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Early identification of bronchiolitis obliterans syndrome may be possible using a brochiolaveolar lavage profile of matrix metalloproteinases and the tissue inhibitors TIMP-1 and TIMP-2. Supplemental digital content is available in the text.

Despite the increasing use of extended lung donors, the shortage of lung donors remains. Usage of non-heart-beating (NHB) lung donors contributes to fight this shortage. We describe our experience in 21 consecutive adult lung transplantations using nonheparinized category III NHB donors and standard flush preservation.

Lung transplantation is a well accepted therapy for end-stage lung disease, despite high mortality rates. Mortality after transplantation is mainly caused by allograft failure in the first years after transplantation. Mannose binding lectin (MBL), a recognition molecule of innate immunity, has been associated with transplant outcome in other solid organ transplantation. In this study, the effect of donor- and recipient-MBL genotype on lung transplant outcome was investigated.

Posttransplant lymphoproliferative disease (PTLD) is a serious complication after lung transplantation and its relation with Epstein-Barr virus (EBV) is well recognized. It has been postulated that preemptive reduction of immunosuppression guided by EBV-DNA load may lead to a significantly lower incidence of PTLD, because of the reconstitution of T-cell control. In this report, we describe the feasibility of this approach in terms of safety with regard to the risk of acute as well as chronic allograft rejection in 75 lung transplant recipients transplanted between 1990 and 2001 and followed for this study from June 1, 2001 until January 1, 2006.

The Epstein‐Barr virus (EBV)‐specific antibody response was studied in lung transplant patients to assess their value in the diagnosis and prognosis of post‐transplant lymphoproliferative disease. Recently developed synthetic peptides representing Epstein‐Barr nuclear antigen‐1 (EBNA‐1), diffuse early antigen (EA(D)), and virus capsid antigen (VCA) were studied in a semiquantitative enzyme‐linked immunosorbent assay (ELISA) to study antibody patterns in 12 seronegative lung transplant patients, of whom four developed a post‐transplant lymphoproliferative disease, and seven seropositive lung transplant patients, all of whom developed a post‐transplant lymphoproliferative disease. Immunoblot technique was used as a control. All 12 EBV‐seronegative patients had a very limited antibody response that was restricted mainly to VCA antibodies. EA(D) antibodies became detectable in only two patients. Antibody response never preceded clinical diagnosis of post‐transplant lymphoproliferative disease in the four EBV‐seronegative patients who developed post‐transplant lymphoproliferative disease. In the seven seropositive lung transplant patients with post‐transplant lymphoproliferative disease, we found a rise in antibody titer in only two patients. Immunoblot analysis confirmed the serological results. In conclusion, EBV‐specific antibody patterns after lung transplantation are highly restricted and variable and of limited value for the diagnosis or prognosis of post‐transplant lymphoproliferative disease. J. Med. Virol. 69:258–266, 2003. © 2003 Wiley‐Liss, Inc.

Frequencies of alloreactive T cells determined by limiting dilution assays (LDA) may not adequately reflect the donor-reactive immune status in transplant recipients. To reevaluate LDA frequencies, we developed a flow cytometry test for direct determination of alloreactive T-cell frequencies and compared these frequencies with classical LDA estimates of frequencies.

This study is designed to examine a possible association of cardiopulmonary bypass (CPB) support and outcome of lung transplantation in a well-balanced group of emphysema patients.

Rituximab, a humanized antiCD20 monoclonal antibody, is a promising new tool for the treatment of posttransplant lymphoproliferative disease PTLD, especially for patients transplanted with rejection prone transplants of vital organs, such as patients after lung transplantation. Thus far, no major complications have been described. We treated three lung transplant recipients with Rituximab because of PTLD.

Posttransplant lymphoproliferative disease (PTLD) is a frequent and severe Epstein-Barr virus (EBV)–associated complication in transplantation recipients that is caused by iatrogenic suppression of T-cell function. The diagnostic value of weekly EBV DNA load monitoring was investigated in prospectively collected unfractionated whole blood and serum samples of lung transplantation (LTx) recipients with and without PTLD. In PTLD patients, 78% of tested whole blood samples were above the cut-off value of quantitative competitive polymerase chain reaction (Q-PCR) (greater than 2000 EBV DNA copies per mL blood), with the majority of patients having high viral loads before and at PTLD diagnosis. Especially in a primary EBV-infected patient and in patients with conversion of immunosuppressive treatment, rapid increases in peripheral blood EBV DNA load diagnosed and predicted PTLD. In non-PTLD transplantation recipients, only 3.4% of the whole blood samples was above the cut-off value (P < .0001) despite heavy immune suppression and cytomegalovirus (CMV)-related disease. These findings illustrate the clinical importance of frequent EBV DNA load monitoring in LTx recipients. The increased EBV DNA loads in PTLD patients were restricted to the cellular blood compartment, as parallel serum samples were all below cut-off value, which indicates absence of lytic viral replication. EBV+ cells in PTLD patients have a very short doubling time, which can be as low as 56 hours, thereby creating the need for high screening frequency in high-risk patients. Furthermore, it is shown that EBV and CMV can reactivate independently in LTx recipients and that EBV DNA load monitoring may be useful in discriminating PTLD from rejection.

