The success of lung transplantation has followed in the wake of other solid organ transplant populations. Regrettably, the survival of lung transplant recipients lag behind that of other solid organ transplant recipients (1, 2). However, emerging data suggest that graft survival after lung transplantation is set to improve.
Unique characteristics may influence survival after lung transplantation. Unlike other solid organ transplants, the lung allograft is exposed to the environment. Approximately 11,000 liters of air, including particulates and microorganisms, move through the lung each day. A mucociliary escalator system normally maintains a sterile environment. This mechanism is disrupted in lung transplant recipients who have both abnormal ciliary function and an impaired cough reflex resulting from denervation of the lung. Therefore, the lung allograft is potentially exposed to two major sources of injury: first, the expected phenomenon of rejection leading to alloimmune injury, and second, nonalloimmune injury such as infection.
Obliterative bronchiolitis results in graft failure late after lung transplantation. This is a patchy process that limits the ability of transbronchial biopsy to secure a diagnosis. This problem of sampling error has lead to the emergence of a clinical classification as a surrogate for obliterative bronchiolitis. This clinical correlate is referred to as bronchiolitis obliterans syndrome (BOS) and is primarily based on estimates of FEV^sub 1^ and FEF^sub 25-75^ (3).
Alloimmune injury, identified histologically as acute cellular rejection, is a significant risk factor for the development of obliterative bronchiolitis. Both the frequency and the grade of severity are important. Three or more episodes of acute rejection within 12 months of transplantation results in a three- to fourfold increase in risk of BOS (4). At least one episode of mild (A2) rejection is associated with BOS (5). New insights into the natural history of acute cellular rejection and the impact of recurrent minimal (A1) rejection on graft survival are provided by Hopkins and coworkers in this issue of the Journal (pp. 1022-1026) (6). Their study challenges the conventional belief that minimal A1 rejection does not have significant consequences. In this clinical series, 42% of patients experienced multiple Al rejection episodes in the first 12 months after transplantation. In 34% of patients, surveillance biopsies showed progression from minimal Al to high-grade rejection. BOS developed in 68% of patients with multiple minimal A1 rejection biopsies, at a mean of 599 days. These data indicate that repetitive low-grade acute cellular rejection episodes lead to clinically relevant alloimmune-mediated injury. Broad interpretation of this detailed study suggests that all lung transplant patients should be subjected to histologie surveillance for rejection and also that augmented treatment for rejection prevents the onset of BOS. However, neither assumption can currently be corroborated.
Valentine and colleagues have shown that the outcome of patients who are not subjected to a routine surveillance biopsies for the identification of acute rejection is similar to that of the international registry (7). They used a strict care pathway that triggered a biopsy only in specific clinical circumstances. Using this approach, 55% of patients were managed with only a single biopsy procedure. These results imply that the elective identification and treatment of acute rejection may not influence long-term graft function. These contrasting approaches to the elective histologie diagnosis of rejection emphasize the need for noninvasive estimates of rejection after lung transplantation.
Recent data describe a possible role for serum concentrations of hepatocyte growth factor (HGF) as a surrogate marker for rejection (8). In a prospective blinded study of 106 lung transplant recipients, elevated levels of HGF discriminated between infection and rejection. Patients with rejection had significantly greater HGF levels, 3,972 ng/L compared with 1,559 ng/L for those with infection. Receiver-operator curve characteristics were predictive of rejection at 0.99 (95% confidence interval, 0.997-1.001). Perhaps a surprising observation was the rapid escalation of HGF, within 1 to 2 days, before the diagnosis of rejection. Biologically, one might expect a delayed lead in time for the evolution of rejection in patients receiving immunosuppression. If the observations pertaining to HGF are validated, its measurement may provide further insight into the natural history of alloimmune injury and BOS.
Hopkins and coworkers imply that the treatment of minimal Al rejection may lead to reduced rates of BOS. Although treatment largely leads to histologic resolution of rejection, there is no compelling evidence that augmented treatment of acute rejection prevents BOS. In a large international study, 32% of patients demonstrated progression from recurrent acute rejection to BOS despite optimization of immunosuppression (9). Alternative sources of injury may therefore be important. Data provided by Hopkins and colleagues support this concept, as BOS occurred in 43% of patients with less than one episode of minimal Al rejection.
