Advanced therapy in thoracic surgery - part 7 pps

330 / Advanced Therapy in Thoracic Surgery tice, the allograft is gently reinflated before reperfusion and ventilated with an FiO2 of 0.5, PEEP of cm H2O, and a pressure-control ventilation limiting the peak airway pressures to 25 cm H2O.100,101 Gene Therapy The utilization of gene therapy in the transplantation setting is advantageous because immunosuppressive therapy may potentially allow repeated transfection with the same viral vector without developing immunization.102,103 Multiple strategies have been used experimentally to transfect donor lungs with variable success Genes have been administered to the donor before lung retrieval, on the back table during the cold ischemic time, and to the recipient after reperfusion They have been delivered intravascularly, intramuscularly, and transtracheally as naked deoxyribonucleic acid (DNA) or with the help of a vector, either viral or nonviral, such as cationic liposomes.102–108 We have demonstrated that transfection of the donor lung is possible through the transtracheal route using a second-generation adenoviral vector without contaminating other organs such as the heart, liver, or kidneys.104 Since the transfection rate is significantly decreased at cold temperatures, this mode of administration is useful in that it allows for efficient transfection before retrieving and cooling the lungs We have shown that the transtracheal administration of the gene coding for the antiinflammatory cytokine (human interleukin-10) to the donor 12 and 24 hours prior to lung retrieval reduces ischemia-reperfusion injury and improves lung function in a rat single lung transplant model.108 A high dose of steroids given before the administration of the adenoviral vector can reduce the inflammation induced by the adenoviral vector and allow the transfection time to be reduced to hours before retrieving the lungs We are currently performing similar experiments in a large animal study Once similar results can be reproduced, human lung protection from reperfusion injury by gene therapy may be possible Mechanisms of Ischemia-Reperfusion Lung Injury Calcium Overload Hypothermic storage alters calcium metabolism in cells both by release of calcium from intracellular depots and by pathological influx through the plasma membrane The alteration of pH and intracellular calcium concentration disrupts many intracellular functions causing cellular damage, leading to the activation of phospholipase A and to the production of free radicals by macrophages Elevated cytosolic calcium can also enhance the conversion of xanthine dehydrogenase to xanthine oxidase and potentiate the damaging effect of free radicals on mitochondria Verapamil, a calcium channel blocker, was found to protect the lung from warm- and cold-preservation injury.109,110 If the drug is administered just before reperfusion or immediately after reperfusion, arterial oxygenation may not be improved, although the lung water content has been found to be significantly lower in all groups receiving verapamil In an isolated rabbit lung perfusion model, Yokomise and colleagues observed that verapamil had the most dramatic effect when it was administered to the donor before lung retrieval.110 The administration of verapamil to the donor can reduce lipid peroxidation during the ischemic time and prevent endothelial damage after reperfusion.111,112 In the long term, however, the administration of the drug to the donor and to the recipient did not seem to improve survival.112 Similar results have been observed with other calcium blockers such as nifedipine and diltiazem.113 Oxidative Stress Oxidative stress is characterized by the formation of reactive oxygen species such as superoxide anion (O2-• ∑), H2O2, and hydroxyl radical (HO•∑).114 These molecules, in particular the hydroxyl radical, are highly unstable and react with the first structure they encounter, usually the lipid component of the cell membrane Cell injury produced by lipid peroxidation can range from increased permeability to cell lysis The generation of intracellular oxygen species has been found to predominate in endothelial cells, type II cells, Clara cells, ciliated cells, and in macrophages.115 Commonly, ischemia-reperfusion corresponds to anoxia–reoxygenation However, the lung has to be considered differently because it contains oxygen in the alveoli during ischemia Alveolar oxygen helps maintain aerobic metabolism and prevents hypoxia.84,116 Hence, in the lung, the oxidative stress resulting from ischemia should be distinguished from the oxidative stress resulting from hypoxia Hypoxia and, ultimately, anoxia results in a sharp decrease of ATP and a corresponding increase in the ATP-degradation product hypoxanthine, which generates superoxide when oxygen is reintroduced with reperfusion or ventilation This phenomenon can occur in the lung when alveolar oxygen tension drops below mm Hg during ischemia.117 The mechanism can be blocked by inhibitors of the xanthine oxidase such as allopurinol but not by inhibitors of the reduced form of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase.118–120 Ischemia is characterized by the absence of blood flow into the lung and can cause lipid peroxidation and Lung Preservation for Transplantation / 331 oxidant injury despite the absence of hypoxia.84,120 The mechanism of oxidative stress is different from that occurring during anoxia–reoxygenation, because it is not associated with ATP depletion and it can occur during the storage period.84,116,120 The endothelium appears to be the predominant source of oxidants during nonhypoxic lung ischemia.121 Endothelial cells are highly sensitive to the physical forces resulting from blood flow variation and are able to transform these mechanical forces into electrical and biochemical signals (mechanotransduction).122,123 The absence of the mechanical component of flow during lung ischemia stimulates membrane depolarization of endothelial cells with the activation of NADPH oxidase, nuclear factor kappa-B (NF-␬B), and calcium/calmodulin-dependent nitric oxide synthase (NOS).121,124,125 Other cells such as macrophages and marginated polymorphonuclear leukocytes, which are known to have high NADPH oxidase activity, could also contribute to the lung oxidant burden that takes place during storage.126,127 Several antioxidants and free radical scavengers have been developed and incorporated into preservation solutions to minimize lung injury from the oxidative stress that takes place during ischemia-reperfusion These include xanthine oxidase inhibitors such as lodoxamide and allopurinol, superoxide dismutase, catalase, glutathione, dimethylsulfoxide, and alpha tocopherol.119,128,129 While experimental evidence supporting their use is strong, they have not made a major clinical impact on reperfusion injury Pulmonary Surfactant Dysfunction Surfactant dysfunction has been shown to occur during ischemia-reperfusion injur y of the lung – Ultrastructural analyses have shown an increase in the small to large surfactant aggregate ratio, an increase in sphingomyelin, and a decrease in phosphatidylglycerol and phosphatidylcholine, which correlated with detrimental changes in pulmonary compliance and lung oxygenation.130–132,135 These changes were also associated with a deficit in surfactant adsorption and a decrease in surfactant protein A (SP-A).131,134,136 Alveolar surfactant dysfunction may occur despite the absence of plasma protein leakage or changes in lamellar bodies of type II pneumocytes 130,137 The dysfunction is most likely the result of numerous insults occurring during lung storage such as production of phospholipase A 2, mechanical distorsion, altered phospholipid metabolism, reduced production of SP-A, and accumulation of C-reactive protein.132,134,138 Although some alterations in surfactant can be observed immediately after pulmonary artery flushing, most of the alterations have been shown to progressively increase during ischemic storage and to be significantly less with extracelullar-type preservation solutions.132,133,135,136 Experimental studies and anecdotal clinical observations have found that exogenous surfactant therapy can improve pulmonary function after lung transplantation.139–142 The administration of exogenous surfactant is associated with a higher amount of total surfactant phospholipids, a higher percentage of the heavy subtype of surfactant, a normalized percentage of phosphatidylcholine, and a higher amount of endogenous SP-A— which has been shown to improve oxygenation and compliance of the transplanted lung.140 Exogenous surfactant has also been shown to enhance immediate recovery from transplantation injury and to be persistently beneficial for endogenous surfactant metabolism for up to week after transplantation.143 Exogenous surfactant given to the donor before retrieval has been associated with better and more reliable results than when it was administered just before or immediately after reperfusion.141,144 Since 1995, Struber and coworkers have successfully used a nebulized synthetic surfactant in several patients with reperfusion injury after lung transplantation.142,145 They observed a rapid improvement in pulmonary compliance and in alveolar–arterial oxygen difference (A-aDO2), leading to extubation within a few days after surgery.142 In the future, these promising results need to be confirmed with a prospective, randomized trial Cell Death In human lung transplantation, we have observed that lungs with excellent function and good clinical outcome have up to 30% of their cells undergoing apoptosis after hours of reperfusion Similar findings have been observed experimentally after and 12 hours of cold ischemic time in rats, whereas longer ischemic times were associated with a preponderance of necrotic cell death in lung tissue.147 In contrast to necrosis, which may occur prior to reperfusion, apoptosis appears after reoxygenation, peaks rapidly after reperfusion, and does not correlate with lung function.146,147 Whether apoptotic cells have a deleterious impact on organ function remains controversial Some authors have demonstrated that ischemia-reperfusion injury of kidneys and hearts is reduced when antiapoptotic agents are injected prior to reperfusion in mice models of warm ischemia.148 However, other investigators have argued that by blocking the apoptotic molecular cascade after a period of brain ischemia, injured cells may not be able to recover but may instead continue to release proinflammatory agents and subsequently die by necrosis, a mode of cell death more injurious to surrounding tissue.149 We have observed that for a similar amount of dead cells in the transplanted lung, the presence of apoptotic cells was 332 / Advanced Therapy in Thoracic Surgery associated with better lung function than if the cells had died by necrosis Clearly agents and techniques that prevent cell death in the transplanted lung will play an important role in future strategies for lung preservation The Cytokine Network Experimental studies have shown that ischemiareperfusion of the lung150–152 induces a rapid release of proinflammatory cytokines including tumor necrosis factor (TNF)-␣, interferon (IFN)-␥, IL-1␤, IL-6, membrane cofactor protein (MCP)-1, and IL-8 (Table 26-2) In human lung transplantation, we have demonstrated a striking relationship between IL-8 levels and graft function after lung transplantation IL-8, which is a potent chemokine promoting neutrophil migration and activation, is rapidly released following reperfusion, and levels in lung tissue hours after reperfusion correlated with lung function assessed by the PaO2/FiO2 ratio, the mean airway pressure, and the acute physiology and chronic health evaluation (APACHE) score during the first 24 postoperative hours The potential importance of IL-8 has also been demonstrated in patients with acute respiratory distress syndrome and in human liver transplantation In addition, Sekido and colleagues have shown that the intravenous administration of anti-IL-8 antibody at the beginning of the reperfusion period markedly reduced lung injury and neutrophil infiltration hours after reperfusion in a rabbit model of warm lung ischemia.153 In contrast to liver transplantation, we did not find a significant release of the anti-inflammatory cytokine IL10 after reperfusion in lung transplantation.154 However, we did observe a significant decline in the release of IL10 in lung tissue after reperfusion in older donors Interestingly, the release of IL-10 has also been shown to be decreased in older mice subjected to the stressful event of trauma-hemorrhage.155 This finding may thus, in part, explain why lungs from older donors are more susceptible to ischemic injury and are associated with a higher mortality rate than lungs from younger donors.10 Lentsch and colleagues156 and Daemen and colleagues157 have recently shown in a murine model of warm ischemia that IL-12 and IL-18 cytokines play a significant role in ischemia-reperfusion injury of the liver and kidney by inducing the release of TNF-␣ and IFN-␥ and by enhancing the expression of MHC class I and II In human lung transplantation, we observed that both IL-12 and IL-18 were significantly higher during the ischemic time than after reperfusion In addition, IL-18 was the only cytokine that correlated with the length of ischemic time in our study Since longer ischemic times have been shown to induce the expression of MHC class II, our finding suggests that long ischemic times may influence acute rejection and subsequent chronic allograft dysfunction through the release of IL-18 Clearly, cytokine-mediated injury can have important early and late effects on the lung and further study is ongoing in this area Lipid Mediated Network Cell injury is accompanied by a rapid remodeling of membrane lipids with the generation of bioactive lipids that can serve as both intra- and extracellular mediators.158 Phospholipases such as phospholipase A2 have a pivotal role in the generation of these lipid mediators Phospholipase A2 has been detected in a wide variety of inflammatory conditions such as ischemia-reperfusion The activation of phospholipase A2 induces the production of platelet-activating factor (PAF), an extraordinarily potent mediator of inflammation, and mobilizes arachidonic acid from the membrane lipid pool, which is then degraded by two major pathways into eicosanoids The potent vaso- and bronchoconstrictor thromboxane A2 (TXA2) and various prostaglandins (PGs), such as PGD2, PGE2, PGF2, and PGI2, are produced via the cyclooxygenase pathway The lipoxygenase pathway, on the other hand, catalyzes leukotrienes (LTs) such as LTB4, LTC4, LTD4, and LTE4, which can increase capillary permeability To date, only a few studies have analyzed the effect of phospholipase A2 inhibitors in lung ischemia-reperfusion injury Shen and colleagues found that mepacrine TABLE 26-2 Source and Function of Cytokines Potentially Involved in Ischemia-Reperfusion Injury Cytokine Main Cell Source Function Tumor necrosis factor-␣ Interferon-␥ Macrophage chemoattractant protein-1 Interleukin-1␤ Interleukin-2 Interleukin-6 Interleukin-8 Interleukin-10 Interleukin-12 Interleukin-18 Macrophages, lymphocytes Lymphocytes Immune