Posttransplant lymphoproliferative disease (PTLD) is a frequent and severe Epstein-Barr virus (EBV)–associated complication in transplantation recipients that is caused by iatrogenic suppression of T-cell function. The diagnostic value of weekly EBV DNA load monitoring was investigated in prospectively collected unfractionated whole blood and serum samples of lung transplantation (LTx) recipients with and without PTLD. In PTLD patients, 78% of tested whole blood samples were above the cut-off value of quantitative competitive polymerase chain reaction (Q-PCR) (greater than 2000 EBV DNA copies per mL blood), with the majority of patients having high viral loads before and at PTLD diagnosis. Especially in a primary EBV-infected patient and in patients with conversion of immunosuppressive treatment, rapid increases in peripheral blood EBV DNA load diagnosed and predicted PTLD. In non-PTLD transplantation recipients, only 3.4% of the whole blood samples was above the cut-off value (P< .0001) despite heavy immune suppression and cytomegalovirus (CMV)-related disease. These findings illustrate the clinical importance of frequent EBV DNA load monitoring in LTx recipients. The increased EBV DNA loads in PTLD patients were restricted to the cellular blood compartment, as parallel serum samples were all below cut-off value, which indicates absence of lytic viral replication. EBV+cells in PTLD patients have a very short doubling time, which can be as low as 56 hours, thereby creating the need for high screening frequency in high-risk patients. Furthermore, it is shown that EBV and CMV can reactivate independently in LTx recipients and that EBV DNA load monitoring may be useful in discriminating PTLD from rejection.

A decrease in donor-specific T cell precursor frequencies as seen late, one or more years, after transplantation is assumed to reflect transplantation tolerance, a condition important for long term acceptance of the allograft. However, such late decreases also occur in recipients that developed chronic transplant dysfunction questioning its relevance in transplantation tolerance. We investigated whether early, i.e., the first 6 months, decreases in donor-specific T cell precursor frequencies reflect transplantation tolerance and predict graft outcome after liver and lung transplantation.

The importance of HLA mismatch in determining long-term outcome in lung transplantation remains largely uncertain.

The influence of bronchiolitisobliterans syndrome (BOS) on costs after lung transplantation wasinvestigated by comparing the costs of patients with and without thiscondition.

Decreased in vitro T cell alloreactivity, demonstrated by decreased frequencies of peripheral blood donor-specific T cell precursors, may reflect a tolerant state after transplantation and lower the risk for development of chronic graft dysfunction. It is unknown whether a decrease in donor-specific T cell frequencies also occurs after clinical lung transplantation and if such a decrease lowers the risk for bronchiolitis obliterans syndrome (BOS), a hallmark of chronic graft dysfunction. Therefore, we compared changes in posttransplant donor-specific cytotoxic T lymphocyte (CTLp) and helper T lymphocyte precursor (HTLp) frequencies in lung allograft recipients with good graft function and in recipients with BOS.

Although diagnosis of CMV infections and treatment of CMV disease with effetive antiviral drugs have become much easier, the persistent problem of CMV infection after solid-organ transplantation still requires solid knowledge of the pathophysiology of its clinical manifestations in order to minimize the impact of CMV infections in the future. The complex symptomatology of CMV infection after solid-organ transplantation is reviewed as well as some of the new theories attempting to explain the myriad of symptoms seen after transplantation.

The Human Cytomegalovirus antigenemia (HCMV-Agemia) test has been accepted worldwide as a clinical tool in the diagnosis and management of HCMV-associated syndromes in immunocompromised patients. The many modifications proposed since the first description by our laboratory make standardisation of the HCMV-Agemia assay necessary to enable multicenter clinical trials. We report the initial work for standardization of the HCMV-Agemia assay. A standard protocol is proposed, the optimal distribution conditions are investigated and the results of the shipment of positive and negative test slides as well as of two sets of coded internal standard slides are discussed. The main conclusions are that standard slides can be distributed at room temperature and that the results of participating laboratories with the coded internal standard slides were strikingly similar in spite of differences in HCMV-Agemia protocols used by participating laboratories.