Nonalloimune injury represents an increasingly relevant form of injury in which prcventativc interventions may impact on graft survival. Gastroesophageal reflux disease (GERD) is recognized as a common event after lung transplantation, believed to result from vagal injury at the time of surgery. GERD has been documented in as many as 73% of patients using esophageal pH probe monitoring (10). Those with normal pH studies had significantly better survival, 82% at 5 years compared with 48% for patients with GERD. On the basis of a high index of suspicion for aspiration, patients were subjected to laparoscopic fundoplication. There was a 24% increase in FEV^sub 1^ after fundoplication in a cohort of 43 patients. This intervention was most successful when undertaken at the early stages of BOS; only 17% of patients with advanced Grade 3 BOS improved after fundoplication.
Infection, the most frequent cause of death after lung transplantation, is another potential source of nonalloimmune injury. Bronchial dilatation, characteristic of bronchiectasis, on HRCT is a typical finding in patients with BOS. Bacterial infection is difficult to associate with BOS because of the range of organisms and the variability in the definition of infection. Nevertheless, two studies including a total of 390 patients implicate bacterial infection as a risk factor for BOS (4, 5). Following this theme, emerging data suggest that antimicrobial therapy may influence outcome. In an open label, uncontrolled pilot study, Gerhart and coworkers used prolonged low-dose oral azithromicin in a cohort of six patients with established BOS (11). Such therapy resulted in a mean increase of 17.5% in predicted FEV^sub 1^. HRCT data relating to the presence or absence of graft bronchiectasis may also be complimentary in identifying patients who might benefit from prolonged macrolide therapy.
A major challenge exists to dissect the dynamic relationship between alloimmune injury and nonalloimune injury after lung transplantation. Each injury, be it rejection, GERD/aspiration, or infection, is potentially additive. Hopkins describes a group of patients, at risk for BOS, who experienced multiple minimal Al rejection episodes. This emphasizes that alloimmune injury remains the critical insult in the hierarchy of events experienced by the lung allograft. Repetitive nonalloimmune injury may augment the alloimmune response by enhancing an indiscriminate innate inflammatory cell response. Airway wall neutrophilia is a common finding in lung transplant recipients (12). In light of the irreversible characteristics of established histologic obliterative bronchiolitis, curtailing both alloimmune and nonalloimmune epithelial cell injury may provide opportunities for improving graft survival after lung transplantation.
Conflict of Interest Statement: J.J.E. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.
References
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8. Aharinejad S, Taghavi S, Kleptko W, Abraham D. Prediction of lung transplant rejection by hepatocyte growth factor. Lancet 2004;363: 1503-1508.
9. Sarahrudi K, Estenne M, Corris P, Niedermayer J, Knoop C, Glanville A, Chaparro C, Verleden G, Gerbase MW, Venuta F, Bottcher H, Aubert JD, Lewey B, Reichenspurner H, Auterith A, Klepetko W. International experience with conversion from cyclosporine to tacrolimus for acute and chronic lung allograft rejection. J Thorac Cardiovasc Surg 2004;127:1126-1132.
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11. Gerhart SG, McDyer JF, Girgis RE, Conte JV, Yang SC, Orens JB. Maintenance azithromycin therapy for bronchiolitis obliterans syndrome results of a pilot study. Am J Respir Crit Care Med 2003;168: 121-125.
12. Zheng L, Walters EH, Ward C, Wang N, Orsida B, Whitford H, Williams TJ, Kotsimbos T, Snell SI. Airway neutrophilia in stable and bronchiolitis obilterans syndrome patients following lung transplantation. Thorax 2000;55:53-59.
DOI: 10.1164/rccm.2408010
JIM J. EGAN, M.D.
The Mater Misericordiae and St. Vincent's University Hospitals
Dublin Molecular Medicine Center
University College Dublin
Dublin, Ireland
Copyright American Thoracic Society Nov 1, 2004
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