cells, lung epithelial cells Macrophages, fibroblasts Lymphocytes Macrophages, endothelial cells, epithelial cells Immune cells, lung epithelial cells, fibroblasts Macrophages, lymphocytes Macrophages Macrophages Cell activation Cell activation Macrophage chemotaxis Cell activation Lymphocyte proliferation Cell activation Neutrophil chemotaxis Anti-inflammatory Proinflammatory Proinflammatory Lung Preservation for Transplantation / 333 reduces lung injury after hypoxia–reoxygenation of the lung, and Nagahiro and colleagues observed that the administration of EPC-K1 in the flush and preservation solution can enhance lung function after reperfusion.159,160 PAF can be released by a wide variety of cells including macrophages, platelets, endothelial cells, mast cells, and neutrophils.158 It exerts its biological effects by activating the PAF receptors, which consequently activates leukocytes, stimulates platelet aggregation, induces the release of cytokines and the expression of cell adhesion molecules.161 PAF has been shown to play a critical role in initiating lung injury The most direct evidence was published by Nagase and colleagues, who demonstrated that PAF receptor knockout mice developed a mild form of acute lung injury after acid aspiration whereas the overexpression of PAF receptor in transgenic mice exaggerated the acute lung injury when compared with control mice.162 A number of studies have demonstrated that the administration of PAF antagonists during the ischemic storage and after reperfusion reduces ischemiareperfusion injury and improves lung function 163–166 Similar results have been observed when PAF acetylhydrolase was administered to the flush solution and after reperfusion to increase the rate of degradation of PAF.167 Wittwer and colleagues have recently reported their clinical experience with a PAF antagonist in 24 patients randomly assigned to a high dose of PAF antagonist in the flush solution and after reperfusion (n = 8), a low dose of PAF antagonist in the flush solution and after reperfusion (n = 8), and a control group (n = 8).168 They observed a trend towards better A-aDO2 within the first 32 hours after reperfusion and better chest radiograph score However, the postoperative ventilation time did not show any significant difference between groups In clinical kidney transplantation, a randomized, doubleblind single center trial with 29 recipients showed a significant reduction in the incidence of primary graft failure after transplantation in the group of patients receiving the PAF antagonist.169 These interesting results from single centers will hopefully stimulate large multicenter trials Arachidonic acid metabolites such as leukotrienes and thromboxanes have been shown to increase in the lung during ischemia-reperfusion in a dog model of warm ischemia Thromboxanes may contribute to reperfusion injury and exacerbate lung edema; however, their role in the development of pulmonary hypertension after reperfusion remains controversial Zamora and colleagues observed in an isolated perfused rabbit lung model that a TXA2 receptor antagonist administered before ischemia and after reperfusion attenuated the degree of lung edema.170 Similar results have been observed with the simultaneous administration of cyclooxygenase inhibitors before and after ischemia in different models of warm ischemia-reperfusion of the lung.171,172 However, Ljungman and colleagues and Kukkonen and colleagues found that the administration of cyclooxygenase or thromboxane inhibitors after reperfusion only did not prevent the development of pulmonary hypertension.171,173 Hence, thromboxane inhibitors may reduce the degree of reperfusion injury when given during storage, but not appear to affect pulmonary artery pressure when administered after reperfusion only Leukotrienes have not been systematically studied during ischemia-reperfusion of the lung However, mast cells, which are known to release large amounts of leukotrienes and histamine, are increased in number after lung ischemia and reperfusion.174 In addition, the administration of mast cell membrane–stabilizing agents before cold or warm ischemia has been shown to improve lung function.175 The effect was associated with a decreased expression of adhesion molecules and an increased expression of NOS-2 and tissue cyclic guanosine monophosphate (cGMP) levels Adhesion Molecules Adhesion molecules can be upregulated on endothelial cells in the lung during the ischemic period Several experiments have shown a reduction in lung ischemiareperfusion injury by alternatively blocking selectins, intracellular adhesion molecule (ICAM) 1, and CD18 before initiating reperfusion Moore and colleagues demonstrated that blockade of P-selectin, ICAM-1, and the integrin CD18 using monoclonal antibodies can reduce lung reperfusion injury as determined by the coefficient of filtration in an in vivo model of warm ischemia.176 The role of P-selectin in the early phase of reperfusion has been confirmed by other studies using monoclonal antibodies and knockout mice deleted for the P-selectin gene.177 In contrast to P-selectin, E-selectin and L-selectin may have little influence in the early phase of reperfusion, while having an established role in late reperfusion.176 This effect may relate to the predominant role of neutrophils in the second phase of reperfusion The use of biostable analogs of the oligosaccharides Lewis X and Lewis A, which are potent ligands for selectin adhesion molecules, has also been shown to reduce ischemia-reperfusion injury and to improve lung function when given before reperfusion in several studies.178–180 ICAM-1 blockade by monoclonal antibody administered in the flush solution or immediately prior to reperfusion has been shown to reduce leukocyte sequestration and to improve lung function.181 Similar results have been observed with an antisense oligodeoxyribonucleotide, which selectively prevented the synthesis of ICAM-1 334 / Advanced Therapy in Thoracic Surgery during lung preservation 182 Blockade of CD18 with monoclonal antibody also improved lung function with an increasing effect after a prolonged period of reperfusion.183 A phase I clinical trial of immunosuppression with anti-ICAM-1 monoclonal antibody in 18 renal allograft recipients showed that the drug could be used safely and that an adequate serum level of antibody was associated with significantly less graft dysfunction and less acute rejection in the postoperative period.184 No clinical trials have been performed in lung transplantation yet Metals and Metalloenzymes Although iron is an essential element for all living cells, it can be highly toxic under pathophysiologic or stress conditions because of its ability to participate in the generation of powerful oxidants Free iron can be released from the ferritin core and from cytochrome P450 during ischemia by a number of factors such as acidosis, proteolysis, and superoxide In addition to tissue oxidation, iron can be released into the circulation and potentially activate platelet aggregation.120 The importance of iron in promoting injury during ischemia-reperfusion has been demonstrated by the increased injury observed in iron-supplemented tissue and conversely, by the protection offered with the iron chelator deferoxamine Recently, a novel iron chelator (desferriexochelin 772SM) has been shown to enhance the effect of a P-selectin antagonist in preventing ischemia-reperfusion injury in a rat liver model Lazaroids, which are aminosteroids that inhibit irondependent lipid peroxidation, have also shown good results in protecting the lung from ischemia-reperfusion injury in all but one study.185–187 Metals other than iron have been less extensively studied in the setting of ischemia-reperfusion injury Zinc has been shown to have a protective effect on the lungs during hyperbaric oxygenation and on the kidneys after a period of ischemia The protective effect may be mediated through the induction of metallothionein or through its interaction with free iron and copper.188 Zinc and copper are both constituents of copper/zincsuperoxide dismutase–an antioxidant enzyme that has been shown to be important in ischemia-reperfusion of the gut and brain Copper may also be involved in the production of the protective antioxidant enzyme heme oxygenase (HO-1) Selenium is involved in the glutathione antioxidant system, and some authors have shown that its addition to the preservation solution can be beneficial in ischemia-reperfusion of the lung.190 Prothrombotic and Antifibrinolytic Agents Hypoxia can induce endothelial cells and macrophages to develop procoagulant properties, which may contribute to the formation of microvascular thrombosis and impede the return of blood flow after reperfusion In vitro studies have shown that endothelial cells subjected to hypoxia can suppress their production of the anticoagulant cofactor thrombomodulin and increase their production of a membrane-associated factor X activator.191 Tissue factor has also been shown to be upregulated on endothelial cells and macrophages by hypoxia and to play a significant role in modulating ischemiareperfusion injury in a model of liver warm ischemia.192 The administration of C1-esterase inhibitor, which inhibits the classical pathway of the complement system as well as the contact phase and the intrinsic pathway of the coagulation system, has been shown to improve early lung function and to reduce ischemia-reperfusion injury in a dog lung transplantation model 193 C1-esterase inhibitor has also been used successfully to treat lung graft failure in two patients, but further clinical studies are required to prove its efficacy.194 Recent experiments have demonstrated that mice placed in a hypoxic environment suppressed their fibrinolytic axis by increasing macrophage release of plasminogen activator inhibitor (PAI-1) and decreasing macrophage release of tissue plasminogen activator (tPA) and urinar y plasminogen activator (u-PA) Additional studies in mice have shown that the beneficial effects of HO-1, carbon monoxide, and IL-10 during lung ischemia are partially mediated by their ability to potentiate the fibrinolytic axis.195,196 Recombinant tissue plasminogen activator (rt-PA) has also been shown to improve early lung function in a canine model of lung transplantation from a non–heart-beating donor 197 Further studies should determine more precisely the role of fibrinolytic agents in ischemia-reperfusion of the lung Role of Vasomodulators Under hypoxic or ischemic conditions, in addition to the release of mediators, endothelial cell dysfunction can lead to an imbalance between vasodilatator and vasoconstrictor agents that may have severe consequences for the microcirculation Endothelin is a potent vasoconstrictor that has been shown to be upregulated during ischemia and after reperfusion, whereas vasodilatators such as NO and cyclic adenosine monophosphate (cAMP) have been shown to be down-regulated Endothelins (ETs) are powerful vasoconstrictors—10 times more active than angiotensin II or vasopressin.198 Three isoforms have been described in human and other mammals, ET-1, ET-2, and ET-3, among which ET-1 has been most extensively studied because it is released by endothelial cells and smooth muscle cells and its expression is predominant in the lung In addition to being a Lung Preservation for Transplantation / 335 potent vasoconstrictor, ET-1 can stimulate the production of cytokines by monocytes and promote the retention of leukocytes in the lung Studies in human liver transplantation have shown that ET-1 accumulates in the vascular space during harvesting and cold storage Similar findings have been observed in lung transplantation with ET-1 levels being elevated in lavage fluid of transplanted allografts or in plasma during the first few hours after reperfusion when compared with preischemic values.199–201 The role of ET-1 in ischemia-reperfusion injury is supported by the improvement in lung function when endothelin receptor antagonists were administered before or during reperfusion.202,203 The administration of ET-1 receptor antagonist is associated with a reduction in the expression of inducible NOS (iNOS) and with a lower proportion of apoptotic cells in the lung.204 Paradoxically, in vitro studies with pulmonary endothelial cells have shown that hypoxia and oxidant stress can decrease the production of ET-1.205 This finding suggests that the production of ET-1 in vivo could result from stimuli other than hypoxia or oxidant stress and could be related to, for instance, the absence of blood flow into the vascular bed during ischemia NO is a messenger gas molecule with many physiologic effects, including potent vasoregulatory and immunomodulatory properties.206 It is produced by a family of enzymes—the NOSs, which catalyze the conversion of l-arginine to l-citrulline with the help of five cofactors Endogenous NO has been found to be decreased after ischemia and reperfusion of the lung in human and animal studies.207 The fall in detectable endogenous NO may be due to an accelerated destruction of NO by oxygen free radicals or the presence of NOS inhibitors that may be produced during ischemia-reperfusion of the lung.207,208 Multiple strategies have been developed to compensate for the fall in endogenous NO during lung transplantation These strategies have been applied in the donor and in the recipient and have targeted each step of the pathway described above, including the administration of the upstream molecule l-arginine,209 the increment of the downstream molecule cGMP, or the administration of exogenous NO Exogenous NO has been given directly by inhalation (inhaled NO),210,211 or indirectly by infusion of an NO-donating agent (NO donor), such as FK409, 212 nitroprusside, 213,214 glyceryl trinitrate,215 nitroglycerin,216,217 or SIN-1.218 Other strategies have been directed at increasing the activity of the NOS enzyme by the addition of one of its cofactors (tetrahydrobiopterin) to the preservation solution,219 or by transfecting the donor with an adenovirus containing endothelial derived NOS (eNOS) before lung retrieval.107 These experimental strategies have been shown to be effective and to have a prolonged effect if they are initiated before the occurrence of reperfusion injury However, NO can react with superoxide anion and form peroxynitrous acid (ONOOH), which is a highly reactive oxidant that can induce the release of ET-1, damage alveolar type II cells even after a short period of ischemia, and cause structural and functional alterations of surfactant 220 Hence, this reaction may explain some of the conflicting reports in the literature, where some authors have shown that NO administered during ischemia or early reperfusion may be ineffective or even harmful, in particular when it is given with a high fraction of inspired oxygen at the time of reperfusion.210,221,222 Inhaled NO has been extremely useful clinically to treat ischemia-reperfusion injury of the lung because it can improve ventilation-perfusion mismatch and decrease pulmonary artery pressures without affecting systemic pressures.223 However, the role of inhaled NO in preventing ischemia-reperfusion injury during clinical lung transplantation remains controversial Ardehali and colleagues