In November 1990, a lung transplantation program began at the University Hospital in Groningen, the Netherlands. As of April 1994, 300 patients were referred for lung transplantation and we investigated the decisions that have been made concerning these referrals up to January 1, 1995. The patients were evaluated according to a stepwise procedure. In stage 1, written information about the referred patients was discussed during the weekly, multidisciplinary lung transplantation meeting. In this stage, 14% of the patients were rejected and 2% were postponed. If no major objections for transplantation were identified, the patient was invited for a visit to the outpatient clinic, stage 2. The newly acquired information from that visit was discussed again at the transplantation meeting. In this stage, 11% of the patients were rejected and 18% postponed. The remaining patients underwent an (partial or complete) inpatient evaluation, stage 3. From all patients about whom a decision was made in this stage, only 5% were rejected, respectively 35% after partial evaluation and only 1.5% after complete evaluation. A total of 110 patients (37% of all referred patients) were listed for lung transplantation, stage 4. Of the listed patients, 20% died while awaiting an appropriate donor. The group of patients with COPD/emphysema had by far the lowest death rate on the waiting list. Patients with short stature (≤1.65 m) had a much higher risk to die on the waiting list compared with patients with longer stature, 42% vs 13%. As of January 1, 1995, 55 patients have undergone transplantation, which is 50% of all patients on the waiting list and 18% of all referred patients. The stepwise selection procedure identifies patients with potential contraindications at an early stage. In this way, unrealistic expectations and unnecessary examinations, expense, and/or hospital admissions may be prevented. Donor shortage, and thus waiting list problems, still remains a significant drawback in the further development of lung transplantation.

To calculate cost-effectiveness of scenarios concerning lung transplantation in the Netherlands.

Methods to quantitate the effects of immunosuppressive drugs on immune reactivity might be helpful for monitoring immunosuppressive treatment. Cyclosporine (CsA) inhibits the induction of cytokine synthesis in T cells, and measurement of interleukin (IL)-2 production might constitute a parameter of this drug's effect.

Abstract: The aim of this study was to assess the future need for lung transplantation in the Netherlands in the absence of limiting factors, such as a shortage of donor organs. The need was estimated using two different methods. In method 1, estimation of the need was based on data from the Dutch lung transplantation program, collected during a 4-year period (1 April 1992 until 31 March 1996). In method 2, the need was estimated using national mortality data over a 5-year period (1987–1991) preceding the start of the Dutch lung transplantation program. The results of both methods were corrected for known factors of distortion. The number of lung transplantations needed in the Netherlands in the future was estimated to range from 50 to 80 a year, which corresponds to 3.2–5.2 transplantations per million inhabitants per year. Considering the current supply of donor lungs in the Netherlands, only about one-third of the patients in need of a lung transplant in the future will be able to receive one.

Despite an expanding number of centres which provide lung transplantation, information about the incremental costs of lung transplantation is scarce. From 1991 until 1995, in The Netherlands a technology assessment was performed which provided information about the incremental costs of lung transplantation. Costs in the situation with and without a transplantation programme were compared from a lifetime perspective. Because randomization was ethically inadmissible, only costs in the situation with the programme were observed. Both conventional treatment costs and costs of the transplantation programme were registered. Costs in the situation without the programme were based on the conventional treatment costs in the situation with the programme. Due to the study period of four years, long term follow‐up costs were estimated. The total incremental costs per transplanted patient were estimated at Dfl 466 767 (5% discounted costs). The main part of these costs was caused by the high costs during the lifetime follow‐up of the patients. © 1997 John Wiley & Sons, Ltd.

To assess the change in health-related quality of life (HRQL) among Dutch lung transplant patients before and after transplantation.

Pneumatosis intestinalis occurred in a patient with a primary cytomegaloviral (CMV) infection with pneumonitis 6 weeks after single lung transplantation for primary pulmonary hypertension. The possible causal relationship between pneumatosis intestinalis, an uncommon disorder with an obscure pathogenesis, and active CMV infection has been observed before; however, to our knowledge, this is the first report of this combination after lung transplantation. The patient had no abdominal complaints, and after treatment of the CMV infection, the pneumatosis intestinalis resolved spontaneously. The early diagnosis of active CMV infection and the prevention of unnecessaryabdominal surgery were essential in this case.