Lung Transplantation (out of print)

Pulmonary rehabilitation is an important component of the management of patients with advanced lung disease. Small increments in exercise capacity are important to patients and potentially complement post-transplant rehabilitation and the preservation of bone density. Noninvasive positive pressure ventilatory support (NIPPV) is an accepted strategy for bridging cystic fibrosis (CF) patients to transplantation. However, for patients with chronic obstuctive pulmonary disease (COPD), the indications for NIPPV are more contentious. Recent data suggests that no survival advantage is acquired from NIPPV in COPD. However, indirect benefits may be achieved by enhancing pulmonary rehabilitation and reducing the need for invasive ventilation. Many patients with advanced COPD find NIPPV difficult to tolerate. Malnourishment is associated with both increased mortality, awaiting transplantation and impaired survival following transplantation. Therefore, every effort should be made to optimise the patients body mass index. This frequently involves the placement of gastrostomy feeding devices in patients with CF.

Oxygen therapy is the cornerstone for the management of secondary pulmonary hypertension and this should be pursued aggressively. There are a number of potential important developments in this area including nebulised iloprost, the administration of nitric oxide and/or new oral therapies including sildenafil and bozantin.

Occult infection is an important aspect of the management of patients with advanced lung disease. Infection frequently remains undiagnosed because of the difficulty performing invasive techniques to identify or exclude infection. The application of palliative strategies is a key component of the management of patients with advanced lung disease. Discussions should be undertaken with the patient and their family, regarding mechanical ventilation (MV) strategies or the absence of such treatment. Broadly speaking, MV is contraindicated in patients awaiting lung transplantation, except in specific reversible situations.

Lung volume reduction surgery (LVRS) has become a palliative therapeutic option for selected patients with advanced pulmonary emphysema who suffer from shortness of breath at minimal activity. The beneficial effects have been documented by numerous case series and by several randomised, controlled trials. In well-selected patients, the perioperative mortality does not exceed >5% in experienced centres, and the expected improvement in forced expiratory volume in one second ranges 30–60% at 3–6 months. Thereafter, the lung function steadily declines, but the effect lasts for up to 4–6 yrs. This therapeutic option was used alternatively in patients who were suitable candidates for lung transplantation, and several groups demonstrated that transplantation could be postponed by 2–4 yrs after bilateral LVRS. The procedure itself does not jeopardise the chances for subsequent successful transplantation.

Organ transplantation not only provides the possibility of saving lives, but it also has the best cost/benefit ratio in terms of economics and the quality of life. Despite all the advantages conferred by organ transplantation, many people cannot benefit from such an opportunity.

Different alternatives have been proposed to even this gap. The continuous overview on the donation and retrieval process will provide both the opportunity for improvement and the guarantee that all potential is transformed into actual. The possibility of widening the criteria for accepting organs or to move to other alternatives, such as living or nonheart-beating donation, is also another possibility. A comprehensive and effective organ allocation system needs to be put in place. Although there are no universally accepted rules, there are official recommendations from the Council of Europe, indicating the need for public and transparent allocation rules that should ensure, as far as possible, that no group of patients is waiting longer than another.

Primary graft dysfunction remains a potentially devastating problem in 10–20% after lung transplantation with a significant impact on early and late clinical outcomes. Risk factors that have been identified are donor-, preservation- or recipient-related.

Ischaemia/reperfusion injury is the term commonly used to summarise the insult that leads to graft dysfunction. A better understanding of the pathophysiological mechanisms that take place during ischaemia and subsequent reperfusion has resulted in new refinements in lung preservation techniques and solutions over the last decade. Reperfusion models for ex vivo assessment and conditioning of the pulmonary graft have recently been developed that may allow the safe expansion of the pulmonary donor pool using lungs from nonheart-beating donors (NHBDs) as well as from extended (marginal) heart-beating donors.

The purpose of this chapter is to describe, what is believed to be, the optimal method of lung procurement and preservation based on current scientific knowledge. In addition the latest developments in preservation and ex vivo assessment of lungs from NHBDs are presented.

Immunosuppressive strategies after lung transplantation (LTx) concern induction therapy, maintenance immunosuppression and the treatment of acute and chronic rejection.

In 2002, equal numbers of LTx were performed with or without induction therapy with antilymphocyte antibodies, monoclonal anti-CD3 antibody or anti-interleukin-2-receptor monoclonal antibodies. It remains to be established if induction therapy after LTx is beneficial or deleterious for long-term graft and patient survival.

The vast majority of lung transplant recipients receive a triple-drug maintenance regimen including a calcineurin inhibitor, a cell-cycle inhibitor and steroids. Equal proportions receive cyclosporin A (CsA) and tacrolimus (Tac). There is also a trend to prescribe mycophenolate mofetil (MMF) instead of azathioprine (Aza). Steroid withdrawal is uncommon even 5 yrs after transplantation. The superiority of Tac over CsA as a maintenance agent has not been established to date. An international, prospective, randomised, controlled trial comparing CsA with Tac in combination with MMF and steroids is currently under way. In contrast to trials in renal and heart transplant recipients, the administration of MMF instead of Aza in combination with CsA and steroids did not result in improved graft or patient survival in a recent international, prospective, randomised, controlled trial. It is possible that the MMF dose was not optimal in this trial.

High-dose intravenous steroid pulses are the first-line treatment of uncomplicated acute rejection. The shift from CsA to Tac has emerged as the first treatment step of refractory acute rejection followed by high-dose steroids or antilymphocyte agents, total lymphoid irradiation or photopheresis.

The treatment of chronic rejection remains deceptive and includes varied strategies such as modification of the maintenance regimen, augmentation of the net immunosuppression, addition of inhaled immunosuppressants and/or other immunomodulatory treatments, such as total lymphoid irradiation and photopheresis.