have shown that the application of inhaled NO to 28 consecutive recipients after lung transplantation did not prevent the occurrence of reperfusion injury.224 We have recently completed a randomized and blinded placebo-controlled trial of inhaled NO administered to lung transplant recipients, starting 10 minutes after reperfusion for a minimum of hours 2 We observed no significant differences in the immediate oxygenation, time to extubation, and length of stay in the intensive care unit (ICU) or 30-day mortality In conclusion, while our clinical experience indicates that inhaled NO therapy appears to be useful in improving gas exchange in cases of established reperfusion injury, the role for NO in the prevention of ischemia-reperfusion injury remains unproven in clinical lung transplantation Prostaglandins PGE1 has been shown to be beneficial when added to intracellular preservation solutions such as EC and UW.87,226 The beneficial effect of PGE1 was initially attributed to its vasodilatative property that may lead to a better distribution of the preservation solution and to the stimulation of cyclic-3Ј,5Јadenosine monophosphate (cAMP)-dependent protein kinase during the cold ischemic time, which may reduce endothelial permeability, neutrophil adhesion and platelet aggregation upon reperfusion.226 However, its association with the already improved LPD solution has not been shown to further enhance lung preservation.85 The continuous intravenous administration of PGE1 to the recipient during the early phase of reperfusion has 336 / Advanced Therapy in Thoracic Surgery been shown to reduce ischemia-reperfusion injury of the lung.227 Although this effect can be partially attributed to the vasodilatative property of PGE1 during the initial 10 minutes of reperfusion,228 after a longer period of reperfusion PGE1 achieved significantly better lung function than other vasodilatative agents such as prostacyclin and nitroprusside.229 Hence, the continuous infusion of PGE1 clearly has a beneficial role on ischemia-reperfusion injury, some of which can be attributable to its beneficial action on pro- and anti-inflammatory cytokines.230,231 We have recently demonstrated that the continuous administration of PGE1 during reperfusion is associated with a shift from proinflammatory cytokines such as TNF-␣, IFN-␥, and IL-12 to anti-inflammatory cytokines such as IL-10 in a rat lung transplant model Other effects of PGE1, such as its antiaggregant action on platelets,232 have not been specifically explored in the setting of lung transplantation but may also potentially contribute to its beneficial role Although experimental studies suggest a beneficial effect of PGE1 after reperfusion, no randomized clinical trial has yet been reported in lung transplantation to demonstrate that it prevents ischemia-reperfusion injury In human liver transplantation, two randomized trials have shown a significant reduction in the duration of ICU stay, although no difference in the incidence of primary graft dysfunction was detected.233,234 Studies in clinical lung transplantation are required to determine whether PGE1 has a beneficial effect in the postoperative course Such studies should probably use the newly developed aerosolized form of PGE 1, which has been shown experimentally to reduce ischemia-reperfusion injury of the lung without having the systemic side effects of intravenous PGE1.235 Macrophages Alveolar macrophages have been shown to produce a large number of cytokines, cell surface receptors, and procoagulant agents in vitro in response to oxidative stress or hypoxia In an in vivo model of warm ischemia, Eppinger and colleagues demonstrated the importance of TNF-␣, IFN-␥, and MCP-1 in the early phase of reperfusion and suggested that alveolar macrophages could play an important role during that period Fiser and colleagues recently confirmed this hypothesis by specifically inhibiting pulmonary passenger macrophages with gadolinium chloride before a period of cold ischemia, showing significant improvement in lung function immediately after reperfusion.237,238 The Complement System Complement is a collective term used to designate a group of plasma and cell membrane proteins that play a key role in the cell defense process Studies in ischemia-reperfusion of the lung have shown an activation of the complement system after reperfusion that may lead to cellular injury through direct and indirect mechanisms.239,240 Products of complement activation cause smooth muscle contraction and increase vascular permeability as well as degranulation of phagocytic cells, mast cells, and basophils The activated complement product C5a is also capable of amplifying the inflammatory response via its chemoattractant properties, its induction of granule secretion from phagocytes, and its ability to induce neutrophil and monocyte or macrophage generation of toxic oxygen metabolites Activation of C3 and C5 via their respective convertases is essential for activation of the complement cascade and generation of the membrane attack complex, which leads to direct cell lysis.241 Complement receptor is a natural complement antagonist present on erythrocytes and leukocytes This protein was cloned and the transmembrane portion was removed to obtain a soluble form of CR1 (sCR1) sCR1 suppresses complement activation in vivo by inhibiting C3 and C5 convertases, which prevent the activation of both the classical and alternative pathways In a swine single lung transplant model, we and others have shown that the administration of sCR1 to the recipient before reperfusion reduced lung edema as well as the accumulation of neutrophils in BAL and improved oxygenation.242,243 Similar findings have been observed in a rat single lung transplant model.239 Following these results, a multicenter randomized, double-blinded, placebocontrolled trial with 59 lung transplant recipients was carried out.244 Among 29 patients receiving a dose of sCR1 before reperfusion, 14 (48%) were extubated within 24 hours, which was significantly better than in the control arm, with only patients of a total of 30 (20%) In addition, the overall duration of mechanical ventilation and length of ICU stay tended to be shorter in the group receiving sCR1, but the PaO2/FiO2 ratio was not different between groups Recently, Stammberger and colleagues have demonstrated that the administration of a molecule combining sCR1 with sialyl Lewis X (a selectin receptor antagonist), can achieve significantly better results than the adminsitration of sCR1 alone.245 Neutrophils Neutrophils progressively infiltrate the transplanted lung during the initial 24 hours of reperfusion Although they certainly play an important role in perpetuating reperfusion injury, their function in the early phase of reperfusion remains more controversial Several experiments have been performed with the use of a leukocyte filter to deplete the blood at the time of reperfusion, demonstrating a beneficial effect of leukocyte depletion even after short periods of reperfusion.246,247 However, few studies Lung Preservation for Transplantation / 337 have examined the specific role of neutrophils Using an isolated rat lung perfusion model, Deeb and colleagues demonstrated that the addition of neutrophils to the perfusion system was not necessary for the induction of reperfusion injury after a period of warm ischemia.248 With an antineutrophil antibody, the same group went on to demonstrate that reperfusion injury exhibited a bimodal pattern, consisting of neutrophilindependent events during the early phase of reperfusion and of neutrophil-mediated events in the late phase of reperfusion 249 Other studies with specific antibodies against neutrophils confirm these findings and show that other leukocytes such as macrophages have a more important role in the early phase of reperfusion.238,250,251 Clinical Lung Preservation at the University of Toronto When a potential lung donor is identified, g of intravenous Solumedrol is administered After the lungs have been assessed and the other procurement teams have finished their dissection, the donor is fully heparinized, and the main pulmonary artery is cannulated with a 20 French cannula Prostaglandin PGE (Prostin VR, UpJohn) 500 µg is added to the preservation solution (Perfadex), and 500 µg is injected directly into the main pulmonary artery just prior to flushing the lungs The lungs are recruited with 25 cm H2O prior to flushing to remove atelectasis After inflow occlusion, the left atrial appendage is transected for drainage and the lungs are flushed antegrade with 50 mL/kg of Perfadex solution at 4°C, with the bag approximately 30 cm above the heart The lungs are ventilated throughout the flush with a tidal volume of 10 mL/kg, a PEEP of cm H2O, and an FiO2 of 50% A retrograde flush is then performed in situ with ventilation being continued (250 mL Perfadex into each pulmonary vein orifice) After completion of the flush, the heart and then the lungs are extracted We inflate the lungs with a pressure of approximately 20 cm H O before tracheal cross-clamping to obtain lung expansion but avoid overdistension The lungs are then packaged floating in L of flush solution and stored on ice for transport (Table 26-3) TABLE 26-3 Current Recommendations for Lung Preservation Volume of flush solution Pressure during flush solution Temperature of flush solution Lung ventilation Lung inflation (airway pressure) Oxygenation Storage temperature 50 mL/kg 10–15 mm Hg 4°C–8°C 10 mL/kg 20 cm H2O ≤ 50% FiO2 4°C–8°C At the beginning of the recipient operation we administer 500 mg of Solumedrol The donor lung is kept cool with a cooling jacket in the chest during implantation After implantation, the lung is gently recruited and ventilated: FiO2 = 0.5, PEEP = cm H2O, and pressure control ventilation limiting the peak airway pressure to a maximum of 25 cm H2O The lung is then reperfused slowly over a 10-minute period by gradually removing the pulmonary artery clamp or by allowing the right heart to eject in a controlled fashion if on cardiopulmonary bypass We give no other routine pharmacologic therapy following reperfusion—nitric oxide or PGE1 are used only for clinical indications of reperfusion injury Summary It is now 20 years since the first successful single lung transplant Considerable progress has been made in lung preservation since that time The development of a specific lung preservation solution has been an important advance and the clinical introduction of the lowpotassium dextran solution has been a long time coming In general the lung transplant community has been slow to translate the findings from animal experimental work to the bedside, but this is changing Ischemiareperfusion injury is still a significant clinical problem, and our goals for the future are to be able to better assess the degree of injury, to predict the degree of dysfunction, and hopefully to develop strategies to treat or prevent the injury in the first place Ultimately, we strive towards repairing or modifying a donor lung, allowing time for repair of the injuries, and then testing the lungs ex vivo to ensure good function before transplanting the organ into the recipient References Hosenpud JD, Bennett LE, Keck BM, et al The registry of the international society for heart and lung transplantation: seventeenth official report-2000 J Heart Lung Transplant 2000;19:909–31 Anderson DC, Glazer HS, Semenkovich JW, et al Lung transplant edema: chest radiography after lung transplantation—the first 10 days Radiology 1995;195:275–81 Kundu S, Herman SJ, Winton TL Reperfusion edema after lung transplantation: radiographic manifestations Radiology 1998;206:75–80 King RC, Binns OA, Rodriguez F, et al Reperfusion injury significantly impacts clinical outcome after pulmonary transplantation Ann Thorac Surg 2000;69:1681–5 Meyers CH, Purut CM, D’Amico TA, et al Pulmonary arterial impedance after single lung transplantation J Surg Res 1992;52:459–65 338 / Advanced Therapy in Thoracic Surgery Qayumi AK, Nikbakht-Sangari MN, Godin DV, et al The relationship of ischemia-reperfusion injury of transplanted lung and the up-regulation of major histocompatibility complex II on host peripheral lymphocytes J Thorac Cardiovasc Surg 1998;115:978–89 Toronto Lung Transplant Group Unilateral lung transplantation for pulmonary fibrosis N Engl J Med 1986;314:1140–5 Sommers KE, Griffith BP, Hardesty RL, Keenan RJ Early lung allograft function in twin recipients from the same donor: risk factor analysis Ann Thorac Surg 1996;62:784–90 Madill J, Gutierrez C, Grossman J, et al Nutritional assessment of the lung transplant patient: body mass index as a predictor of 90-day mortality following transplantation J Heart Lung Transplant 2001;20:288–96 10 Meyer DM, Bennett LE, Novick RJ, Hosenpud JD Effect of donor age and ischemic time on intermediate survival and morbidity after lung transplantation Chest 2000;118:1255–62 11 Pierson RN, Milstone AP, Loyd JE, et al Lung allocation in the United States, 1995–1997: an analysis of equity and utility J Heart Lung Transplant 2000;19:846–51 12 deMeester J, Smits JM, Persijn GG, Haverich A Lung transplant waiting list: differential outcome of type of end-stage lung disease, one year after registration J Heart Lung Transplant 1999;18:563–71 13 Cohen RG, Starnes VA Living donor lung transplantation World J Surg 2001;25:244–50 14 Steen S, Sjoberg T, Pierre L, et al Transplantation of lungs from a non-heart-beating donor Lancet 2001;357:825–9 15 Pierre AF, Sekine Y, Hutcheon M, et al Evaluation of extended donor and recipient criteria for lung transplantation J Heart Lung Transplant 2001;20:256 16 Sundaresan S, Trachiotis GD, Aoe M, et al Donor lung procurement: assessment and operative technique Ann Thorac Surg 1993;56:1409–13 17 Gabbay E, Williams TJ, Griffiths AP, et al Maximizing the utilization of donor organs offered for lung transplantation Am J Respir Crit Care Med 1999;160:265–71 18 Sundaresan S, Semenkovich J, Ochoa L, et al Successful outcome of lung transplantation is not compromised by the use of marginal donor lungs J Thorac Cardiovasc Surg 1995;109:1075–9 19 Bhorade SM, Vigneswaran W, McCabe MA, Garrity ER Liberalization of donor criteria may expand the donor pool without adverse consequence in lung transplantation J Heart Lung Transplant 2000;19:1199–204 20 Bittner HB, Kendall SW, Chen EP, et al The effects of brain death on cardiopulmonary hemodynamics and pulmonary blood flow characteristics Chest 1995;108:1358–63 21 Follette DM, Rudich SM, Babcock WD Improved oxygenation and increased lung donor recovery with highdose steroid administration after brain death J Heart Lung Transplant 1998;17:423–9 22 Takada M, Nadeau KC, Hancock WW, et al Effects of explosive brain death on cytokine activation of peripheral organs in the rat Transplantation 1998;65:1533–42 23 Pratschke J, Wilhelm MJ, Kusaka M, et al Accelerated rejection of renal allografts from brain-dead donors Ann Surg 2000;232:263–71 24 DerHoeven JA, TerHorst GJ, Molema G, et al Effects of brain death and hemodynamic status on function and immunologic activation of the potential donor liver in the rat Ann Surg 2000;232:804–13 25 Koo DD, Welsh KI, McLaren AJ, et al Cadaver versus living donor kidneys: impact of donor factors on antigen induction