis obliterans syndrome (BOS) at month 58 (patient 10) and month 65 (patient 5).
Infections
Despite the fact that chronic colonization of the bronchial tree was present in 10/13 recipients prior to Tx, only 2 patients developed pneumonia in the early posttransplant period, both suffering from cystic fibrosis. One of these cases occurred in the abovementioned patient who developed necrosis of the left donor bronchus and consecutive intrapulmonal bleeding from the left pulmonary artery (Table 4, patient 8). Microbiological investigation of the necrotic area revealed Burkholderia cepacia, Pseudomonas aeruginosa, and Enterococcus spp. as well as Candida albicans and glabrata. The other case of early postoperative pneumonia (Table 4, patient 6) was caused by P. aeruginosa and Stenotrophomonas maltophilia and treated successfully with targeted antibiotics.
TABLE 4: CMV IgG status and posttransplant infections
Three other patients developed pneumonia 3, 4, 5, and 53 months after transplantation. In 1patient pneumonia occurred as a result of aspiration after gastroscopy at month 4 and a second episode of pneumonia developed at month 53 leading to death from septic multiorgan failure (Table 4, patient 1). Two further episodes of nonfatal pneumonias are listed in Table 4.
One patient (Table 4, patient 6) developed cholangitis with multiple intrahepatic abscess formation. This patient was treated successfully with antibiotics and percutaneous transhepatic bile duct drainage (PTCD).
Viral infections occurred in four patients (Table 4). Three patients developed four episodes of CMV infections; two of them with a high-risk profile (donor CMV IgG+/recipient CMV IgG–). Three of four CMV infections occurred within 3 months after transplantation. In 3 cases, CMV infection was successfully treated with intravenous gancyclovir. However, 1 patient (Table 4, patient 13) developed a CMV relapse 9 months after transplantation with CMV hepatitis and colitis. His course was complicated by leucopenia and septic candidiasis. Despite treatment with intravenous gancyclovir, caspofungin (Cancidas, MSD) and fluconazole (Diflucan, Pfizer), reduction of the immunosuppressive therapy and surgical debridements the patient died from multiorgan failure 12 months after transplantation.
In one patient (Table 4, patient 3), Epstein-Barr virus reactivation occurred in the fifth year postoperatively, which was successfully treated with foscarnet (Foscavir, AstraZeneca). One patient (Table 4, patient 9) developed de novo hepatitis B infection 15 months after transplantation. Serological evaluation prior to transplantation showed HBs-Ag negative, anti-HBs negative, and anti-HBc negative results. The corresponding donor was HBs-Ag negative, anti-HBs negative but anti-HBc positive. The first virological status of the donor did not contain the findings of the anti-Hbc investigation. When the positive result was detected during further virological examination, the lung allografts had already been transplanted and the liver split done, so that the routine HBV prevention regimen with anti-HBV surface antigen immunoglobulin and lamivudine (Epivir, GaloxoSmithKline) was not performed (10); the patient was treated with lamivudine after transplantation.
In one patient (Table 4, patient 9), cerebral aspergillosis was detected 2 months after transplantation, which was successfully treated with voriconazole and caspofungin administered intravenously for 6 months together with reduction of immunosuppressive therapy.
Patient and Graft Survival
Overall, 6 of 13 patients died; no patient underwent retransplantation. Three patients died from infectious complications as described above. One patient died from acute right heart failure after reperfusion of the liver graft (POD 1) and another patient died from a rupture of a splenic artery aneurysm at POD 67. The sixth patient was killed during a car accident 28 months after Tx.
The resulting patient and graft survival rates after combined Lu-LTx were 69% after 1, 62% after 3, and 49% after 5 years (Fig. 1).
FIGURE 1.:
Patient survival (Kaplan-Meier analysis) > Number of patients at risk at 0.7 months n=12, 1.8 months n=11, 2.2 months n=10, 9.8 months n=9, 28 months n=8, 52.5 months n=4.
Further details on the postoperative functions of lungs, livers, and kidneys are shown in Table 5.
TABLE 5: Patient outcome
DISCUSSION
The present series demonstrates that combined Lu-LTx is a viable option for selected patients who would not be considered candidates for either isolated lung transplantation or isolated liver transplantation because of advanced dysfunction of the respective other organ. The survival rates in this series were 69% after 1 year, 62% after 3 years and 49% after 5 years, respectively. The identification of suitable candidates for combined organ transplantation is a complex procedure, especially since the decision of whether to perform a single or a combined transplantation has to take into account the presumed function of the non-transplanted organ in case of a single organ transplantation. Thus, the selection criteria for combined organ transplantation cannot be the same as for single organ transplantation. For instance, a patient with cystic fibrosis and child B cirrhosis with portal hypertension may not per se require liver transplantation but may not survive a lung transplant procedure because of the high likelihood of postoperative deterioration of liver function.
Our series describes patients with various diseases and the indications for combined Lu-LTx were based on advanced dysfunctions of both organs in all cases. Each individual case was discussed extensively among a team consisting of hepatologists, pulmonologists, psychologists, thoracic and visceral surgeons. End-stage pulmonary disease was caused either by severe pulmonary hypertension or by advanced parenchymal lung disease due to cystic fibrosis (CF), α1-PID or sarcoidosis, respectively. Liver cirrhosis was a result of the underlying disease (CF, α1-PID) or coexisting conditions as indicated in Tables 1 and 2.