Lung transplantation pathology is a challenging topic for the specialised pulmonary pathologist. The pathological journey begins with the accurate diagnosis of the condition requiring transplantation and its confirmation in the explanted organ, together with the identification of other unsuspected or supplementary pathological processes. Following transplantation, histological diagnosis is required of early, mid and late complications, which include ischaemic and reperfusion injury, acute rejection and infection followed by chronic rejection. There is an established grading system for the diagnosis of acute and chronic lung rejection based on perivascular and airway infiltrates acutely, and fibrosis of the airway with and without infiltrates chronically. Infrequently, transbronchial biopsies are insufficient for diagnosis and thoracoscopic or open-lung biopsies are required, the commonest unsuspected diagnoses in these being obliterative bronchiolitis and post-transplant lymphoproliferative disease.

Opportunistic infections are particularly common in lung transplant recipients although are much reduced in incidence by improvements in management including prophylaxis and targeted antimicrobial therapy. Most commonly, the pathologist sees nonspecific features in biopsy material that need careful interpretation in a multidisciplinary setting, and where the exclusion of significant pathology is as critical as the less common specific entities. Full autopsies are critical in the evaluation of lung transplant deaths at all intervals following implantation.

Unsuspected findings are common as in general autopsy practice and their evaluation is critical to the success of lung transplant programmes. A full understanding of lung transplant pathology is also essential to the interpretation of experimental and molecular studies that will no doubt impact clinically in the near future.

The success of lung transplantation (LTx) has improved over time as evidenced by better long-term survival and functional outcomes. Despite the success of this procedure, there are numerous problems and complications that may develop over the life of a lung transplant recipient. With proper monitoring and treatment, the frequency and severity of these problems can be decreased. Still, significant improvement for the overall outcomes of LTx will only occur when better methods exist to prevent or effectively treat chronic rejection.

Noninfectious complications after lung transplantation (LTx) can be divided according to time post-transplantation into initial postoperative, intermediate and late complications.

Initial postoperative complications of the bronchial anastomosis are early necrosis, dehiscence or disruption followed by stenosis due to ceased bronchial artery circulation. Bronchial dehiscence and disruption could be managed by bronchoplastic surgery but may need acute retransplantation. Bronchial stenosis is mostly managed by repeated-use dilating balloon catheters, neodymium:yttrium aluminium garnet laser treatment or introduction of bronchial stents and only occasionally bronchoplastic surgery is needed. Phrenic nerve dysfunction as well as vagus nerve injury or other initial operative-related complications are also included in this category.

Intermediate and late complications, such as reactivated Epstein-Barr virus may cause a post-transplant lymphoproliferative disease (PTLD) of a mostly B-cell phenotype. PTLD treatment includes reduced immunosuppression and antiviral therapy alone or in combination with a variety of treatments. Late complications are also often immunosuppressant drug-induced cancers, nephrotoxicity, systemic hypertension, hyperlipedaemia and osteoporosis.

Single LTx represents a specific situation as only one of the diseased organs is transplanted. The native lung may influence both the clinical outcome and the occurrence of complications (e.g. hyperinflation, distension of bullae, pneumothorax), and be the source of early and late problems related to the progression of the underlying disease. Differences in compliance between the graft and the native lung can result in ventilation/perfusion mismatches. Noninfectious complications following single LTx are successfully treated in most cases, even when a surgical approach is required.

Lung transplantation (LTx) was pioneered in adults with end-stage lung disease. Over the past decade, this life-saving procedure has been applied to a small but significant number of infants, children and adolescents in a relatively small number of centres around the world. The published results of paediatric LTx demonstrate that post-transplant survival approaches that seen in adults. With the exception of cystic fibrosis, the single leading indication for LTx in individuals <18 yrs of age, the disease entities leading to transplant candidacy are decidedly different in the paediatric age group.

The majority of patients with pulmonary vascular disease have associated congenital heart disease. The remainder of diagnoses represents a small number of a heterogeneous group of disorders. The surgical approach usually includes cardiopulmonary bypass and single LTx and is much less common than in the adult population. Immunosuppression and antimicrobial prophylaxis are similar to those used in adult LTx. Post-transplant complications of greater prevalence and importance in paediatric lung transplant recipients include a much higher incidence of severe primary viral infections, post-transplant lymphoproliferative disease, and disorders of growth and development. Furthermore, the fact that the transplantation of a child often involves translocation and marked disruption of an entire family leads to potentially deep psychosocial costs to the patient and their family, requiring devoted comprehensive, multidisciplinary team care.

It seems reasonable to expect that further refinements in the details of care together with improvements in antimicrobial diagnosis and therapy and in both immunosuppression and immunomodulation will lead to better survival, both qualitatively and quantitatively, in the years to come.

During the last decades, most Western countries began to experience rising expenditures for healthcare. Since then, health policy-makers try to control these healthcare expenditures. Economic evaluations provide important information on the costs and consequences of different healthcare interventions. For this reason, economic evaluations are a particularly useful tool for decision-makers. The following four types of economic evaluation can be distinguished: the cost-minimisation analysis, the cost-effectiveness analysis, the cost-utility analysis, and finally, the cost-benefit analysis. Results of cost-effectiveness analyses of lung transplantation (LTx) programmes showed that LTx is an effective but expensive treatment. The effectiveness is reflected by the considerable number of life-yrs provided to the recipient.

However, survival is not the only yardstick by which to measure treatment effectiveness. Quality-of-life data are increasingly important for evaluating the consequences of an intervention such as LTx. Results of most studies showed that patients surviving LTx can expect a considerable improvement in most domains of quality of life.