before transplantation Kidney Int 1999;56:1551–9 26 Schwarz C, Regele H, Steininger R, et al The contribution of adhesion molecule expression in donor kidney biopsies to early allograft dysfunction Transplantation 2001;71:1666–70 27 Fisher AJ, Donnelly SC, Hirani N, et al Elevated levels of interleukin-8 in donor lungs is associated with early graft failure after lung transplantation Am J Respir Crit Care Med 2001;163:259–65 28 Hopkinson DN, Bhabra MS, Hooper TL Pulmonary graft preservation: a worldwide survey of current clinical practice J Heart Lung Transplant 1998;17:525–31 29 Fujimura S, Handa M, Kondo T, et al Successful 48-hour simple hypothermic preservation of canine lung transplants Transplant Proc 1987;19:1334–6 30 Keshavjee SH, Yamazaki F, Cardoso PF, et al A method for safe twelve-hour pulmonary preservation J Thorac Cardiovasc Surg 1989;98:529–34 31 Yamazaki F, Yokomise H, Keshavjee SH, et al The superiority of an extracellular fluid solution over Euro-Collins’ solution for pulmonary preservation Transplantation 1990;49:690–4 32 Keshavjee SH, Yamazaki F, Yokomise H, et al The role of dextran 40 and potassium in extended hypothermic lung preservation for transplantation J Thorac Cardiovasc Surg 1992;103:314–25 33 Date H, Matsumura A, Manchester JK, et al Evaluation of lung metabolism during successful twenty-four hour canine lung preservation J Thorac Cardiovasc Surg 1993;105:480–91 34 Steen S, Kimbald PO, Sjoberg T, et al Safe lung preservation for twenty-four hours with Perfadex Ann Thorac Surg 1994;57:336–41 35 Date H, Izumi S, Miyade Y, et al Successful canine bilateral single-lung transplantation after 21-hour lung preservation Ann Thorac Surg 1995;59:336–41 Lung Preservation for Transplantation / 339 36 Spaggiari L, Bobbio P Dextran 40 at 2% versus 5% in lowpotassium solutions: which is best? Ann Thorac Surg 1994;58:1784–6 37 Miyoshi S, Shimokawa S, Schreinemakers HH, et al Comparision of the University of Wisconsin perservation solution and other crystalloid perfusates in a 30-hour rabbit lung preservation model J Thorac Cardiovasc Surg 1992;103:27–32 38 Wagner FM, Jamieson SW, Fung J, et al A new concept for successful long-term pulmonary preservation in a dog model Transplantation 1995;59:1530–6 39 Chien S, Zhang F, Niu W, et al Comparison of university of wisconsin, euro-collins, low-potassium dextran, and krebs-henseleit solutions for hypothermic lung preservation J Thorac Cardiovasc Surg 2000;119:921–30 40 Roberts RF, Nishanian GP, Carey JN, et al A comparison of the new preservation solution Celsior to Euro-Collins and University of Wisconsin solutions in lung reperfusion injury Transplantation 1999;67:152–5 41 Wittwer T, Wahlers T, Fehrenbach A, et al Improvement of pulmonary preservation with Celsior and Perfadex: impact of storage time on early post-ischemic lung function J Heart Lung Transplant 1999;18:1198–201 42 Keshavjee SH, McRitchie DI, Vittorini T, et al Improved lung preservation with dextran 40 is not mediated by a superoxide radical scavenging mechanism J Thorac Cardiovasc Surg 1992;103:326–8 43 Kimbald PO, Sjoberg T, Massa G, et al High potassim contents in organ preservation solutions cause strong pulmonary vasocontraction Ann Thorac Surg 1991;52:523–8 44 Fukuse T, Albes JM, Wilhelm A, et al Influence of dextrans on lung preservation: is the molecular weight important? J Heart Lung Transplant 1996;15:903–10 45 Sakamaki F, Goffmann H, Munzing S, et al Effects of lung preservation solutions on PMN activation in vitro Transplant Int 1999;12:113–21 46 Maccherini M, Keshavjee SH, Slutsky AS, et al The effect of low-potassium-dextran versus Euro-Collins solution for preservation of isolated type II pneumocytes Transplantation 1991;52:621–6 47 Suzuki S, Inoue K, Sugita M, et al Effects of EP4 solution and LPD solution vs Euro-Collins solution on Na(+)/K(+)-ATPase activity in rat alveolar type II cells and human alveolar epithelial cell line A549 cells J Heart Lung Transplant 2000;19:887–93 48 Struber M, Hohlfeld JM, Fraund S, et al Low-potassium dextran solution ameliorates reperfusion injury of the lung and protects surfactant function J Thorac Cardiovasc Surg 2000;120:566–72 49 Sakamaki F, Hoffmann H, Muller C, et al Reduced lipid peroxidation and ischemia-reperfusion injury after lung transplantation using low-potassium dextran solution for lung preservation Am J Respir Crit Care Med 1997;156:1073–81 50 Hopkinson DN, Odom JJ, Bridgewater BJ, Hooper TL University of Wisconsin solution for lung graft preservation: which components are important? J Heart Lung Transplant 1994;13:990–7 51 Fischer S, Hopkinson D, Liu M, Keshavjee SH Raffinose improves the function of rat pulmonary grafts stored for twenty-four hours in low-potassium dextran solution J Thorac Cardiovasc Surg 2000;119:488–92 52 Fischer S, Hopkinson D, Liu M, et al Raffinose improves 24-hour lung preservation in low potassium dextran glucose solution: a histologic and ultrastructural analysis Ann Thorac Surg 2001;71:1140–5 53 Muller C, Furst H, Reichenspurner H, et al Lung procurement by low-potassium dextran and the effect on preservation injury Munich Lung Transplant Group Transplantation 1999;68:1139–43 54 Struber M, Wilhelmi M, Harringer W, et al Flush perfusion with low potassium dextran solution improves early graft function in clinical lung transplantation Eur J Cardiothorac Surg 2001;19:190–4 55 Fischer S, Matte-Martyn A, DePerrot M, et al Lowpotassium dextran preservation solution improves lung function after human lung transplantation J Thorac Cardiovasc Surg 2001;121:594–6 56 Haverich A, Aziz S, Scott WC, et al Improved lung preservation using Euro-Collins solution for flush-perfusion Thorac Cardiovasc Surg 1986;34:368–76 57 Sasaki M, Muraoka R, Chiba Y, Hiramatu Y Influence of pulmonary arterial pressure during flushing on lung preservation Transplantation 1996;61:22–7 58 Tanaka H, Chiba Y, Sasaki M, et al Relationship between flushing pressure and nitric oxide production in preserved lungs Transplantation 1998;65:460–4 59 Andrade RS, Wangensteen OD, Jo JK, et al Effect of hypothermic pulmonary artery flushing on capillary filtration coefficient Transplantation 2000;70:267–71 60 Kimbald PO, Sjoberg T, Steen S Pulmonary vascular resistance related to endothelial function after lung transplantation Ann Thorac Surg 1994;58:416–20 61 Wang LS, Nakamoto K, Hsieh CM, et al Influence of temperature of flushing solution on lung preservation Ann Thorac Surg 1993;55:711–5 62 Albes JM, Fischer F, Bando T, et al Influence of the perfusate temperature on lung preservation: is there an optimum? Eur Surg Res 1997;29:5–11 63 Steen S, Ingemansson R, Budrikis A, et al Successful transplantation of lungs topically cooled in the non-heart-beating donor for hours Ann Thorac Surg 1997;63:345–51 64 VanRaemdonck DE, Jannis NC, Rega FR, et al External cooling of warm ischemic rabbit lungs after death Ann Thorac Surg 1996;62:331–7 65 Hall SM, Odom N, McGregor CG, Haworth SG Transient ultrastructural injury and repair of pulmonary capillaries in transplanted rat lung: effect of preservation and reperfusion Am J Respir Cell Mol Biol 1992;7:49–57 368 / Advanced Therapy in Thoracic Surgery FIGURE 29-2 Freedom from bronchiolitis obliterans syndrome for lung transplant recipients at Barnes-Jewish Hospital, 1988–2000 (n = 497) usually related to ischemia-reperfusion lung injury, and bacterial infections have caused most of the early (0 to 30 days) deaths Cytomegalovirus (CMV) infection and acute rejection have been very common problems in the first year after transplantation, but they have rarely been fatal Non-CMV infections of various types, however, have been a major source of mortality throughout the first years Beyond the first year after transplantation, the prevalence of chronic rejection increases, and in most series 50% of recipients have been afflicted by years after transplantation (Figure 29-2) 3–5 Thus, chronic rejection has been the main cause of death after the first post-transplantation year The real contribution of chronic rejection to mortality is probably understated in Table 29-1 Graft failure is a very nonspecific classification, and some late deaths in this category were probably caused or precipitated by chronic rejection Moreover, some of the late mortality that has been attributed to infection may have been incurred as a complication of treating chronic rejection with more intensive immunosuppression Hence, chronic rejection, or BOS, has emerged as the “thorn in the side” of lung transplantation It is the primary impediment to better medium-term survival, but the true impact is even broader BOS is a major source of morbidity in long-term survivors because of its adverse impact on lung function and quality of life, and it adds substantial extra costs to patient care.7,8 The diagnosis of BOS still hinges on pathological and physiological criteria,9,10 but these manifestations are far downstream from the primary immunologic events that might be amenable to adjustments in the immunosuppressive regimen When the diagnosis of BOS is confirmed, the fibroproliferative process in the bronchioles is already underway, and the allograft has been irreparably damaged to some degree Not surprisingly, treatment of chronic rejection has been disappointing Classification of Rejection Allograft rejection has traditionally been classified as hyperacute, acute, or chronic Hyperacute rejection is caused by preformed antibodies that react with major histocompatibility complex (MHC) determinants or other alloantigens on the vascular endothelium in the donor organ However, it has been virtually eliminated by prescreening recipients for such antibodies (the so-called panel reactive antibodies) before transplantation and adopting an appropriate management strategy if antibodies are present The revised working formulation for the histologic classification of acute and chronic pulmonary allograft rejection is shown in Table 29-2.11 Acute rejection is a process of vascular and airway injury that is mediated by alloreactive T lymphocytes Histologically, the principal feature is perivascular mononuclear infiltrates, with or without an accompanying lymphocytic bronchitis or bronchiolitis, and the severity is graded by the intensity and extent of the inflammation Airway inflammation has been emphasized in the revised formulation because lymphocytic bronchiolitis may be a precursor of obliterative bronchiolitis.12 However, since there are many potential causes of airway inflammation, the implications of bronchiolitis in a biopsy depend on clinical correlation Chronic rejection is a clinicopathologic syndrome of graft dysfunction that is characterized histologically by bronchiolitis obliterans (obliterative bronchiolitis) and physiologically by airflow limitation.9,10 Bronchiolitis obliterans can be caused by other insults, and airflow limitation can be related to factors other than obliterative bronchiolitis Thus, the term bronchiolitis obliterans syndrome has been applied to graft dysfunction with obstructive pathophysiology if there is no discernable explanation other than chronic rejection Pathologic confirmation of bronchiolitis obliterans is not necessary to make a diagnosis of BOS, but other causes of graft dysfunction, such as acute rejection and infection, must be excluded Pathology and Pathogenesis In all solid organ allografts the pathologic trademark of chronic rejection is fibrous obliteration of endothelialTABLE 29-2 Classification of Lung Allograft Rejection A Acute (vascular) rejection With airway inflammation Without airway inflammation* B Lymphocytic bronchitis or bronchiolitis C Chronic airway rejection (bronchiolitis obliterans) Active Inactive D Chronic vascular rejection Adapted from Yousem SA et al.11 *The presence or absence of airway inflammation should be explicitly designated for all cases of acute rejection Bronchiolitis Obliterans Syndrome / 369 ized or epithelialized luminal structures,13–15 and the hallmark in the lung is bronchiolitis obliterans , 1 , , Bronchiolitis obliterans is a cicatricial process that is characterized by total or subtotal obliteration of bronchioles by intraluminal or subepithelial deposits of mature collagen A chronic inflammatory infiltrate or granulation tissue may accompany the pattern, but the term bronchiolitis obliterans should be reserved for lesions with dense fibrous scarring involving the small airways If inflammatory cells are present, bronchiolitis obliterans is classified as active; if there is no inflammation, it is considered inactive Bronchiolitis obliterans is spatially heterogeneous, and confirming it by transbronchial lung biopsy has had a relatively low yield.18–21 The pathogenesis of chronic lung rejection has not been fully elucidated, but is an area of intense clinical and experimental investigation Current hypotheses incorporate both alloimmune-dependent and alloimmune-independent mechanisms of graft injury that provoke a stereotypical response.14,15,17,22–24 In this scheme the instigator could be an alloantigen-dependent immunologic insult such as acute rejection or an alloantigen-independent proinflammatory process such as ischemia-reperfusion injury or infection In some cases, the graft injury itself may promote immune recognition and thereby abet additional immunological damage in a potentially self-perpetuating, irreversible cycle In obliterative bronchiolitis, repetitive epithelial injury is allied with a deranged repair process that permanently remodels the airway Inflammatory cells (T and B lymphocytes, neutrophils, and even eosinophils), macrophages, various cytokines, adhesion molecules, antibodies, and growth factors are involved in this complex, poorly understood quagmire.25–46 Areas of the bronchiole that have been denuded by injury to the epithelium are initially covered by extracellular matrix proteins like fibronectin and fibrin, which will be resorbed if the epithelial layer regenerates normally However, in some instances, myofibroblasts and fibroblasts migrate through defects in the basement membrane into this provisional extracellular matrix and deposit connective tissue (collagen) that forms a fibromyxoid polyp This polyp may be degraded by macrophage collagenases, but otherwise it can mature into a fibrous scar that partially or totally effaces the airway lumen There is no standard animal model for post-transplant obliterative bronchiolitis Although whole lung transplant models have been developed in rodents and miniature swine, the murine heterotopic tracheal allograft has been more widely used In this model a tracheal allograft is implanted into the omentum or a dorsal subcutaneous neck pouch Lesions develop that are histologically similar to human bronchiolitis obliterans, and the relative convenience and simplicity of the model have been attractive features The results of studies with the murine tracheal allograft have recently been thoroughly reviewed.24 Research with this model has authenticated clinical observations and contributed new insights The tracheal allografts have exhibited the sequence of epithelial damage, lymphocytic infiltration and airway inflammation, proliferation of myofibroblast-like cells, and gradual occlusion of the airway In the initial phase the airway epithelial cells express MHC class II