J.M. Kwakkel-van Erp

Diabetes before and after lung transplantation in patients with cystic fibrosis and other lung diseases.

Diabet. Med. 29, e159–e162 (2012)

A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation

Complement activation leads primarily to membrane attack complex formation and subsequent target cell lysis. Protection against self‐damage is regulated by complement regulatory proteins, including CD46, CD55, and CD59. Within their promoter regions, single‐nucleotide polymorphisms (SNPs) are present that could influence transcription. We analyzed these SNPs and investigated their influence on protein expression levels. A single SNP configuration in the promoter region of CD59 was found correlating with lower CD59 expression on lung endothelial cells (p = 0.016) and monocytes (p = 0.013). Lung endothelial cells with this SNP configuration secreted more profibrotic cytokine IL‐6 (p = 0.047) and fibroblast growth factor β (p = 0.036) on exposure to sublytic complement activation than cells with the opposing configuration, whereas monocytes were more susceptible to antibody‐mediated complement lysis (p < 0.0001). Analysis of 137 lung transplant donors indicated that this CD59 SNP configuration correlates with impaired long‐term survival (p = 0.094) and a significantly higher incidence of bronchiolitis obliterans syndrome (p = 0.046) in the recipient. These findings support a role for complement in the pathogenesis of this posttransplant complication and are the first to show a deleterious association of a donor CD59 promoter polymorphism in lung transplantation.

Serum thymus and activation regulated chemokine levels post‐lung transplantation as a predictor for the bronchiolitis obliterans syndrome

The main reason for mortality after lung transplantation is the bronchiolitis obliterans syndrome (BOS), which represents chronic rejection. As soluble CD30, which is produced mainly by activated T helper 2 (Th2) cells, was shown to be related to development of BOS, we aimed to investigate the relation between development of BOS and Th2 chemoattractant thymus and activation regulated chemokine (TARC/CCL17). In 54 patients we measured serum TARC levels prior to transplantation by enzyme‐linked immunosorbent assay, and in 44 of these patients sera were analysed at months 1, 2 and 3 after lung transplantation. In addition, longitudinal measurements were performed in sera from eight healthy controls and 14 patients, the latter taken over a period of 2 years post‐transplantation from seven patients developing BOS plus seven clinically matched BOS‐free patients. Median serum TARC levels post‐transplantation of patients who developed BOS were significantly lower than those of the matched BOS‐free patients (P = 0·05). A receiver operating characteristics analysis (area under the curve 0·77), together with a Kaplan–Meyer analysis, showed that serum TARC levels below 325 pg/ml in the first month post‐transplantation can predict development of BOS post‐transplantation (P = 0·001). In contrast, pretransplant serum TARC levels were not significantly different between patients developing BOS, BOS‐free patients or healthy controls. In conclusion, pretransplantation serum TARC levels do not predict the development of BOS post‐transplantation, but measurement of the serum TARC levels in the first month directly after transplantation can provide us with a tool to identify the group at risk of developing BOS.

Anti-ETAR and anti-AT1R autoantibodies are elevated in patients with endstage cystic fibrosis

Autoantibodies against endothelin-1 type A receptor (ETAR) are present in systemic sclerosis complicated by lung fibrosis and pulmonary hypertension. As increased serum levels and local overproduction of endothelin-1 in the airways are reported in cystic fibrosis (CF) patients, we reasoned that anti-ETAR antibodies could be prevalent in endstage CF patients prior to lung transplantation (LTx). Also, ETAR autoantibodies are frequently associated with autoantibodies against the angiotensin II type 1 receptor (AT1R). We analyzed the presence of anti-ETAR and anti-AT1R autoantibodies in 43 LTx patients (chronic obstructive pulmonary disease (COPD), n=20; CF, n=13; interstitial lung disease (ILD), n=1). We observed overall higher anti-ETAR and anti-AT1R autoantibody titers in sera taken prior to LTx in the CF patient group as compared to COPD. No difference was found in autoantibody levels between patients with CF versus ILD. In sera taken post-LTx we found the same difference in anti-ETAR and anti-AT1R autoantibody titers between patients with CF versus COPD. No difference was found in antibody titers between sera taken prior to or 6 months after LTx. There was no association between autoantibody levels and other relevant demographic parameters, and we found no association between autoantibody titers and the development of the bronchiolitis obliterans syndrome. Both autoantibody titers were strongly correlated. We hypothesize that due to prolonged exposure to bacterial infection, increased levels of AT1R and ETAR result in a deregulated immune response causing autoantibody formation. Further research is expedient to elucidate the occurrence of autoantibodies against ETAR and AT1R and their role in disease progression.

