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American Journal of Respiratory and Critical Care Medicine Vol 175. pp. 432-435, (2007)
© 2007 American Thoracic Society
doi: 10.1164/rccm.200701-029UP

Pulmonary and Critical Care Updates

Update in Transplantation 2006

Paul A. Corris1 and Jason D. Christie2

1 Institute of Cellular Medicine, School of Clinical Medical Sciences, Newcastle University and Freeman Hospital, Newcastle upon Tyne, United Kingdom; and 2 Pulmonary, Allergy, and Critical Care Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania

Correspondence and requests for reprints should be addressed to Paul A. Corris, M.B. B.S., F.R.C.P., Institute of Cellular Medicine, School of Clinical Medical Sciences, Newcastle University and Freeman Hospital, Newcastle upon Tyne, NE7 7DN, UK. E-mail: paul.corris{at}ncl.ac.uk

The breadth of published work in 2006 complements the wide spectrum of research reported in last year's update article by Estenne and Kotloff (1). Important review publications included one on consensus guidelines for the referral and listing for lung transplantation (2) and the 23rd official report from the International Society for Heart and Lung Transplantation (ISHLT) (3). This latter report from Trulock and colleagues confirms chronic obstructive pulmonary disease (COPD) as the main worldwide indication for lung transplantation, comprising 38% of all lung transplantations in 2005. The number of lung transplantations reported to the ISHLT registry continued to increase to an all-time high of 1,815. Benchmark survival figures were reported as 78% at 1 year, 61% at 3 years, 49% at 5 years, and 25% at 10 years. The survival half-life was approximately 5 years.

RECIPIENT SELECTION

In a consensus statement from the ISHLT, Orens and colleagues addressed updates in consideration for listing of lung transplant recipients since the prior guidelines of 1998 (2). Other investigations addressed specific aspects of recipient selection, including evidence that patients older than 61 years can tolerate bilateral transplantation (4), that noncritical coronary artery disease is generally well tolerated after transplantation (5), and that higher preoperative doses of corticosteroids are associated with worse outcomes after the transplant procedure (6). Although, these studies may have been affected by bias due to selection of the patients, they illustrate general trends in safety and risk of lung transplantation for subjects in these traditionally higher risk categories.

The past year represented the first full year under the new organ allocation system guided by a lung allocation score (LAS) in the United States (7). Preliminary studies indicate that the major impact of this change was on listing of patients with idiopathic pulmonary fibrosis (IPF) (8). Topically, there were two studies illustrating important prognostic variables in patients with advanced lung disease awaiting lung transplantation. Lederer and colleagues investigated the relationship between six-minute-walk distance and mortality in patients with IPF (9). The authors found that a distance of less than 207 m was associated with an almost fivefold increase in mortality rate, even when adjusted for other physiological variables. Another variable included in the LAS, the FVC %predicted, was also found to be associated with mortality, although to a lesser degree than the six-minute-walk distance. This study was conducted before the institution of the LAS; however, it appears that the importance of these risk factors is being accounted for in the current U.S. listing scheme, given the observation that patients with IPF seem to have shorter waiting times (8).

Belkin and colleagues found several variables not accounted for in the LAS scoring to be associated with waiting-list mortality in patients with cystic fibrosis (CF) (10). In a multicenter cohort study of 343 subjects with CF, the authors concluded that FEV1 of 30% predicted or greater and PaCO2 of 50 mm Hg or greater were associated with mortality in those awaiting transplantation. Because this study was conducted before the newer allocation scheme in the United States, the implications of these findings on future listing of patients with CF remains to be determined.

Although the management of severe pulmonary arterial hypertension (PAH) in adults and children has been revolutionized by the development of effective medical therapies, including prostaglandins, endothelin antagonists, and phosphodiesterase V inhibitors, transplantation still has a role (11, 12). There is concern among physicians who treat patients with PAH that the LAS regulations are currently not ideal for this group of patients and lead to listing at too late a stage when survival to transplantation is unlikely. The issue of PAH listing represents an area for further consideration in 2007.

