Folke Nilsson

Persistent high BAL fluid granulocyte activation marker levels as early indicators of bronchiolitis obliterans after lung transplant

The major cause of mortality in the long-term in lung transplant recipients is chronic rejection. This is a fibroproliferative process in the small airways leading to obliterative bronchiolitis and progressive loss of lung function, both constituting the clinical entity bronchiolitis obliterans syndrome (BOS). Granulocyte activation has been implicated as one factor behind BOS. Granulocyte markers in bronchoalveolar lavage (BAL) fluid were prospectively and longitudinally studied in order to identify possible association with BOS. BAL fluid from 266 bronchoscopy procedures performed in twelve single lung, eight bilateral lung and five heart/lung transplant recipients were analysed. The majority (19 of 25) were studied for a period of 2 yrs after surgery. Myeloperoxidase (MPO), eosinophil cationic protein (ECP) and interleukin-8 (IL-8) levels were used as indirect markers of activation and attraction of granulocytes. Five patients developed BOS. Ninety-eight episodes of acute rejection, nine of bacterial infection, 19 of cytomegalovirus pneumonitis, nine of Pneumocystis carinii infection, two of aspergillus infection and two of respiratory syncytial virus infection were diagnosed. BOS patients had significantly higher mean levels of MPO, ECP and IL-8 compared to patients without BOS, irrespective of acute rejection status. Over time, the five patients with BOS had significantly elevated BAL fluid levels of MPO and ECP as well as neutrophil percentages, and in four patients this increase preceded the clinical diagnosis of BOS by several months. Elevated bronchoalveolar lavage fluid neutrophil percentage as well as levels of the granulocyte activation markers myeloperoxidase and eosinophil cationic protein appear to be early signs of development of BOS in lung transplant recipients.

Pain and health related quality of life after heart, kidney, and liver transplantation

No study has focused particularly on the sensory and affective experience of bodily pain among transplanted patients. The aim of this study was to explore pain and other factors that influence health related quality of life (HRQOL) in heart, kidney, and liver transplant recipients during the first 2 yr after transplantation, and to define similarities and/or differences in the three groups.A total of 76 patients, 18–60 yr old, undergoing heart, kidney, or liver transplantation between 1995 and 1997 with a follow‐up of 6–24 months were included. HRQOL and pain were investigated by using the Short‐Form‐36 items (SF‐36), the Hospital Anxiety and Depression Scale (HAD), and the Pain‐O‐Meter (POM).Overall, the patients show satisfactory HRQOL. There were no differences in experienced HRQOL 6–24 months after transplantation between kidney, liver, and heart transplant recipients except in the area of Role‐Physical (RP). Fifty‐three percent of all patients reported bodily pain. The most common locations were the hands, feet, and back, and sensory experiences were burning, stabbing, or dull pain. There was a correlation between number of rejections and total score for POM‐VAS (p<0.05) (rho=0.47). There was also a correlation between the number of rejection episodes and the total pain intensity score for POM‐WDS (p<0.05) (rho=0.48). Patients with pain scored higher in the area of depression (p<0.05).Bodily pain is an important problem after organ transplantation, affecting daily living even in patients with good allograft function and it limits physical function, vitality, and general health.

Prolonged Extracorporeal Membrane Oxygenation and Circulatory Support as Bridge to Lung Transplant

A 38-year-old man with progressive alveolitis secondary to polymyositis was treated for 52 days with venovenous and venoarterial extracorporeal membrane oxygenation as a bridge to bilateral lung transplantation. The patient survived, despite multiple complications, and is now back home with good pulmonary function. He is working part-time nearly 3 years post-transplant. This case shows that long-term extracorporeal lung assist is a viable but demanding alternative for bridging patients to pulmonary transplantation. This case also shows that right ventricular failure necessating conversion to veno-arterial assist does not necessarily predict right ventricular failure post-transplant.

The feasibility of left ventricular mechanical support as a bridge to cardiac recovery

To study the achievability of device weaning in patients receiving left ventricular assist devices (LVADs) as a bridge to transplantation.

Inflammatory cells and activation markers in BAL during acute rejection and infection in lung transplant recipients: a prospective, longitudinal study

Acute rejection of the transplanted lung is a clinical problem, since it decreases graft survival and predisposes the patient to chronic rejection and obliterative bronchiolitis (OB). In an earlier study, we had indications that eosinophil cationic protein (ECP) from activated eosinophils and hyaluronan (HYA) from fibroblasts were associated with acute pulmonary rejection. This prospective longitudinal study was designed to investigate whether molecules from activated inflammatory cells in bronchoalveolar lavage (BAL) fluid could serve as clinically useful diagnostic markers for acute rejection. BAL fluid from 138 bronchoscopies performed in 10 single lung, four bilateral lung and five heart-lung transplant recipients were analysed. Nine patients were studied for a period of more than 1 yr (mean 13.4 months) after surgery. Differential cell counts were made from the BAL fluid. ECP, myeloperoxidase (MPO), HYA and interleukin-8 (IL-8) were used as indirect markers for activation and attraction of eosinophils, neutrophils and fibroblasts, respectively. Fifty four episodes of acute rejection were diagnosed. Two patients developed OB. Nine episodes of bacterial infection, 13 episodes of cytomegalovirus (CMV) pneumonitis, three of Pneumocystis carinii infection and one of respiratory syncytial virus (RSV) infection were diagnosed. The mean levels of ECP, MPO, HYA and IL-8 were all higher during rejection episodes, but differences were not statistically significant compared to no rejection, when the confounding factors of time, concomitant infection, and repeated measures in the same individual had been accounted for. We could not confirm that measurements of eosinophil cationic protein, myeloperoxidase, hyaluronan and interleukin-8 in bronchoalveolar lavage fluid can be used as diagnostic markers for acute rejection in the postoperative follow-up of lung transplant recipients.

