Ed A. van de Graaf

Systemic and exhaled cytokine and chemokine profiles are associated with the development of bronchiolitis obliterans syndrome

BACKGROUND The mechanisms that lead to the fibrotic obliteration in bronchiolitis obliterans syndrome (BOS) may involve the interactions between T-helper (Th)1 and Th2 cytokines. The aim of this study is to determine the Th1 and Th2 cytokine and chemokine profiles in serum and exhaled breath condensate (EBC) in lung transplant recipients and to assess their usefulness as biomarkers to predict the development of BOS. METHODS Serum and EBC from 10 patients with BOS (BOS(pos)) and 10 patients without BOS (BOS(neg)), matched for clinical and demographic variables, were analyzed with a multiplex immunoassay to measure a panel of 27 cytokines and chemokines. RESULTS The pro-inflammatory cytokines in serum were elevated in lung transplant recipients compared with controls. BOS(pos) patients had significantly lower concentrations of interleukin (IL)-4, IL-13, and vascular endothelial growth factor (VEGF) compared with BOS(neg) patients. The concentration of IL-5, however, was significantly higher in BOS(pos) patients. Levels of IL-4 and IL-5 were hardly detectable in EBC. IL-13 and VEGF, both decreased in serum in BOS(pos) patients, were also decreased in EBC in BOS(pos) patients compared with BOS(neg) patients. Longitudinal analysis of cytokines and chemokines in serum and EBC from the time of lung transplantation onwards did not reveal significant trends in cytokines and chemokines that preceded the diagnosis of BOS. CONCLUSIONS Levels of pro-inflammatory cytokines were increased in lung transplant recipients compared with controls. From the moment of transplantation onwards, there is a different pattern of Th2 cytokines in serum in BOS(pos) patients than in BOS(neg) patients.

Genetic polymorphisms in MMP7 and reduced serum levels associate with the development of bronchiolitis obliterans syndrome after lung transplantation

BACKGROUND Pulmonary epithelium is the primary target of injury in the development of bronchiolitis obliterans syndrome (BOS) after lung transplantation. Matrix metalloproteinases (MMP)-8 and -9 already have been implicated in the pathogenesis of BOS. MMP-7, which is involved in the repair of the lung epithelium, has not been studied in this respect. We hypothesized that genetic polymorphisms in MMP7 influence its expression and correlate with serum MMP-7 levels and the development of BOS. METHODS DNA was collected from 110 lung transplant recipients, including 21 patients with BOS. We genotyped 7 single nucleotide polymorphisms in MMP7 and measured serum MMP-7 levels. The control group comprised 422 healthy individuals. RESULTS BOS(pos) patients had lower levels of MMP-7 than BOS(neg) patients (7.87 vs 10.18 ng/ml). Significant differences in genotype and haplotype distribution between the BOS(pos) and BOS(neg) patients and controls were found. An increased risk for BOS development was found in patients homozygous for the major alleles of rs17098318, rs11568818, and rs12285347, and for the minor allele rs10502001 (odds ratio, 3.88-5.30). Haplotypes constructed with 3 or 4 risk alleles correlated with lower MMP-7 levels. CONCLUSIONS Genetic polymorphisms of MMP7 predispose to the development of BOS. Patients carrying these risk alleles express lower levels of MMP-7, which may contribute to aberrant tissue repair and culminate in the development of BOS.

Chimerism of dendritic cell subsets in peripheral blood after lung transplantation.

BACKGROUND Passenger leukocytes of donor origin are transferred to the patient resulting in circulatory microchimerism after lung transplantation (LTx). This chimeric state has been shown to occur in the total leukocyte fraction as well as unseparated peripheral blood mononuclear cells (PBMCs). In this study we determined the microchimerism levels of B cells, monocytes, natural killer (NK) and T cells and dendritic cell (DC) subsets (mDC1, mDC2 and pDC) during the first year after lung transplantation. METHODS To identify circulating donor cells, 11 donor-patient combinations were selected, which were mismatched for HLA-B8. Analysis consisted of flow cytometry on a minimum of 1 million PBMCs taken monthly up to 1 year after LTx. RESULTS Levels of microchimerism were found to be stable after LTx for all cell types investigated, although for NK+T cells an above-baseline chimerism of donor cells from the donor lung was observed in the first month after transplantation. Circulating PBMCs consisted of, on average, 0.002%, 1.7%, 0.03% and 0.001% of B cells, monocytes, NK+T cells and DCs, respectively, indicating that overall levels of microchimerism differed between the cell types investigated. In 2 patients no B-cell chimerism and in 1 patient no DC chimerism could be detected. Cell types and DC subsets of recipient origin were normally distributed. Conversely, monocytes, B cells and DCs of donor origin were increased and donor NK+T cells were decreased in number, compared with the recipient ratios. Analysis of circulating recipient DCs showed a normal distribution of mDC1s (70%), mDC2s (5%) and pDCs (25%). However, circulating donor DCs consisted of 80%, 20% and <1% of DC subsets mDC1, MDC2 and pDC, indicating that donor plasmacytoid dendritic cells were not detectable in the circulation. CONCLUSIONS In the first year after lung transplantation a stable microchimerism was detected for all cell types investigated. However, donor pDCs were consistently absent in all samples investigated, which may be linked with graft rejection often observed after LTx.