antigens that can be directly presented to alloreactive T lymphocytes Thereafter, T lymphocytes and macrophages that are recruited into the airway secrete cytokines and growth factors that promote fibroproliferation and the development of bronchiolitis obliterans Some of the data with immunosuppressive interventions in this model have been inconsistent However, in the review of the studies, the consensus was that immunosuppression was probably beneficial in the early stages of the process, but that this might not completely forestall progression of the obliterative lesions Risk Factors Risk factor analyses have been confined to single-center studies, and their power is constrained by their relatively small sample sizes Nonetheless, these reports have disclosed remarkably consistent risks for the development of BOS, especially antecedent episodes of acute rejection , , – Unfortunately, neither the United Network for Organ Sharing (UNOS) US Scientific Registry nor the Registry of the International Society for Heart and Lung Transplantation (ISHLT) is robust enough to verify or extend these institutional results because neither collects comprehensive data about acute rejection and some other potential risk factors Acute rejection has regularly been identified as the prime hazard for BOS.3,5,47–52 Three or more episodes of acute rejection (usually grade A2) has often been the threshold,3,5,48 but the cumulative burden of acute rejection may be the key factor In addition, late episodes of acute rejection may be a predilection Many analyses have focused on the vascular component of acute rejection, but lymphocytic bronchitis and bronchiolitis have posed a significant risk too.49,53 CMV infection, disease, or donor-recipient serologic status have been indicted as a predisposition in many analyses.3–5,50,52,54,55 Obliterative bronchiolitis can be caused by some viral infections, but it has not been attributed to CMV infection or pneumonia in other solid organ transplant recipients However, CMV infection or pneumonia could potentiate allograft injury and the development of BOS by indirect routes, like cytokine-induced up- 370 / Advanced Therapy in Thoracic Surgery regulation of donor MHC antigens or immunologic cross-reactivity of CMV and donor MHC antigens.56 The impact of CMV may be mitigated by prophylaxis, and although there is no standard practice, most centers now employ some prophylactic or preemptive strategy against CMV infection Lower respiratory tract infections with other viruses (respiratory syncytial virus, parainfluenza virus, influenza virus, and adenovirus) have been increasingly recognized as a problem, 57–60 and in some cases these have been incriminated in the development of BOS Infection with one of these viruses could damage the respiratory epithelium by a direct cytopathic effect or by stimulating or amplifying an alloimmune reaction The relative risk for BOS that may be associated with these infections cannot be quantified right now, but it might be considerable The extent of donor–recipient human leukocyte antigen (HLA) matching has a strong influence on mediumterm graft survival after cadaveric renal transplantation,1 and this has stimulated interest in the effect of HLA matching on the outcome of other solid organ transplants Prospective donor–recipient HLA matching for lung transplantation has not been routinely feasible, and only 4.6% of lung transplant recipients in a recent survey of the UNOS/ISHLT registry had HLA mismatches.61 Hence, with so few well-matched recipients, any beneficial effect of HLA matching could be obscured Indeed, most studies have not established an association between donor–recipient HLA mismatching and BOS in multivariate risk factor analyses,5,48,49,53,61 but a few have found a relationship.5,50–52 Other immunologic factors have been connected to the risk of developing BOS, but these are probably just markers of the inflammatory response rather than the real foundation Persistent donor-specific alloreactivity in bronchioalveolar lavage (BAL) lymphocytes has been associated with an increased incidence of later BOS.62 Likewise, higher neutrophil and lymphocyte counts, the presence of eosinophilic granulocytes, and higher concentrations of interleukin (IL)-6 and IL-8 in BAL have enhanced the likelihood of BOS.28,39 Recipients with donor antigen-specific hyporeactivity in their peripheral blood lymphocytes or with donor-specific microchimerism in peripheral blood have had a low risk of chronic rejection in some, but not all, studies.63–65 The detection of antiHLA antibodies in peripheral blood after transplantation has been linked to the development of BOS,4,35 but a positive recipient panel reactive antibody screen for anti-HLA antibodies before transplantation has not correlated with the probability of BOS after transplantation.66,67 Airway ischemia has not been included as a variable in some of the BOS risk factor analyses, but it was examined in two series In one of these, airway ischemia was not a significant risk factor,52 and in the other, it was a significant risk factor in the univariate, but not in the multivariate, analysis.3 Bronchial artery revascularization has been employed to minimize airway ischemia; however, it has not been widely adopted, and it has not had a profound effect on the incidence of BOS.68,69 The ISHLT Registry has been probed for risk factors for BOS Although this database is large, currently it does not contain some of the essential elements (eg, acute rejection data) for a comprehensive multivariate analysis; therefore, risk factors that otherwise would be weak might appear more important Nevertheless, in a multivariate analysis of the registry, several variables emerged as significant risk factors for the development of BOS within years of transplantation.2 Retransplantation was the most prominent risk factor, and transplantation in the early 1990s carried a significantly higher risk of BOS than transplantation in the late 1990s In adults, recipient age was a significant risk factor only at the extremes, around age 20 years and 65 years A high recipient body mass index (> 27) and a long donor ischemic time (> h) surfaced as significant determinants, too Other donor and recipient characteristics, including underlying disease and type of transplant operation, generally have not affected the incidence of BOS However, recipients with primary pulmonary hypertension seemed to be at higher risk in one institutional study.55 Diagnosis BOS is defined as lung allograft dysfunction with irreversible, and usually progressive, airflow limitation that is presumed to be a manifestation of chronic rejection.9 The pathologic counterpart is bronchiolitis obliterans, but confirmation by biopsy is not necessary for the diagnosis of BOS However, other causes of declining graft function, including such complications as acute rejection, infection or bronchial anastomotic stenosis or malacia, must be excluded After transplantation, lung function improves rapidly if there are no major complications, and it usually reaches a stable plateau by to months after surgery The pulmonary function tests of bilateral lung and heart–lung recipients will be essentially normal, but the pattern of single lung recipients will display the combined physiologic properties of the normal allograft and the remaining diseased native lung Nonetheless, once lung function has stabilized, the coefficient of variation for forced vital capacity (FVC) and forced expiratory volume in second (FEV1) is quite small, and a decrement of 15% in the first year or 10% thereafter is significant.70 The main clinical feature of BOS is deteriorating lung Bronchiolitis Obliterans Syndrome / 371 function that evolves months or more after transplantation The mean time to onset of BOS in most series has been 16 to 20 months, but the range has been broad The presentation can be relatively acute and can either mimic an infectious bronchitis or unfold in the aftermath of a true lower respiratory infection However, it can also evolve as a more insidious erosion of lung function that is initially asymptomatic The lung examination may be unremarkable, but basilar inspiratory crackles are the signature finding The chest radiograph is usually normal or unchanged from its baseline appearance High-resolution computed tomography (CT) has shown abnormalities such as bronchial dilatation and bronchiectasis, decreased peripheral vascular markings or mosaic perfusion, and air trapping,71–76 but air trapping on expiratory CT has been the most useful marker.75,76 The diagnosis of BOS is ultimately made by bronchoscopy and spirometry Spirometric criteria for the diagnosis and staging of BOS have been standardized, and a revision has been proposed recently (Table 29-3).9,10 A new stage, BOS 0-p, with a lower threshold for possible BOS has been created, but the new scheme will have to be tested to determine whether category BOS 0-p reliably identifies recipients who will progress to higher stages of BOS Other lung function tests that are more sensitive for small airway disease have been used to detect evolving BOS before the conventional FEV1 criterion is fulfilled A decline in midexpiratory flow rates, an increase in the slope of the nitrogen washout curve, and abnormalities in other indices of the distribution of ventilation have preceded the decline in FEV1 in recipients who developed BOS.77–80 Nonspecific bronchial hyperreactivity has been demonstrated in lung and heart–lung transplant recipients, and one study correlated a positive methacholine challenge test at months after transplantation with an increased risk of BOS later.81 Although histological proof of bronchiolitis obliterans is not necessary to diagnose BOS, other causes of graft dysfunction must be excluded by bronchoscopy and transbronchial lung biopsy The yield of transbronchial biopsy for detecting bronchiolitis obliterans has been variable but low at most centers.18–20 The sensitivity has been in the range of 15 to 38%, but cumulative positivity rates have reached 38 to 87% in afflicted recipients who underwent more than one procedure.21 Since a complete bronchoscopy usually excludes other problems, surgical lung biopsy is not necessary unless the diagnosis is in doubt.82 BAL is a useful adjunct to transbronchial lung biopsy, but its clinical role is limited to the diagnosis of infection Differential counts of BAL cells and analysis of lymphocyte subsets have not segregated rejection from infection.83 BAL neutrophilia has been linked to BOS,28,31,79 but while it is a very worrisome and suspicious finding in the absence of infection, it is not sufficient to prove a diagnosis of BOS Management and Outcome The repercussions of BOS cannot be overemphasized Besides the functional impairment and extra costs for care that are related to BOS,7,8 the survival rates beyond years after transplantation are much lower in recipients with BOS (Figure 29-3) While the clinical course can be prolonged, the disease is progressive regardless of therapy in most cases.84 Median survival after onset of BOS has been approximately 2.7 years at our center (Figure 29-4) Prevention of BOS is the goal, but current strategies have not shown much promise Induction therapy can reduce the incidence of acute rejection,85,86 and thereby it could reduce the risk of BOS Ultimately, however, induction immunosuppression has not decreased the overall incidence of BOS,85 and its role in lung transplantation remains debatable The optimal maintenance immunosuppressive regimen is unknown, and the incidence of acute rejection in the first year after transplantation has been relatively high with all protocols.87–89 In regimens with tacrolimus plus mycophenolate mofetil or azathioprine, less than onehalf of recipients have remained rejection-free in the first TABLE 29-3 Spirometric Criteria* for the Diagnosis and Staging of Bronchiolitis Obliterans Syndrome Original Proposed Stage Criterion Stage Criterion BOS FEV1 = 80% of baseline BOS BOS BOS FEV1 66 –80% of baseline FEV1 55 – 65% of baseline FEV1 = 50% of baseline BOS BOS 0-p BOS BOS BOS FEV1 > 90% and FEF25–75 > 75% of baseline FEV1 81–90% or FEF25–75 = 75% of baseline FEV1 66 – 80% of baseline FEV1 51 – 65% of baseline FEV1 = 50% of baseline Adapted from Estenne M et al.10 BOS = bronchiolitis obliterans syndrome; FEF = forced expiratory flow; FEV1 = forced expiratory volume at second *Baseline is the average of the two highest (not necessarily consecutive) measurements that are obtained at least weeks apart Bronchiolitis Obliterans Syndrome / 373 Nonetheless, lung function has declined more rapidly, and BOS has recurred more frequently, after retransplantation for BOS than for other indications.108,109 The variable that has been most strongly associated with freedom from BOS years after retransplantation is an interval of more than years between the first and second transplant Thus, retransplantation may be appropriate for recipients with graft failure from BOS who are otherwise suitable candidates for transplantation, are ambulatory, are not ventilator-dependent and have survived at least years since their first transplant Summary Chronic rejection is still an “undefined conundrum” that is often “inexorable, and as yet uncontrollable.”13 BOS is the major cause of medium-term morbidity and mortality after lung transplantation In spite of advances in posttransplantation management and the advent of newer immunosuppressive agents, the incidence has remained high, and the results of treatment have been disappointing References 2000 Organ Procurement and Transplantation Network (OPTN)/US Scientific Registry for Transplant Recipients (SRTR) Annual Report Transplant data: 1990–1999 Rockville, (MD): US Department of Health and Human Services, Health Resources and Services Administration, Office of Special Programs, Division of Transplantation; Richmond (VA): United Network for Organ Sharing; 2000 Hosenpud JD, Bennett LE, Keck BM, et al The Registry of the International Society for Heart and Lung Transplantation: Eighteenth Official Report — 2001 J Heart Lung Transplant 2001;20:805–15 Bando K, Paradis IL, Similo S, et al Obliterative bronchiolitis after lung and heart-lung transplantation: an analysis of risk factors and management J Thorac Cardiovasc Surg 1995;110:4–14 Smith MA, Sundaresan S, Mohanakumar T, et al Effect of development of antibodies to HLA and cytomegalovirus mismatch on lung transplantation survival and development of bronchiolitis obliterans syndrome J Thorac Cardiovasc Surg 1998;116:812–20 Heng D, Sharples LD, McNeil K, et al Bronchiolitis obliterans syndrome: incidence, natural history, prognosis and risk factors J Heart Lung Transplant 1998;17:1255–63 Levine SM, Bryan CL Bronchiolitis obliterans in lung transplant recipients The “thorn in the side” of lung transplantation Chest 1995;107:894–7 van den Berg JWK, Geertsma A, van der Bij W, et al Bronchiolitis obliterans syndrome after lung transplantation and health-related quality of life Am J Respir Crit Care Med 2000;161:1937–41 van den Berg JW, van Enckevort PJ, Ten Vergert EM, et al Bronchiolitis obliterans syndrome and additional costs of lung transplantation Chest 2000;118:1648–52 Cooper JD, Billingham M, Egan T, et al A working formulation