DONOR EVALUATION AND MANAGEMENT

One rate-limiting factor to increasing the number of transplant procedures is the availability of suitable donors. Angel and colleagues sought to directly address this issue by implementing the San Antonio Lung Transplant (SALT) donor management protocol (13). The protocol included educational and donor management interventions, as well as changes in the donor classification and selection criteria. Using the SALT criteria, the investigators were able to increase the percentage of lungs procured per eligible donor from 11.5 to 22.5%, resulting in a dramatic increase in the number of transplant procedures. Recipient outcomes were not adversely affected by using the SALT protocol.

Kaneda and colleagues used gene expression methods in an effort to further evaluate the suitability of donor organs (14). Using a split-sample design in a cohort study of 169 donors, the investigators evaluated the association between biopsy expression of pro- and antiinflammatory mediators and 30-day mortality. The authors found an association between the ratio of IL-6 and IL-10 expression in the donor lung and 30-day mortality. Given the low mortality rate in this study, and the relatively small derivation set, the findings should be viewed as preliminary and in need of validation. However, this study represents an exciting first step in using molecular diagnostics on donor lungs to predict outcomes.

Several notable studies addressed ex vivo preservation and evaluation of donor lungs (15–17). Both studies used an ex vivo preservation strategy including both perfusion and ventilation of the explanted lungs, and illustrated that gas exchange can be preserved during this period. Weirup and colleagues demonstrated that organs otherwise deemed unsuitable for transplantation could be improved with the use of ex vivo preservation techniques (16). Expanding on prior work in rats (15), Egan and coworkers illustrated that this technique can be used in non–heart beating human donors (17). In addition, several authors evaluated methods for expanding the use of non–heart beating human-donated lungs, including treatment with nitric oxide (18), nitroglycerin (19), urokinase (20), and high-flow cooling ventilation (21).

ISCHEMIA REPERFUSION INJURY AND PRIMARY GRAFT DYSFUNCTION

Epidemiology and Clinical Risk Factors
The recent consensus standardization of the clinical definition of primary graft dysfunction (PGD) called for studies aimed at validation of the consensus criteria (22, 23). Two studies addressed this issue in 2006 (24, 25). Prekker and colleagues retrospectively evaluated 402 lung transplant subjects to apply the consensus definition (25). The authors concluded that grade 3 PGD was associated with worse short- and long-term outcomes at each of the scoring time points up to 48 hours. However, the authors were limited in their ability to evaluate difference in lower grades due to missing chest radiograph data. Likewise, Oto and colleagues illustrated that higher grades of PGD were associated with worse outcomes (24). However, in this study, there were differences in the incidence of PGD between single and bilateral transplants, perhaps due to the influence of native lungs on the PaO2/FIO2 ratio. These two studies illustrate that the operational definition of PGD is a work in progress. While the 48- and 72-hour scores discriminate mortality best, both early and late PGD grade may have important impact on outcomes, and are important for future study.

Whitson and colleagues (26) used the new classification scheme and confirmed prior studies illustrating that pulmonary hypertension, recipient diagnosis, and increasing donor age were associated with PGD risk (27, 28). In addition, the authors reported that donor smoking history had an association with PGD, and that the incidence of PGD was higher before 1998 than in the more modern era, in part due to improved preservation. Similarly, Oto and colleagues added to the body of literature by suggesting that Perfadex is associated with a lower incidence of PGD than other solutions (29).

Pathogenesis and Experimental Therapeutics
Liu and colleagues used a rat model of orthotopic transplantation to evaluate the effects of the novel cytosolic enzyme indoleamine 2,3-dioxygenase (IDO) on allograft dysfunction (30). IDO has both T-cell–suppressive and antioxidant properties, and was found to reduce a variety of physiological and biochemical lung injury parameters when delivered via nonviral gene transfer. Rodents treated with IDO had improved oxygenation, histological appearance, and T-cell suppression.