The Induction of IgM and IgG Antibodies against HLA or MICA after Lung Transplantation

The production of IgG HLA antibodies after lung transplantation (LTx) is considered to be a major risk factor for the development of chronic rejection, represented by the bronchiolitis obliterans syndrome (BOS). It has recently been observed that elevated levels of IgM HLA antibodies also correlates with the development of chronic rejection in heart and kidney transplantation. This study investigates the relationship between IgM and IgG antibodies against HLA and MICA after lung transplantation. Serum was collected from 49 patients once prior to transplantation and monthly for up to 1 year after lung transplantation was analyzed by Luminex to detect IgM and IgG antibodies against HLA and MICA. The presence of either IgM or IgG HLA and/or MICA antibodies prior to or after transplantation was not related to survival, gender, primary disease, or the development of BOS. Additionally, the production of IgG alloantibodies was not preceded by an increase in levels of IgM, and IgM levels were not followed by an increase in IgG. Under current immune suppressive regimen, although the presence of IgM antibodies does not correlate with BOS after LTx, IgM high IgG low HLA class I antibody titers were observed more in patients with BOS compared to patients without BOS.

Soluble CD30 Measured After Lung Transplantation Does Not Predict Bronchiolitis Obliterans Syndrome in a Tacrolimus/ Mycophenolate Mofetil-based Immunosuppressive Regimen

BACKGROUND The purpose of this study was to determine the utility of post-transplant serum soluble CD30 levels as a biomarker for the development of the bronchiolitis obliterans syndrome (BOS) after lung transplantation during a tacrolimus/mycophenolate mofetil-based regimen. METHODS Soluble CD30 (sCD30) concentrations were measured prior to transplantation and in 175 samples taken after transplantation in 7 patients developing BOS and 7 non-BOS patients closely matched for age, underlying diseases, follow-up and gender. RESULTS High pre-transplant sCD30 levels dropped significantly after lung transplantation, but in the post-transplant samples no differences could be detected between patients developing BOS or not, and no changes were found prior to or during the development of BOS. CONCLUSIONS After transplantation, sCD30 levels are consistently suppressed, but BOS is not prevented, indicating that sCD30 cannot be used as a biomarker to predict BOS after transplantation in the regimen employed.

Emphysema Is Common in Lungs of Cystic Fibrosis Lung Transplantation Patients: A Histopathological and Computed Tomography Study.

Background Lung disease in cystic fibrosis (CF) involves excessive inflammation, repetitive infections and development of bronchiectasis. Recently, literature on emphysema in CF has emerged, which might become an increasingly important disease component due to the increased life expectancy. The purpose of this study was to assess the presence and extent of emphysema in endstage CF lungs. Methods In explanted lungs of 20 CF patients emphysema was semi-quantitatively assessed on histology specimens. Also, emphysema was automatically quantified on pre-transplantation computed tomography (CT) using the percentage of voxels below -950 Houndfield Units and was visually scored on CT. The relation between emphysema extent, pre-transplantation lung function and age was determined. Results All CF patients showed emphysema on histological examination: 3/20 (15%) showed mild, 15/20 (75%) moderate and 2/20 (10%) severe emphysema, defined as 0–20% emphysema, 20–50% emphysema and >50% emphysema in residual lung tissue, respectively. Visually upper lobe bullous emphysema was identified in 13/20 and more diffuse non-bullous emphysema in 18/20. Histology showed a significant correlation to quantified CT emphysema (p = 0.03) and visual emphysema score (p = 0.001). CT and visual emphysema extent were positively correlated with age (p = 0.045 and p = 0.04, respectively). Conclusions In conclusion, this study both pathologically and radiologically confirms that emphysema is common in end-stage CF lungs, and is age related. Emphysema might become an increasingly important disease component in the aging CF population.