for the standardization of nomenclature and for clinical staging of chronic dysfunction in lung allografts J Heart Lung Transplant 1993;12:713–6 10 Estenne M, Maurer JR, Boehler A, et al Bronchiolitis obliterans syndrome 2001: an update of the diagnostic criteria J Heart Lung Transplant 2002; 21:297–310 11 Yousem SA, Berry GJ, Cagle PT, et al Revision of the 1990 working formulation for the classification of pulmonary allograft rejection: Lung Rejection Study Group J Heart Lung Transplant 1996;15:1–15 12 Yousem SA Lymphocytic bronchitis/bronchiolitis in lung allograft recipients Am J Surg Pathol 1993;17:491–6 13 Tilney NL, Whitley WD, Diamond JR, et al Chronic rejection — an undefined conundrum Transplantation 1991;52:389–98 14 Paul LC, Benediktsson H Chronic transplant rejection: magnitude of the problem and pathogenetic mechanisms Transplant Rev 1993;7:96–113 15 Tullius SG, Tilney N Both alloantigen-dependent and -independent factors influence chronic allograft rejection Transplantation 1995;59:313–8 16 Yousem SA, Berry GJ, Brunt EM, et al A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: lung rejection study group J Heart Transplant 1990;9:593–601 17 Boehler A, Kesten S, Weder W, Speich R Bronchiolitis obliterans after lung transplantation A review Chest 1998;114:1411–26 18 Kramer MR, Stoehr C, Whang JL, et al The diagnosis of obliterative bronchiolitis after heart-lung and lung transplantation: low yield of transbronchial lung biopsy J Heart Lung Transplant 1993;12:675–81 19 Yousem SA, Paradis I, Griffith BP Can transbronchial biopsy aid in the diagnosis of bronchiolitis obliterans in lung transplant recipients? Transplantation 1994;57:151–3 20 Chamberlain D, Maurer J, Chaparro C, Idolor L Evaluation of transbronchial lung biopsy specimens in the diagnosis of bronchiolitis obliterans after lung transplantation J Heart Lung Transplant 1994;13:963–71 21 Trulock EP Flexible bronchoscopy in lung transplantation Clin Chest Med 1999;20:77–87 22 Halloran PF, Homik J, Goes N, et al The “injury response”: a concept linking nonspecific injury, acute rejection, and long-term transplant outcomes Transplant Proc 1997;29:79–81 23 Paradis I Bronchiolitis obliterans: pathogenesis, prevention, and management Am J Med Sci 1998;315:161–78 374 / Advanced Therapy in Thoracic Surgery 24 Hele DJ, Yacoub MH, Belvisi MG The heterotopic tracheal allograft as an animal model of obliterative bronchiolitis Respir Res 2001;2:169–83 25 Hertz MI, Henke CA, Nakhleh RE, et al Obliterative bronchiolitis after lung transplantation: a fibroproliferative disorder associated with platelet-derived growth factor Proc Natl Acad Sci U S A 1992;89:10385–9 26 Al-Dossari GA, Jessurun J, Bolman RM III, et al Pathogenesis of obliterative bronchiolitis Possible roles of platelet-derived growth factor and basic fibroblast growth factor Transplantation 1995;59:143–5 27 Magnan A, Mege J-L, Escallier J-C, et al Balance between alveolar macrophages IL-6 and TGF-␤ in lung transplant recipients Am J Respir Crit Care Med 1996;153:1431–6 28 DiGiovine B, Lynch JPI, Martinez FJ, et al Bronchoalveolar lavage neutrophilia is associated with obliterative bronchiolitis after lung transplantation: role of IL-8 J Immunol 1996;157:4194–202 29 Jonosono M, Fang KC, Keith FM, et al Measurement of fibroblast proliferative activity in bronchoalveolar fluid in the analysis of obliterative bronchiolitis among lung transplant recipients J Heart Lung Transplant 1999;18:972–85 30 Ross DJ, Moudgil A, Bagga A, et al Lung allograft dysfunction correlates with gamma-interferon gene expression in bronchoalveolar lavage J Heart Lung Transplant 1999;18:627–36 31 Riise GC, Andersson BA, Kjellstrom C, et al Persistent high BAL fluid granulocyte activation marker levels as early indicators of bronchiolitis obliterans after lung transplant Eur Respir J 1999;14:1123–30 32 El-Gamel A, Sim E, Haselton P, et al Transforming growth factor beta (TGF-beta) and obliterative bronchiolitis following pulmonary transplantation J Heart Lung Transplant 1999;18:828–37 33 Hirsch J, Elssner A, Mazur G, et al Bronchiolitis obliterans syndrome after (heart-)lung transplantation Impaired antiprotease defense and increased oxidant activity Am J Respir Crit Care Med 1999;160:1640–6 34 Nakajima J, Poindexter NJ, Hillemeyer PB, et al Cytotoxic T lymphocytes directed against donor HLA class I antigens on airway epithelial cells are present in bronchoalveolar lavage fluid from lung transplant recipients during acute rejection J Thorac Cardiovasc Surg 1999;117:565–71 35 Jaramillo A, Smith MA, Phelan D, et al Development of ELISA-detected anti-HLA antibodies precedes the development of bronchiolitis obliterans syndrome and correlates with progressive decline in pulmonary function after lung transplantation Transplantation 1999;67:1155–61 36 SivaSai KSR, Smith MA, Poindexter NJ, et al Indirect recognition of donor HLA class I peptides in lung transplant recipients with bronchiolitis obliterans syndrome Transplantation 1999;67:1094–8 37 Smith CR, Jaramillo A, Duffy B, Mohanakumar T Airway epithelial cell damage mediated by antigen-specific T cells: implications in lung allograft rejection Human Immunol 2000;61:985–92 38 Elssner A, Jaumann F, Dobmann S, et al Elevated levels of interleukin-8 and transforming growth factor-beta in bronchoalveolar lavage fluid from patients with bronchiolitis obliterans syndrome: proinflammatory role of bronchial epithelial cells Transplantation 2000;70:362–7 39 Scholma J, Slebos D-J, Boezen HM, et al Eosinophilic granulocytes and interleukin-6 level in bronchoalveolar lavage fluid are associated with the development of obliterative bronchiolitis after lung transplantation Am J Respir Crit Care Med 2000;162:2221–5 40 Behr J, Maier K, Braun B, et al; Munich Lung Transplant Group Evidence for oxidative stress in bronchiolitis obliterans syndrome after lung and heart-lung transplantation Transplantation 2000;69:1856–60 41 Zheng L, Walters EH, Ward C, et al Airway neutrophilia in stable and bronchiolitis obliterans syndrome patients following lung transplantation Thorax 2000;55:53–9 42 Reznik SI, Jaramillo A, Zhang L, et al Anti-HLA antibody binding to HLA class I molecules induces proliferation of airway epithelial cells: a potential mechanism for bronchiolitis obliterans syndrome J Thorac Cardiovasc Surg 2000;119:39–45 43 Jaramillo A, Naziruddin B, Zhang L, et al Activation of human airway epithelial cells by non-HLA antibodies developed after lung transplantation: a potential etiological factor for bronchiolitis obliterans syndrome Transplantation 2001;71:1–11 44 Agostini C, Calabrese F, Rea F, et al Cxcr3 and its ligand CXCL10 are expressed by inflammatory cells infiltrating lung allografts and mediate chemotaxis of T cells at sites of rejection Am J Pathol 2001;158:1703–11 45 Belperio JA, Keane MP, Burdick MD, et al Critical role for the chemokine MCP-1/CCR2 in the pathogenesis of bronchiolitis obliterans syndrome J Clin Invest 2001;108:547–56 46 Devouassoux G, Pison C, Drouet C, et al Early lung leukocyte infiltration, HLA and adhesion molecule expression predict chronic rejection Transplant Immunol 2001;8:229–36 47 Bando K, Paradis IL, Komatsu K, et al Analysis of timedependent risks for infection, rejection and death after pulmonary transplantation J Thorac Cardiovasc Surg 1995;109:49–59 48 Sharples LD, Tamm M, McNeil K, et al Development of bronchiolitis obliterans syndrome in recipients of heartlung transplantation — early risk factors Transplantation 1996;61:560–6 49 Girgis RA, Tu I, Berry GJ, et al Risk factors for the development of obliterative bronchiolitis after lung transplantation J Heart Lung Transplant 1996;15:1200–8 Bronchiolitis Obliterans Syndrome / 375 50 Kroshus TJ, Kshettry VR, Savik K, et al Risk factors for the development of bronchiolitis obliterans syndrome after lung transplantation J Thorac Cardiovasc Surg 1997;114:195–202 51 van den Berg JWK, Hepkema BG, Geertsma A, et al Long-term outcome of lung transplantation is predicted by the number of HLA-DR mismatches Transplantation 2001;71:368–73 52 Schulman LL, Weinberg AD, McGregor CC, et al Influence of donor and recipient HLA locus mismatching on development of obliterative bronchiolitis after lung transplantation Am J Respir Crit Care Med 2001;163:437–42 53 Husain AN, Siddiqui MT, Holmes EW, et al Analysis of risk factors for the development of bronchiolitis obliterans Am J Respir Crit Care Med 1999;159:829–33 54 Reichenspurner H, Girgis RE, Robbins RC, et al Obliterative bronchiolitis after lung and heart-lung transplantation Ann Thorac Surg 1995;60:1845–53 55 Kshettr y VR, Kroshus TJ, Savik K, et al Primar y pulmonary hypertension as a risk factor for the development of obliterative bronchiolitis in lung allograft recipients Chest 1996;110:704–9 56 Rubin RH The indirect effects of cytomegalovirus infection on the outcome of organ transplantation JAMA 1989;261:3607–9 57 Wendt CH, Hertz MI Respiratory syncytial virus and parainfluenza virus infections in the immunocompromised host Semin Respir Infect 1995;10:224–31 58 Palmer SM, Henshaw NG, Howell DN, et al Community respiratory viral infection in adult lung transplant recipients Chest 1998;113:944–50 59 Garantziotis S, Howell DN, McAdams HP, et al Influenza pneumonia in lung transplant recipients: clinical features and association with bronchiolitis obliterans syndrome Chest 2001;119:1277–80 60 Billings JL, Hertz MI, Wendt CH Community respiratory virus infections following lung transplantation Transplant Infect Dis 2001;3:138–48 61 Quantz MA, Bennett LE, Meyer DM, Novick RJ Does human leukocyte antigen matching influence the outcome of lung transplantation? An analysis of 3,549 lung transplantations J Heart Lung Transplant 2000;19:473–9 62 Duquesnoy R, Zeevi A Immunological monitoring of lung transplant patients by bronchoalveolar analysis Transplant Rev 1992;6:218–30 63 Reinsmoen NL, Bolman RM, Savik K, et al Improved long-term graft outcome in lung transplant recipients who have donor antigen-specific hyporeactivity J Heart Lung Transplant 1994;13:30–7 64 Reinsmoen NL Posttransplant donor antigen-specific hyporeactivity in human transplantation Transplant Rev 1995;9:17–28 65 Calhoun R, SivaSai KSR, Sundaresan S, et al Development of bronchiolitis obliterans syndrome despite blood chimerism in human lung transplant recipients Transpl Int 1999;12:439–46 66 Gammie JS, Pham SM, Colson YL, et al Influence of panel-reactive antibody on survival and rejection after lung transplantation J Heart Lung Transplant 1997;16:408–15 67 Lau CL, Palmer SM, Posther KE, et al Influence of panelreactive antibodies on posttransplant outcomes in lung transplant recipients Ann Thorac Surg 2000;69:1520–4 68 Pettersson G, Nørgaard MA, Arendrup H, et al Direct bronchial artery revascularization and en bloc double lung transplantation — surgical techniques and early outcome J Heart Lung Transplant 1997;16:320–33 69 Nørgaard MA, Andersen CB, Pettersson G Does bronchial artery revascularization influence results concerning bronchiolitis obliterans syndrome and/or obliterative bronchiolitis after lung transplantation Eur J Cardiothorac Surg 1998;14:311–8 70 Martinez JAB, Paradis IL, Dauber JH, et al Spirometry values in stable lung transplant recipients Am J Respir Crit Care Med 1997;155:285–90 71 Loubeyre P, Revel D, Delignette A, et al Bronchiectasis detected with thin-section CT as a predictor of chronic lung allograft rejection Radiology 1995;194:213–6 72 Ikonen T, Kivisaari L, Harjula ALJ, et al Value of highresolution computed tomography in routine evaluation of lung transplantation recipients during the development of bronchiolitis obliterans syndrome J Heart Lung Transplant 1996;15:587–95 73 Ikonen T, Kivisaari L, Taskinen E, et al High-resolution CT in long-term follow-up after lung transplantation Chest 1997;111:370–6 74 Leung AN, Fisher K, Valentine V, et al Bronchiolitis obliterans after lung transplantation — detection using expiratory HRCT Chest 1998;113:365–70 75 Lee E-S, Gotway MB, Reddy GP, et al Early bronchiolitis obliterans following lung transplantation: accuracy of expiratory thin-section CT for diagnosis Radiology 2000;216:472–7 76 Bankier AA, Van Muylem A, Knoop C, Gevenois PA Bronchiolitis obliterans syndrome in heart-lung transplant recipients: diagnosis with expiratory CT Radiology 2001;218:533–9 77 Patterson GM, Wilson S, Whang JL, et al Physiologic definitions of obliterative bronchiolitis in heart-lung and double lung transplantation: a comparison of the forced expiratory flow between 25% and 75% of the forced vital capacity and forced expiratory volume in one second J Heart Lung Transplant 1996;15:175–81 376 / Advanced Therapy in Thoracic Surgery 78 Estenne M, Van Muylem A, Knoop C, Antoine M; Brussels Lung Transplant Group Detection of obliterative bronchiolitis after lung transplantation by indexes of ventilation distribution Am J Respir Crit Care Med 2000;162:1047–51 79 Reynaud-Gaubert M, Thomas P, Badier M, et al Early detection of airway involvement in obliterative bronchiolitis after lung transplantation Functional and bronchoalveolar lavage cell findings Am J Respir Crit Care Med 2000;161:1924–9 80 Chacon RA, Corris PA, Dark JH, Gibson GJ Tests of airway function in detecting and monitoring treatment of obliterative bronchiolitis after lung transplantation J Heart Lung Transplant 2000;19:263–9 90 Palmer SM, Baz MA, Sanders L, et al Results of a randomized, prospective, multicenter trial of mycophenolate mofetil versus azathioprine in the prevention of acute lung allograft rejection Transplantation 2001;71:1772–6 91 Keenan RJ, Konishi H, Kawai A, et al Clinical trial of tacrolimus versus cyclosporine in lung transplantation Ann Thorac Surg 1995;60:580–5 92 Tamm M, Sharples LD, Higenbottam TW, et al Bronchiolitis obliterans syndrome in heart-lung transplantation: surveillance biopsies Am J Respir Crit Care Med 1997;155:1705–10 93 Pham SM, Rao AS, Zeevi A, et al Effects of donor bone marrow infusion in clinical lung transplantation Ann Thorac Surg 2000;69:345–50 81 Stanbrook MB, Kesten S Bronchial hyperreactivity after lung transplantation predicts early bronchiolitis obliterans Am J Respir Crit Care Med 1999;160:2034–9 94 Glanville AR, Baldwin JC, Burke CM, et al Obliterative bronchiolitis after heart-lung transplantation: apparent arrest by augmented immunosuppression Ann Intern Med 1987;107:300–4 82 Chapparo C, Maurer JR, Chamberlain DW, Todd TR Role of open lung biopsy for diagnosis in lung transplant recipients: ten-year experience Ann Thorac Surg 1995;59:928–32 95 Snell GI, Esmore DS, Williams TJ Cytolytic therapy for the bronchiolitis obliterans syndrome complicating lung transplantation Chest 1996;109:874–8 83 Clelland C, Higenbottam T, Stewart S, et al Bronchoalveolar lavage and transbronchial lung biopsy during acute rejection and infection in heart-lung transplant patients: studies of cell counts, lymphocyte phenotypes, and expression of HLA-DR and interleukin-2 receptor Am Rev Respir Dis 1993;147:1386–92 96 Kesten S, Rajagopalan N, Maurer J Cytolytic therapy for the treatment of bronchiolitis obliterans syndrome following lung transplantation Transplantation 1996;61:427–30 97 Iacono AT, Keenan RJ, Duncan SR, et al Aerosolized cyclosporine in lung recipients with refractory chronic rejection Am J Respir