Of note, the presented patients were operated between 1999 and 2003. Since then, the management of some of the underlying diseases has evolved. This is especially true for pulmonary hypertension, since the availability of novel treatments including prostanoids, endothelin receptor antagonists and phosphodiesterase-5-inhibitors has dramatically improved treatment options and survival of this patient population (11–13). From a current perspective, it appears that some of the patients with pulmonary hypertension may not have required combined transplantation, had these treatments been available at the time of their operation.
In terms of CF patients, severe impairment of liver function together with repeated episodes of pulmonary infections and markedly impaired lung function was the main indication for combined transplantation, especially when cavernous destruction of the lung parenchyma was present. For patients with cirrhosis and severe pulmonary hypertension, i.e. those with a mean pulmonary artery pressure >35 mmHg (2), the mortality of isolated liver transplantation exceeds 50%; thus combined Lu-LTx may be the only therapeutic option for some of these patients, especially when pulmonary hypertension does not respond to medical treatment.
The surgical approach to combined Lu-LTx is similar to isolated lung or liver transplantations. Technical improvements in isolated LuTx could be transferred into the combined Tx. In the series of combined procedures published by Couetil et al. all operations were performed with the use of CPB, whereas most of the transplantations in our series where performed without extracorporeal circulation. The operative approach already changed in the Couetil series from bilateral en-bloc to a bilateral sequential technique via sternotomy. In our series we used a bilateral sequential technique too, but we chose anterolateral minithoracotomy rather than sternotomy.
There were also differences between the series of Coutetil et al. and our approach regarding bile duct anastomosis. While Couetil et al. favored Roux-en-Y choledocho-jejunostomy to avoid biliary duct strictures, we preferred duct-to-duct biliary anastomosis according to our experiences with liver transplantation in children with CF (14). In the present series, we saw only a single episode of biliary duct stenosis, which occurred in the one patient in whom Roux-en-Y hepatico-jejunostomy was used.
It is interesting to note that early postoperative acute rejection episodes were observed only in the first patients of this series. Immunosuppression of these patients consisted of CsA, Aza and prednisolone. After replacement of Aza by MMF and introduction of induction therapy with basiliximab, no further acute rejection episodes involving lungs or livers were observed during the first year posttransplant. Overall, there were 8 episodes of acute rejections (5 times involving the lungs, 3 times involving the liver) and 2 patients developed BOS. While the number of acute liver rejections was in the expected range (15, 16), the incidence of pulmonary rejections was relatively low, fuelling the discussion about an immunotypical “protective” effect of the liver on the pulmonary graft as previously suggested by Barshes et al. and already reported in multivisceral, liver/intestine and liver/kidney transplantation (17–21). However, the limited follow-up period and the low number of patients in our and the other series do not allow firm conclusions about the occurrence of acute rejections and BOS. Frequent problems were viral, bacterial and mycotic infections. Only 2 patients remained free of severe infections throughout the observation period. Apart from immunosuppression, preexisting risk factors for infections were malnutrition and chronic colonization with bacteria and fungi. For combined organ transplantation in our center an adequate nutritional status was considered to be essential (body mass index >18 kg/m2). It was thought from the experience with isolated lung and liver Tx that the alimentary status is an important predictor of postoperative outcome (22, 23). However, our study provides no conclusive data to support this recommendation.
Because of the relatively low incidence of acute and chronic rejection episodes and the high frequency of infections overimmunosuppression of our patients may be suggested. This is certainly the case for the liver graft because, according to our local experience as well as several studies (15, 16, 24, 25), it is now evident that a CNI-based immunosuppressive dual therapy or monotherapy with or without induction therapy with an IL2-receptor antibody is able to prevent acute allograft rejection in more than 70% of all cases. However, it is well recognized that lung transplant patients require more aggressive immunosuppression and we adopted the immunosuppressive strategy of our lung transplant program in the present series of lung-liver transplant patients. This approach may not have been appropriate and further investigations are needed to define the optimal immunosuppressive strategy in patients undergoing combined organ transplantation.
Of note, the long-term survival after combined Lu-LTx varies substantially among published series. The reported outcomes range from a discouraging 1-year-survival rate of 20% (3) up to 1-year survival rates of 79% and 5-year survival rates of 63% (6, 26–28).
Despite the morbidity caused by infections and other complications, in this series patient and graft survival after combined Lu-LTx was 69% after 1, 62% after 3, and 49% after 5 years. These results are inferior to those reported in isolated liver transplantation (1-year survival approx. 80% and 5-year survival approx. 64%) (29, 30), but similar to isolated LuTx (1-year survival approx. 78% and 5-year survival approx. 45%) (29, 30). Similar encouraging results with combined Lu-LTx were reported by Couetil et al. (5) with a patient survival of 70% at 1 and 3 years (n=10) and by Barshes et al. (28) with a patient survival of 79% at 1 and 63% at 5 years (n=11).
In conclusion, this report demonstrates the feasibility of combined liver-lung transplantation in carefully selected patients suffering from chronic respiratory failure and advanced cirrhosis. In fact, in rare cases only combined transplantation can offer patients the perspective of survival. Thus our series based on patients with end-stage lung disease with concurrent cirrhosis and patients with end-stage cirrhosis and concurrent lung disease precluding performance of isolated liver transplantation demonstrates that selected patients may benefit from for combined Lu-LTx. Furthermore the encouraging data of two single center series and the improvement of surgical technique, ICU treatment, medical and immunosuppressive options in the recent years should justify the implementation of a combined lung and liver transplant program in other experienced centers to give this patient group a therapeutic option. Close cooperation of the involved specialists is essential to identify patients who may benefit from combined Lu-LTx and to manage the broad array of immunological, infectious, and surgical complications associated with this procedure.
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