Mannose-binding lectin deficiency linked to cytomegalovirus (CMV) reactivation and survival in lung transplantation.

Despite the use of immunosuppressives mainly influencing T and B cell responses, the prevalence of the bronchiolitis obliterans syndrome (BOS) after lung transplantation is high. Mannose‐binding lectin (MBL) is a pattern recognition molecule of complement and an important component of the innate immunity. MBL is associated with rejection, infection and survival in other solid organ transplantations. In this study the relation between functional MBL levels and cytomegalovirus (CMV) reactivations and the development of BOS and survival after lung transplantation was investigated. MBL levels were measured in 85 patients before and in 57 of these patients after lung transplantation. The relation of MBL on survival, CMV reactivation and the development of BOS were investigated with Kaplan–Meier (log‐rank) survival analysis. MBL levels decreased on average by 20% (P < 0·001) after transplantation and eventually returned to pretransplant levels. Fourteen of the 85 patients had deficient pretransplant MBL levels and these patients had a tendency towards a better survival compared to those with normal MBL levels (P = 0·08). Although no correlation was found between MBL deficiency and the development of BOS, more CMV reactivations occurred in recipients with deficient versus normal levels of MBL (P = 0·03). Our results suggest that MBL deficiency is associated with CMV reactivations and a longer overall survival, but not with the development of BOS.

Effective Prolonged Therapy with Voriconazole in a Lung Transplant Recipient with Spondylodiscitis Induced by Scedosporium apiospermum

Scedosporium/Pseudallescheria species are frequently seen in cystic fibrosis patients. However, disseminated forms after lung transplantation in these patients are rarely seen, but often with poor outcome. In this case report we describe a lung transplant recipient with cystic fibrosis who developed a spondylodiscitis that was caused by Scedosporium apiospermum. The patient was treated with anti-fungal treatment by voriconazole for over three years with a clinical good response and without the need for surgical intervention. To our opinion this is the first anti-fungal treated case of invasive disease caused by Scedosporium/Pseudallescheria in a cystic fibrosis (CF) patient who underwent lung transplantation that survived.

Immunoglobulin A in serum: an old acquaintance as a new prognostic biomarker in idiopathic pulmonary fibrosis

Immunoglobulin (Ig)A is an important immunoglobulin in mucosal immunity and protects the lungs against invading pathogens. The production of IgA is regulated by transforming growth factor (TGF)‐β, a versatile cytokine and key player in the pathogenesis of pulmonary fibrosis. TGF‐β is up‐regulated in patients with idiopathic pulmonary fibrosis (IPF), but difficult to use as a biomarker. The aim of this study was to evaluate the prognostic value of IgA in serum in patients with IPF. We examined IgA levels at time of diagnosis in 86 patients diagnosed with IPF. Mean serum IgA level in IPF is 3·22 g/l and regression analyses showed a significant association with mortality (hazard ratio = 1·445, P = 0·002). A significantly worse survival was found in patients with IgA serum levels > 2·85 g/l compared to patients with lower IgA serum levels (P = 0·003). These findings were confirmed in a duplication cohort. In conclusion, the level of IgA in blood is a promising prognostic marker in IPF and can be implemented easily in the hospital setting. Future studies are warranted to investigate if repeated measurements of serum IgA can further improve the performance of serum IgA as a prognostic marker.