Two studies evaluated the role of carbon monoxide in reducing experimental allograft injury (31, 32). Kohmoto and colleagues illustrated that low doses of CO reduced endothelial injury, inflammatory gene expression, and cellular infiltrates in a rat lung transplant model (31). In an elegant series of experiments, Mishra and colleagues found that CO reduces early growth response gene 1 (erg1) expression, and thus has downstream effects on both inflammation and prothrombotic mechanisms (32).

Chen and colleagues evaluated the effects of beta-agonists on ischemia reperfusion injury in rats (33). The authors illustrated that nebulized salmeterol given during warm ischemia maintained cyclic AMP levels and reduced lung injury. Thus, long-acting beta-agonists may be important agents for future clinical studies of reducing PGD in humans.

BRONCHIOLITIS OBLITERANS SYNDROME

Experimental Approaches in Animal Models
Bronchiolitis obliterans syndrome (BOS) remains the leading cause of chronic lung allograft dysfunction and continues to stimulate research in animal models. Mikols and coworkers, using a murine lung allograft model, studied the role of concurrent viral infections on epithelial cell injury, immune cell accumulation, and collagen deposition in the transplanted airway (34). Epithelial injury was more marked with concurrent viral infection and was followed by an exaggerated accumulation of macrophages and collagen deposition. These pathological features of allograft dysfunction were associated with increases in the innate epithelial cell macrophage chemoattractant IL-12 p80. Blocking or overexpressing this macrophage chemoattractant led to a corresponding abrogation or enhancement of macrophage accumulation. Furthermore, human recipients of lung transplants with bronchiolitis and viral infections showed increased epithelial IL-12 p80 expression, suggesting that this may be an important epithelial marker of disease.

The potential role of viruses in promoting BOS was investigated in a murine orthotopic tracheal transplantation model by Kuo and colleagues (35). Infection with Sendai virus, a murine parainfluenza type I virus, initiated a dose-dependent transient suppression of alloreactivity at 30 days followed by reversal at Day 60 and enhanced allograft fibrosis. Pretransplant immunization against the Sendai virus reduced the immunopathological response after transplantation, thus indicating the potential benefit of vaccination against common respiratory viral infections in the prevention of BOS. The same group confirmed the essential role of epithelial cell injury and defective reepithelialization in promoting allograft fibrosis (36). They used heterotopic tracheal allografts in matrix metalloproteinase-7 knockout mice that constitutionally fail to reepithelialize.

Tikkanen and coworkers investigated the role of platelet-derived growth factor (PDGF) and vascular endolethial growth factor (VEGF) in the development of experimental BOS using a rat heterotopic allograft model (37). Prophylactic blocking of VEGF reduced blood vessel formation and diminished inflammation. Prophylactic blocking of PDGF inhibited smooth muscle proliferation. A combination of both inhibitors given prophylactically prevented the development of airway obstruction. Early treatment at Day 7 reduced airway obliteration, but delaying treatment to Day 14 had no effect on airway obliteration compared with control animals. This work suggests that tyrosine kinase inhibitors may be considered in the treatment of patients with BOS but emphasizes the need for early diagnosis and early therapy.

Experimental Approaches in Humans
Luckraz and colleagues studied the potential role of microvascular damage to small airways in the genesis of BOS in 99 post mortem lung allografts (38). In a multivariate analysis, a reduction in blood vessels per unit length of airway was associated with the development of obliterative bronchiolitis and was time independent. Obliterative bronchiolitis was preceded by a decrease in microvascular supply to the airway, but after the onset of airway scarring there was an apparent increase in very small vessels, suggestive of neovascularization.