Crit Care Med 1996;153:1451–5 84 Date H, Lynch JP, Sundaresan S, et al The impact of cytolytic therapy on bronchiolitis obliterans syndrome J Heart Lung Transplant 1998;17:869–75 98 Ross DJ, Lewis MI, Kramer M, et al FK506 ‘rescue’ immunosuppression for obliterative bronchiolitis after lung transplantation Chest 1997;112:1175–9 85 Palmer SM, Miralles AP, Lawrence CM, et al Rabbit antithymocyte globulin decreases acute rejection after lung transplantation Chest 1999;116:127–33 99 Whyte RI, Rossi SJ, Mulligan MS, et al Mycophenolate mofetil for obliterative bronchiolitis syndrome after lung transplantation Ann Thorac Surg 1997;64:945–8 86 Garrity ER Jr, Villanueva J, Bhorade SM, et al Low rate of acute lung allograft rejection after the use of daclizumab, an interleukin receptor antibody Transplantation 2001;71:773–7 87 Griffith BP, Bando K, Hardesty RL, et al A prospective randomized trial of FK506 versus cyclosporine after human pulmonary transplantation Transplantation 1994;57:848–51 88 Treede H, Klepetko W, Reichenspurner H, et al Tacrolimus versus cyclosporine after lung transplantation: a prospective, open, randomized, two-center trial comparing two different immunosuppressive protocols J Heart Lung Transplant 2001;20:511–7 89 Corris P, Glanville A, McNeil K, et al One year analysis of an ongoing international randomized study of mycophenolate mofetil (MMF) vs azathioprine (AZA) in lung transplantation [abstract] J Heart Lung Transplant 2001;20:149–50 100 Dusmet M, Maurer J, Winton T, Kesten S Methotrexate can halt the progression of bronchiolitis obliterans syndrome in lung transplant recipients J Heart Lung Transplant 1996;15:948–54 101 Verleden GM, Buyse B, Delcroix M, et al Cyclophosphamide rescue therapy for chronic rejection after lung transplantation J Heart Lung Transplant 1999;18:1139–42 102 Snell GI, Levvey BJ, Chin W, et al Rescue therapy: a role for sirolimus in lung and heart transplant recipients Transplant Proc 2001;33:1084–5 103 Diamond DA, Michalski JM, Lynch JP, Trulock EP III Efficacy of total lymphoid irradiation for chronic allograft rejection following bilateral lung transplantation Int J Radiation Oncology Biol Phys 1998;41:795–800 104 Salerno CT, Park SJ, Kreykes NS, et al Adjuvant treatment of refractory lung transplant rejection with extracorporeal photopheresis J Thorac Cardiovasc Surg 1999;117:1063–9 Bronchiolitis Obliterans Syndrome / 377 105 O’Hagan AR, Stillwell PC, Arroliga A, Koo A Photopheresis in the treatment of refractory bronchiolitis obliterans complicating lung transplantation Chest 1999;115:1459–62 108 Novick RJ, Stitt LW, Al-Kattan K, et al Pulmonary retransplantation: predictors of graft function and survival in 230 patients Ann Thorac Surg 1998;65:227–34 106 Mentzer SJ, Reilly JJ, Caplan AL, Sugarbaker DJ Ethical considerations in lung retransplantation J Heart Lung Transplant 1994;13:56–8 109 Novick RJ, Stitt L, Schäfers H-J, et al Pulmonary retransplantation: does the indication for operation influence postoperative lung function? J Thorac Cardiovasc Surg 1996;112:1504–14 107 Novick RJ Heart and lung retransplantation: should it be done? J Heart Lung Transplant 1998;17:635–42 CHAPTER 30 LUNG RETRANSPLANTATION STEFAN FISCHER, MD, MSC MARTIN STRUEBER, MD AXEL HAVERICH, MD coworkers in 1991.6 The main purpose of the foundation was to determine the predictors of outcome after retransplantation, so as to facilitate decisions concerning the appropriateness of lung retransplantation in individual patients In their latest report in 1998, 230 patients were recorded by the registry who underwent lung retransplantation in 47 centers.7 Since the number of patients is low, but the number of centers is relatively high (mean of patients per center), it is possible that many of these centers may have contributed to the registry with data derived from only a single case Lung transplantation has evolved to an accepted treatment modality for end-stage lung diseases.1 According to the twentieth official report of the International Society for Heart and Lung Transplantation (ISHLT) registry, more than 14,000 adult lung transplant procedures (single and bilateral) have been performed worldwide, including more than 2,000 adult heart–lung transplants.2 Of all lung transplant indications, retransplants account for only 2.2 to 3%, dependant on the type of transplant (eg, single, bilateral, or heart–lung transplantation) Indications for redo lung transplantation are acute and chronic graft failure following primary transplantation.3 In rare instances such as severe therapy-refractory bronchial healing complications following lung transplantation, retransplantation has been considered to be the ultimate treatment option.4 However, owing to the small total number (approximately 450) of retransplantation procedures that have been performed worldwide, there is only little evidence reported in the literature regarding the outcome following lung retransplantation Moreover, intense debate is currently ongoing regarding the indications for redo lung transplantation It is not clear which patient benefits from this high-risk procedure and which does not Nevertheless, lung transplantation, as other fields of organ transplantation, is limited by a shortage of available donor organs At our institution approximately 70 lung transplant procedures are performed annually, which accounts for only 30% of all patients listed.5 Considering this issue it is indeed relevant to determine the target group of patients that really benefit from a redo lung transplant A first and important step towards a systematic analysis of the world experience in redo lung transplantation was the foundation of the Pulmonary Retransplant Registry by Novick and Special Aspects in Pulmonary Retransplantation Patients and Indications Because of the increased number of patients waiting for a lung transplantation on one hand, but also the increasing lack of available donor lungs for transplantation on the other hand, recipients for redo lung transplantation should be selected thoroughly According to the ISHLT registry for 2001, repeat lung transplantation is a risk factor that contributes significantly to the 1-year mortality in adult lung transplantation Since only little evidence exists in redo lung transplantation, patient selection criteria are not systematically established and most lung transplant centers still not offer the option of repeat lung transplantation to their patients with acute or chronic lung graft failure However, some centers have established redo lung transplant programs, and their patient selection criteria are based on their own, individual expertise; their outcome is relatively similar to that following primary adult lung transplantation 378 Lung Retransplantation / 379 There are basically two major indications for repeat lung transplantation—acute graft failure during the early perioperative phase and chronic graft failure following lung transplantation, which is mainly related to the clinical manifestation of bronchiolitis obliterans syndrome (BOS) and the histopathological manifestation of a obliterative bronchiolitis (OB) Patients who develop acute graft failure during the perioperative phase following lung transplantation mostly have never been weaned from mechanical ventilatory support and require extended intensive care treatment with well-known risks, including pulmonary infection, continuous catecholamine administration, and failure of other organ systems (eg, renal or liver) At the end stage of their graft failure a number of these patients require support by extracorporeal membrane oxygenation (ECMO) devices for bridging to retransplant, if a retransplant is considered a feasible treatment option in the individual case The second group of lung retransplantation candidates consists of patients who developed chronic graft failure after primary or even after repeat lung transplantation Most of these patients well after initial lung transplantation and usually show onset of chronic graft failure or BOS in routine lung function test This is often associated with a need for intermittent or continuous oxygen insufflation If other potential reasons for the deterioration of lung graft function are excluded, such as viral or bacterial infection, bronchial mucus obstruction, or acute graft rejection, a variety of interventions and treatments will be initiated (see Chapter 29: Bronchiolitis Obliterans Syndrome) However, if BOS progresses, the patient should be introduced to a lung transplant surgeon in order to discuss the option of retransplantation in a multidisciplinary setting It is important to discuss the option of retransplantation at a very early stage of BOS, since Novick and Stitt have confirmed in multivariable analyses of 3-month survival following redo lung transplantation the cardinal importance of ambulatory status in predicting early outcome after retransplantation.9 Patients, who are ambulatory immediately before retransplantation had a threefold increased likelihood of postoperative survival From their data the authors concluded that, in view of the marked shortage of donor organs, lung retransplantation should be limited to ambulatory patients only A third group of patients who have repeatedly been considered as retransplant candidates includes patients who develop severe bronchial healing problems following lung transplantation.10 Bronchial anastomosis dehiscence is associated with a high mortality rate in lung recipients, and there is intense ongoing debate as to whether these patients should undergo further surgical intervention or be treated conservatively and, if surgery is preferred, if a redo lung transplant should be favored over bronchial resection Technical Aspects The technical aspects of lung transplantation have been refined over the past two decades The original doublelung technique was performed through a median sternotomy with the recipient on cardiopulmonary bypass The donor lungs were implanted en bloc with a single tracheal anastomosis While this operation was successful, its limitations became apparent as it was extended to more difficult cases In 1989 the bilateral sequential operation was introduced and has become the current standard approach The lungs are sequentially and separately implanted through an anterior transverse thoracosternotomy (clamshell incision) 11 This incision provides excellent exposure of the pleural space However, there are many disadvantageous effects associated with this extremely invasive and traumatizing approach According to the literature and our own clinical observation, early postoperative pain following thoracotomy is a significant problem Additionally, chronic post-thoracotomy neuralgia is seen in many patients, which impacts on the quality of life and often requires chronic analgesic drug consumption.12 In order to achieve optimal function of the transplanted lung, sufficient breathing activity is critical Postoperative pain, however, leads to flat chest movements and insufficient graft ventilation, which further allows the occurrence of pneumonia Currently, most immunosuppressive regimens include the application of steroids, which are well known to cause impaired wound healing This is especially true in large wounds such as the clamshell incision.13 Therefore, we developed a novel video-assisted minimally invasive approach in clinical bilateral lung transplantation, and we are now routinely using this approach in patients undergoing bilateral lung transplantation We also adopt this approach, which includes an anterior thoracotomy on both sides of the chest, for select cases of redo lung transplantation The technical difference between primary and redo lung transplantation is that patients after previous lung transplantation develop extensive scar tissue within their chest Adhesions are especially problematic if the primar y lung graft was size-reduced by atypical parenchymal resection using a surgical stapler and bovine pericardial stripes to fortify the staple lines This xenogeneic tissue causes severe adhesions that can usually not be cleared from the surrounding native tissue and which therefore increases the risk of injury to other structures such as nerves or vessels Whereas adhesions of the lung with the chest wall are relatively easy to manage, scar tissue in the hilar region may provide major obstacles in the dissection of the hilar structures In particular, 380 / Advanced Therapy in Thoracic Surgery the phrenic nerve can be totally undetectable in the scar tissue and injury of the nerve can cause respiratory insufficiency or, in extremis, can make weaning from mechanical ventilator y support impossible Figure 30-1 illustrates severe adhesions from the lung graft to the leftsided anterior chest wall and the pericardium after redo lung transplantation during a re-retransplant procedure These kinds of adhesions can usually be cut using an electronic cutting device However, they can involve important structures such as the phrenic nerve, which can easily be injured or cut even during thorough tissue dissection Figure 30-2 demonstrates the hilum of a transplanted lung during a re-retransplant procedure The previous transplant was performed years ago Even though the phrenic nerve is FIGURE 30-1 View into an opened chest through a clamshell incision in a patient undergoing a third lung transplantation Intense and widespread scar tissue formation is visible between lung graft, chest wall, and pericardium The right lung was already excised FIGURE 30-2 View on the right hilum in the same patient as in Figure 30-1 Note the severe adhesions between hilar structures The phrenic nerve is surprisingly easily identified surprisingly easily identified, the vascular and bronchial structures of the hilum are massively wrapped with rigid conglomerative scar tissue, and surgical division of these structures can be impossible without injury to those structures, which can further cause massive bleeding and significant blood loss In order to identify the vascular hilar structures in redo lung transplant procedures, we routinely open the pericardium and snare the pulmonary artery intrapericardially, at a site where scar tissue usually does not develop, as shown in Figure 30-3 Intrapericardial tissue dissection towards the hilum makes the distinction between structures easier and helps to avoid injury Figure 30-4 underlines how massive hilar scarring can be following lung transplantation Distinction of the anatomical tissue layers is not possible The bronchus is surrounded by scar tissue, and also the anatomical space FIGURE 30-3 View into the opened pericardium At this site the pulmonary artery is not wrapped in scar tissue and therefore easily identified The right pulmonary artery is snared FIGURE 30-4 Widespread hilar adhesions not allow distinction of tissue layers Lung Retransplantation / 381 between the pulmonary veins and the pericardium cannot be clearly identified The pulmonary artery has been snared inside the pericardium Finally, Figure 30-5 shows an explanted lung graft during a redo lung transplant procedure Note the extensive scar tissue formation over the entire lung surface FIGURE 30-5 Excised lung graft in a case of a third lung transplantation for end-stage bronchiolitis obliterans syndrome Note the