Pulmonary embolism and pulmonary infarction after lung transplantation.

Venous thromboembolism (VTE), which includes pulmonary embolism (PE) and deep vein thrombosis (DVT), is a common occurrence in patients undergoing surgery and is a potentially fatal complication. Especially after lung transplantation, vascular complications can compromise the function of the allograft and limit survival. Typically, the risk of pulmonary infarction after PE in lung transplant recipients is high because the absence or poor development of the collateral bronchial circulation may predispose lung transplant recipients to pulmonary infarction. This article reports 2 cases of PE with associated pulmonary infarction after lung transplantation with significant morbidity.

Non-small cell lung carcinoma of donor origin after bilateral lung transplantation

1] Brunelli A, Charloux A, Bolliger CT, Rocco G, Sculier JP, Varela G, et al. On behalf of the European Society of Thoracic Surgeons joint task force on fitness for radical therapy. Eur J Cardiothorac Surg 2009;36:181–4. 2] Arbane G, Tropman D, Jackson D, Garrod R. Evaluation of an early intervention after thoracotomy for non-small cell lung cancer (NSCLC), effects on quality of life, muscle strength and exercise tolerance: randomised controlled trial. Lung Cancer 2011;71:229–34. 3] Granger CL, McDonald CF, Berney S, Chao C, Denehy L. Exercise intervention to improve exercise capacity and health related quality of life for patients with non-small cell lung cancer: a systematic review. Lung Cancer 2011;72:139–53. 4] Cesario A, Ferri L, Galetta D, Pasqua F, Bonassi S, Clini E, et al. Post-operative respiratory rehabilitation after lung resection for non small cell lung cancer. Lung Cancer 2007;57:175–80. 5] Cesario A, Ferri L, Galetta D, Cardaci V, Piratino A, Bonassi S, et al. Pre-operative pulmonary rehabilitation and surgery for lung cancer. Lung Cancer 2007;57(July (1)):118–9. 6] Cesario A, Dall’Armi V, Cusumano G, Ferri L, Margaritora S, Cardaci V, et al. Postoperative pulmonary rehabilitation after lung resection for NSCLC: a follow up study. Lung Cancer 2009;66(November (2)):268–9.

Clara cell secretory protein and surfactant protein-D do not predict bronchiolitis obliterans syndrome after lung transplantation.

1. Claes K, Bammens B, Evenepoel P, et al. Troponin I is a predictor of acute cardiac events in the immediate postoperative renal transplant period. Transplantation 2010; 89: 341. 2. Badero OJ, Salifu MO. Prediction of hemodynamically significant coronary artery disease using troponin I in hemodialysis patients presenting with chest pain: A casecontrol study. Cardiology 2009; 114: 292. 3. Katerinis I, Nguyen QV, Magnin J, et al. Cardiac findings in asymptomatic chronic hemodialysis patients with persistently elevated cardiac troponin I levels. Ren Fail 2008; 30: 357. 4. Beciani M, Tedesco A, Violante A, et al. Cardiac troponin I (2nd generation assay) in chronic haemodialysis patients: Prevalence and prognostic value. Nephrol Dial Transplant 2003; 18: 942. 5. Martin G, Becker B, Schulman G. Cardiac troponin-I accurately predicts myocardial injury in renal failure. Nephrol Dial Transplant 1998; 13: 1709.

Lung transplantation under a tacrolimus/mycophenolate mofetil-based immunosuppressive regimen results in low titers of HLA and MICA IgG antibodies which are not related to development of BOS

. Novitzky D, Cooper DK, Rosendale JD, et al. Hormonal therapy of the brain-dead organ donor: experimental and clinical studies. Transplantation 2006;82:1396-401. . Nijboer WN, Schuurs TA, van der Hoeven JA, et al. Effects of brain death on stress and inflammatory response in the human donor kidney. Transplant Proc 2005;37:367-9. . Guner M, Pirat A, Zeyneloglu P, et al. Effect of the interval between organ donor brain death and organ harvesting on kidney graft function after transplantation. Transplant Proc 2007;39:837-41. . Novitzky D, Cooper DK, Morrell D, et al. Change from aerobic to anaerobic metabolism after brain death, and reversal following triiodothyronine therapy. Transplantation 1988;45:32-6.