Lung transplantation affects expression of the chemokine receptor type 4 on specific T cell subsets

Alloreactive T cells that infiltrate the graft after lung transplantation (LTx) play a role in chronic rejection. Chemokines such as thymus and activation‐regulated chemokine (TARC), macrophage‐derived chemokine (MDC) and monocyte chemotactic protein‐1 (MCP‐1) are produced locally in the lung and attract T cells via chemokine receptor 4 (CCR4). In a TARC gradient, cells expressing CCR4++ migrate more efficiently than CCR4+‐expressing cells. In this study, we compared the CCR4 expression of T cells in blood from 20 lung transplant recipients to healthy controls. We then examined whether CCR4 expression is associated with the occurrence of chronic rejection. The CCR4++ expression was decreased on CD4 T cells from LTx patients (P < 0·0001) when compared to healthy controls. The analysis of CD4 T cell subsets showed that this decrease was present on central memory, effector memory and terminally differentiated T cells (P = 0·0007, P < 0·0001 and P = 0·05, respectively), while a trend was found for naive CD4 T cells (P = 0·06). Also, the expression of CCR4+ on regulatory T cells (Tregs) was decreased in LTx patients when compared to healthy controls (P = 0·02). Interestingly, the CCR4++ expression on CD4 effector memory T cells was decreased in patients developing chronic rejection sometimes more than a year before the clinical diagnosis when compared to patients who did not (P = 0·04). The analysis of CD8 T cell subsets only showed the CCR4+ expression to be increased significantly on effector memory and terminally differentiated CD8 T cells (P = 0·02, P = 0·03, respectively) in LTx patients, but no relation was found in chronic rejection. In conclusion, the expression of CCR4 on T cell subsets was altered after LTx and appears to be related to chronic rejection.

Patient-reported health outcomes in long-term lung transplantation survivors : A prospective cohort study

During the last three decades lung transplantation (LTx) has become a proven modality for increasing both survival and health‐related quality of life (HRQoL) in patients with various end‐stage lung diseases. Most previous studies have reported improved HRQoL shortly after LTx. With regard to long‐term effects on HRQoL, however, the evidence is less solid. This prospective cohort study was started with 828 patients who were on the waiting list for LTx. Then, in a longitudinal follow‐up, 370 post‐LTx patients were evaluated annually for up to 15 years. For all wait‐listed and follow‐up patients, the following four HRQoL instruments were administered: State‐Trait Anxiety Inventory, Zung Self‐rating Depression Scale, Nottingham Health Profile, and a visual analogue scale. Cross‐sectional and generalized estimating equation (GEE) analysis for repeated measures were performed to assess changes in HRQoL during follow‐up. After LTx, patients showed improvement in all HRQoL domains except pain, which remained steady throughout the long‐term follow‐up. The level of anxiety and depressive symptoms decreased significantly and remained constant. In conclusion, this study showed that HRQoL improves after LTx and tends to remain relatively constant for the entire life span.

Images in COPD : Combined Pulmonary Emphysema and Fibrosis with Pulmonary Hypertension

Abbreviations: chronic obstructive pulmonary disease, COPD; forced expiratory volume in 1 second, FEV1; forced vital capacity, FVC; computed tomography, CT; 18-fluorodeoxyglucose, 18-FDG; positron emission tomography, PET; usual interstitial pneumonia, UIP; combined pulmonary emphysema and fibrosis, CPFE; non-specific interstitial pneumonia, NSIP; respiratory bronchiolitis-associated interstitial lung disease, RB-ILD; desquamative interstitial pneumonia, DIP; idiopathic pulmonary fibrosis, IPF Citation: Mohamed Hoesein FA, Voortman M, Kwakkel-van Erp JM, Luijk B, de Jong PA. Images in COPD: Combined pulmonary emphysema and fibrosis with pulmonary hypertension. Chronic Obstr Pulm Dis (Miami). 2017; 4(1):76-80. doi: http://dx.doi.org/10.15326/ jcopdf.4.1.2016.0171 Images in COPD