widespread scar tissue covering the entire surface of the lung Outcome after Redo Lung Transplantation Although the results of lung transplantation are improving, a significant number of grafts fail owing to severe early graft dysfunction, intractable airway healing problems, or, especially, OB Since lung transplantation became an accepted treatment modality for patients suffering from end-stage lung failure, an increasing number of redo lung transplants has been performed In 1993 Novick and associates published first international experience in lung retransplantation.15 An international survey of redo lung transplantation was performed to identify the morbidity and mortality rates and factors correlating with increased or decreased survival after this procedure Twenty institutions in North America and Europe participated, and the study cohort included 61 patients who underwent 63 redo lung transplantation operations Patients undergoing a redo heart–lung transplantation were excluded In view of the marked scarcity of suitable donor lung grafts, a pulmonary retransplantation registry was established in 1991 by Novick and Stitt with the goal of determining, via a multi-institutional analysis, the outcome and predictors of survival following pulmonary retransplantation.9 Thirty-five lung transplant centers participated in this study and provided the data of 160 retransplant recipients The indications for redo pulmonary transplantation were OB in 93 cases, primary graft failure in 40 patients, intractable airway complications in 14 cases, severe therapy refractory acute rejection in patients, and miscellaneous conditions in cases With respect to survival, 45% of patients following retransplantation survived the first year The 2-, 3-, and 4-year survival was 41, 33, and 30%, respectively These data suggest a higher mortality after retransplantation than after primary lung transplantation Especially during the past 10 years, novel strategies in lung preservation, infection prevention, and immunosuppression have been introduced to the field of lung transplantation by us and others and have influenced the outcome following lung transplantation.16,17 However, based on the published data following redo lung transplantation and the shortage of available donor organs compared with the number of wait-listed patients, indications for pulmonary retransplantation remain controversial At the Hannover Thoracic Transplant Program we have performed lung retransplantation in 50 patients We compared the outcome of the patients with 458 lung transplant procedures that had been performed at our institution by the time of analysis For this purpose the 50 redo lung recipients were subdivided into three diagnostic groups: acute graft failure (AF, n = 10), chronic graft failure (CGF, n = 34), or airway complications (AW, n = 6) The main endpoints of our analysis included 90day, 1- and 2-year survival, duration of intensive care unit stay, and time of hospitalization These parameters were compared with primary transplant recipients’ outcome Indication for primary transplantation included idiopathic pulmonary fibrosis (32%), emphysema (30%), primary pulmonary hypertension (7%), secondary pulmonary hypertension and Eisenmenger’s syndrome (2%), cystic fibrosis (21%), and others (8%) When pulmonary retransplantation for any kind of graft failure is included in the list of indications, redo transplants account for 9.8% of all lung transplant procedures at our institution The 50 cases of redo lung transplantation include three cases of a third transplantation and one case of a fourth Survival after retransplantation for CGF is comparable to the survival following primary transplantation The AF group and AW group revealed impaired intermediate survival (p = 014) compared with primary lung transplantation or retransplantation for CGF (p = 034) The duration of intensive care unit stay and total length of hospitalization were significantly longer in the AF and AW group compared with CGF and primary transplant recipients, which, once again, were similar Figure 30-6 illustrates the survival of patients following redo lung transplantation at our institution, comparing these groups with each other and also with the cohort of primary lung transplant patients Lung Retransplantation / 383 transplantation, infection and associated sepsis seems to be the most important contributor to mortality following redo lung transplantation From our results we concluded that the outcome following pulmonary retransplantation is dependent on the indication for redo lung transplantation Chronic graft failure leads to similar results as primary lung transplantation Acute graft failure and airway complications were associated with long hospitalization periods and poor intermediate survival Therefore, redo pulmonary transplantation should be offered to patients with chronic graft failure In the event of acute graft failure and post-transplant airway healing complications thorough evaluation of the individual patient for redo lung transplantation is warranted Summary Lung transplantation has certainly evolved to an accepted treatment modality for patients suffering from end-stage lung disease, except for bronchial or pulmonary malignancies The criteria of patient selection for lung transplantation are still tight; however, major lung transplant programs throughout the world have created “special case” lists that include patients who not fulfil the general criteria for lung transplantation because they may be too old, or alternative lists, which are based on the principle to transplant marginal donor organs, which are rejected for elective transplantation into relatively stable patients on the waiting list, into marginal recipients, who would otherwise probably not be considered as lung transplant candidates These activities indicate that an extension of donor and recipient criteria is currently ongoing.18 However, lung retransplantation is still considered to be a high-risk procedure, and many programs that perform primary lung transplant procedures not perform retransplants From the ISHLT registry it becomes very clear that redo lung transplantation is a significant risk factor for early mortality following lung transplantation The evidence regarding pulmonary retransplantation in the literature is very sparse Certainly, the practice of pulmonary retransplantation has evolved since its initial introduction in the late 1980s However, criteria for patient selection for pulmonary retransplantation have not been clearly defined Looking at the distribution of all indications for lung transplantation, including pulmonary retransplantation for any kind of post-transplant lung graft failure in the ISHLT registry, redo lung transplantation accounts for approximately 3% of all indications for lung transplantation The number of centers that include data of patients who underwent pulmonary retransplantation into the registry is relatively high in contrast to the number of patients who undergo retransplantation at these programs To our knowledge, the Hannover Thoracic Transplant Program has performed the largest number of lung retransplant procedures as a single center Therefore, we have collected data on the largest single-center cohort of retransplant patients With 9.8% of all transplant procedures, redo lung transplants are more frequently performed at our institution compared with the entire ISHLT community with approximately 3% First experiences in pulmonar y retransplantation have been collected and thoroughly published by Novick and Stitt, who established the Pulmonary Retransplantation Registry in 1991.9 The main purpose of the registry was to determine the outcome and predictors of survival after lung retransplantation and to ultimately promote the efficient use of scarce donor organs From their data, Novick and coworkers concluded that patients who received a retransplant for advanced BOS have a higher risk of early redevelopment of BO in their retransplanted lung compared with patients who received a retransplant for other indications Novel immunosuppressive regimens may help to overcome this obvious immunological obstacle in lung retransplantation However, currently the literature does not provide sufficient data with regards to this special aspect, and the evidence is very small Looking at the Hannover data, it is clear that pulmonary retransplantation in patients with chronic graft failure leads to outcome comparable to that in patients who receive a primar y lung transplant Therefore, we would like to motivate other programs to introduce their patients with advanced graft failure following previous lung transplantation to retransplantation We must underline that the time point of evaluation for pulmonary retransplantation is not clear However, Novick and Stitt determined that retransplant recipients in BOS stage at and years had a significantly worse actuarial survival compared with those in BOS stages and 2.9 We therefore strive for early reevaluation for redo lung transplantation in patients who show signs of chronic graft failure When BOS becomes apparent in our transplanted patients, we shorten the intervals of medical examination in our outpatient lung transplant clinics Overall, we consider lung retransplantation for chronic graft failure as a standard procedure and offer this option to all patients with BOS who not have any of the generally accepted contraindications for lung transplantation With regards to lung retransplantation for acute graft failure following lung transplantation, we believe that, owing to the very poor outcome, it should be performed in thoroughly selected patients only We only consider patients with acute graft failure for retransplantation if all other organ systems function well and if 384 / Advanced Therapy in Thoracic Surgery the recipient is not elderly However, we have not established an age limit, and the decision for retransplantation in cases of acute graft failure should be reserved for very experienced lung transplant physicians and surgeons Patients who develop bronchial healing complications following lung transplantation have a high mortality risk, and the most appropriate treatment has not been identified Bronchial healing remains a problem in lung transplantation and is most likely influenced by cartilaginous ischemia and impaired post-transplant bronchial blood perfusion Of our six patients who underwent lung retransplantation for bronchial healing complications, four patients received their initial transplant for endstage emphysema It remains speculative whether smoking history and, consequently, airway epithelial changes in the group of emphysema patients leads to impaired bronchial healing We tend towards treatment strategies for bronchial healing complications other than retransplantation The outcome following interventional treatment including stenting, laser therapy, and fibrinous glue application or, if required, surgical interventions such as sleeve resections, seem to lead to favourable outcome when compared with retransplantation However, our experience is based on single cases only and, thus, should not be overinterpreted at this point In summary, pulmonar y retransplantation has evolved to a feasible and reasonable treatment option for patients with chronic end-stage lung graft failure but should otherwise be reserved for only highly selected patients who developed acute graft failure or bronchial healing complications following lung transplantation Retransplantation of the lung is surgically much more demanding than primary transplants and should be performed by very experienced lung transplant surgeons only From the medical point of view, special immunological obstacles certainly exist in redo lung transplantation, but whether novel immunosuppressive strategies will help to overcome those has to be studied in future analyses Acknowledgments The authors acknowledge the professional help of their colleagues at the Hannover Thoracic Transplant Program and especially the tremendous amount of conceptual and medical work that is performed by the Department of Respiratory Medicine (Director, Dr Jost Niedermeyer) including the Lung Transplant Outpatient Clinic and the Cystic Fibrosis Ambulance The authors also thank Ms Petra Oppelt for her expert assistance in recording and analyzing the data and for reviewing statistical analysis as a biostatistician References Fischer S, Strueber M, Haverich A Current status of lung transplantation: patients, indications, techniques and outcome Med Klin 2002;97:137–43 Trulock EP, Edwards LB, Taylor DO, et al The Registry of the International Society for Heart and Lung Transplantation: twentieth official adult lung and heartlung transplant report—2003 J Heart Lung Transplant 2003;22:625–35 Novick RJ, Stitt L, Schafers HJ, et al Pulmonary retransplantation: does the indication for operation influence postoperative lung function? J Thorac Cardiovasc Surg 1996;112:1504–13; discussion 1513–4 Daly RC, McGregor CG Surgical issues in lung transplantation: options, donor selection, graft preservation, and airway healing Mayo Clin Proc 1997;72:79–84 Fischer S, Strueber M, Haverich A Clinical cardiac and pulmonary transplantation: the Hannover experience Clin Transpl 2000;1:311–6 Novick RJ, Stitt L Pulmonary retransplantation Semin Thorac Cardiovasc Surg 1998;10:227–36 Novick RJ, Stitt LW, Al-Kattan K, et al Pulmonary retransplantation: predictors of graft function and survival in 230 patients Pulmonary Retransplant Registry Ann Thorac Surg 1998;65:227–34 Hosenpud JD, Bennett LE, Keck BM, et al The Registry of the International Society for Heart and Lung Transplantation: eighteenth official report—2001 J Heart Lung Transplant 2001;20:805–15 Novick RJ, Stitt L Lung retransplantation In: Franco KL, Putnam JB Jr, editors Advanced therapy in thoracic surgery Hamilton (ON): BC Decker Inc.; 1998 p 387–94 10 Alvarez A, Algar J, Santos F, et al Airway complications after lung transplantation: a review of 151 anastomoses Eur J Cardiothorac Surg 2001;19:381–7 11 Patterson GA Indications Unilateral, bilateral, heart-lung, and lobar transplant procedures Clin Chest Med 1997;18:225–30 12 Rogers ML, Duffy JP Surgical aspects of chronic postthoracotomy pain Eur J Cardiothorac Surg 2000;18:711–6 13 Meyers BF, Sundaresan RS, Guthrie T, et al Bilateral sequential lung transplantation without sternal division eliminates posttransplantation sternal complications J Thorac Cardiovasc Surg 1999;117:358–64 14 Fischer S, Struber M, Simon AR, et al Video-assisted minimally invasive approach in clinical bilateral lung transplantation J Thorac Cardiovasc Surg 2001;122:1196–8 ... Interferon-␥ Macrophage chemoattractant protein-1 Interleukin-1␤ Interleukin-2 Interleukin-6 Interleukin-8 Interleukin-10 Interleukin-12 Interleukin-18 Macrophages, lymphocytes Lymphocytes Immune... lung150–152 induces a rapid release of proinflammatory cytokines including tumor necrosis factor (TNF )-? ??, interferon (IFN )-? ??, IL-1␤, IL-6, membrane cofactor protein (MCP )-1 , and IL-8 (Table 2 6-2 ) In human... binds to cyclophilin, a 17 kD immunophilin with isomerase activity important for intracellular protein folding The cyclosporine–cyclophilin complex engages and inhibits calcineurin, a calcium-dependent