Gene expression microarray profiling of peripheral blood cells is currently being performed prospectively in a large cohort of patients via a multicenter international collaborative trial known as the Lung Allograft Gene Expression Diagnostic Study (LARGO) study. In the meantime, Lu and coworkers have reported on a small experience in 11 recipients with BOS and 9 control transplant recipients without BOS (39). Fifteen genes were found to be differentially expressed involving inflammatory, fibrotic, and apoptopic pathways. The study confirmed the view that multiple pathogens were involved in the genesis of BOS. Previous studies by Gimino and colleagues had indicated that gene expression profiling of bronchoalveolar lavage (BAL) cells may also offer an approach to identified genes of interest in both acute and chronic rejection (40).

Walter and colleagues showed that the epithelial cell glycoprotein KL-6 could be released into the serum of patients post-transplantation and was increased in those with BOS, indicating its potential as a noninvasive biomarker (41). The origin of the fibroblasts involved in the fibroproliferative response seen in BOS remains an important question because it offers potential for novel therapeutic targets. Epithelial-to-mesenchymal transition was demonstrated to occur in human lungs after transplantation and thus offers a potential source of activated fibroblasts (42). Brocker and coworkers have investigated another potential source of fibroblasts—namely, circulating precursor cells (43). Tissue from lung allografts demonstrated evidence of recipient-derived fibroblasts using polymerase chain reaction–based genotyping.

In 2005, Yates and colleagues reported an uncontrolled study of low-dose azithromycin in treating patients with BOS (44). Verleden and coworkers have shown further evidence of benefit in 14 patients with BOS (45). Azithromycin reduced both BAL neutrophilia and IL-18 mRNA levels in patients with BOS. Those patients who showed a functional response in terms of an increase in FEV1 had a significantly higher BAL neutrophilia at the onset of treatment.

Murphy and colleagues reported that the phosphodiesterase inhibitor cilomilast inhibited IL-8 release from primary bronchial cell cultures derived from lung transplant recipients, suggesting a potential clinical role (46). Finally, McNeil and coworkers reported on a multicenter, randomized, open-label, prospective study of mycophenolate mofetil compared with azathioprine in patients receiving induction therapy, cyclosporine, and prednisolone after lung transplantation (47). The primary endpoint was the development of BOS at 3 years. No differences were seen in the incidence of acute rejection or BOS in the two groups. However, the null result may have been influenced by the shorter observation time for azathioprine patients.

OTHER MEDICAL PROBLEMS

The clinical significance of Mycobacterium abscessus infection in the lung transplant population is not well understood. Chernenko and colleagues reported on an international survey to determine incidence and clinical outcomes of M. abscessus infections before and after lung transplantation (48). A total of 17 patients were identified post-transplantation of whom 2 had respiratory colonization pretransplantation. Twelve patients had respiratory infection, three had soft tissue infection, and two had infection in both sites. Eleven patients had a radiological response to therapy, with 10 finally considered cured. There were two deaths attributable to M. abscessus. Cutaneous lesions responded to surgical debridement and drugs.

Hypogammaglobulinaemia may occur in the pre- and post-transplant populations, leading Yip and colleagues to carry out a retrospective cohort study in 40 consecutive recipients (49). Mild and severe hypogammaglobulinaemia were seen in 58 and 15% of post-transplant recipients. Lower pretransplant IgG levels and use of mycophenolate mofetil were associated with more severe hypogammaglobulinaemia post-transplantation with the risk of severe suppression only associated with low pretransplant levels. Patients with COPD were most at risk of hypogammaglobulinaemia within both populations.

Lung transplant recipients are potentially susceptible to rhinovirus infections. Kaiser and coworkers studied 68 lung transplant recipients in a prospective manner over 19 months, after having identified three patients with graft dysfunction due to rhinovirus in both upper and lower respiratory secretions using polymerase chain reaction over the preceding 12 months (50). Ten recipients had evidence of rhinovirus in BAL fluid, and chronic infection was seen in two recipients.

FOOTNOTES

Conflict of Interest Statement: Neither author has a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

Received in original form January 9, 2007; accepted in final form January 9, 2007

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Proc. Am. Thorac. Soc. Am. J. Respir. Cell Mol. Biol.
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