Off-pump CABG reduces complement activation but does not significantly affect peripheral endothelial function: a prospective randomized study.

Objective—Cardiac surgery initiates a systemic inflammatory response, which may affect endothelial function. The aim of this study was to investigate if off‐pump CABG (OPCAB) reduces the postoperative inflammatory response and affects endothelial function less than conventional on‐pump CABG. Design—Fifty‐two patients submitted for elective CABG were included in a prospective, randomized study. Twenty‐six patients were operated with, and 26 without cardiopulmonary bypass (CPB). Plasma levels of complement (C3a), cytokines (IL‐8, TNF‐α), endothelin‐1 and neopterin were measured before and during surgery and 2 and 24 h after surgery. Endothelial function was assessed by forearm plethysmography and acetylcholine infusion in 30 patients 2–4 h after surgery. Results—C3a and neopterin concentrations were significantly higher during and early after surgery in the CPB group while TNF‐α and IL‐8 tended to be higher in the CPB group but the difference did not reach statistical significance. Endothelial function did not differ significantly between the two groups. Conclusion—OPCAB reduces complement activation compared with on‐pump CABG but does not significantly affect TNF‐α and IL‐8 release or endothelial function.

α-ketoglutarate for myocardial protection in heart surgery

Abstract A low myocardial content of α-ketoglutarate during heart surgery might aggravate ischaemic injury. 24 men undergoing coronary surgery participated in a randomised controlled study. 28 g α-ketoglutarate was added to blood cardioplegia for intermittent antegrade intracoronary perfusion in 13 cases. α-ketoglutarate reduced the appearance in blood of the ischaemic markers creatine kinase MB and troponin T (at 4 h after release of aortic cross-clamp; median [95% Cl] 49 [37-60] μg/L in controls vs 32 [27-37] μg/L for creatine kinase MB, 2·0 [1·2-2·8] vs 1·1 [0·8-1·4] μg/L for troponin T). These findings signify attenuated ischaemic injury, possibly secondary to enhanced myocardial oxidative capacity.

Addition of α-Ketoglutarate to Blood Cardioplegia Improves Cardioprotection

Abstract Background . We hypothesized that myocardial content of α-ketoglutarate (α-KG), an intermediate of the Krebs cycle, can be critically low during heart operations, and that provision of α-KG could reduce metabolic abnormalities and lead to improved myocardial protection. Methods . Twenty-four men aged 46 to 78 years who were undergoing heart operations participated in a prospective, controlled, randomized study. In 13 patients, an average of 28 g of α-KG was added to blood cardioplegia. Plasma creatine kinase isoenzyme MB and troponin T, and myocardial extraction of oxygen, substrates, and amino acids were measured. Results . α-Ketoglutarate treatment was associated with lower creatine kinase isoenzyme MB (F = 39.6, df=1.172, p p p p = 0.016). There were no other differences after 30 minutes of reperfusion. Conclusion . Provision of α-KG during blood cardioplegia improves myocardial protection in patients undergoing coronary operations. This may be linked to enhanced oxidation. (Ann Thorac Surg 1997;63:1625–34)

Hepcidin, interleukin-6 and hematological iron markers in males before and after heart surgery.

Anemia of inflammation in patients with acute or chronic acute-phase activation is a common clinical problem. Hepcidin is a peptide shown to be the principal regulator of the absorption and systemic distribution of iron. Main inducers of hepcidin are iron overload, hypoxia and inflammation, where the latter has been linked to hepcidin via increased interleukin-6 (IL-6). This article addresses the impact and time course of postoperative acute-phase reaction in humans following heart surgery on prohepcidin, hepcidin, hematological markers and IL-6 concentrations. Serum concentrations of prohepcidin, hepcidin, IL-6 and hematological iron parameters were studied in five male patients without infection before and after heart surgery. This study, which is the first to report the impact on serum hepcidin and serum prohepcidin concentrations in patients following surgery, clearly demonstrates the induction of hypoferremia due to the postoperative acute-phase reaction. Significant changes were seen for serum iron concentration, transferrin saturation, total iron binding capacity and hemoglobin concentration. A significant increase in ferritin concentration was seen 96-144 h postoperatively. Additionally, there were significant alterations in both serum hepcidin after 96-144 h and serum prohepcidin after 48 h compared with preoperative values. Serum prohepcidin decreased, whereas serum hepcidin increased. In conclusion, changes in serum prohepcidin were followed by an increase in serum hepcidin. This speaks in favor of a chain of action where proteolytic trimming of serum prohepcidin results in increased serum hepcidin. However, hypoferremia appeared prior to the changes in serum prohepcidin and serum hepcidin.

Butylated hydroxytoluene and N-acetylcysteine attenuates tumor necrosis factor-alpha (TNF-alpha) secretion and TNF-alpha mRNA expression in alveolar macrophages from human lung transplant recipients in vitro

BACKGROUND Tumor necrosis factor-alpha (TNF-alpha) is a polypeptide cytokine principally produced by macrophages/monocytes and commonly associated with inflammatory conditions. The present study was designed to investigate whether the antioxidants butylated hydroxytoluene (BHT) and N-acetylcysteine (NAC) modified TNF-alpha production in stimulated and unstimulated alveolar macrophages from lung transplant recipients in vitro. METHODS The effects of BHT and NAC on TNF-alpha production were studied both with and without lipopolysaccharide (LPS) activation of alveolar macrophages from bronchoalveolar lavage fluid. TNF-alpha was quantitated in cell culture medium using an enzyme-linked immunosorbent assay. TNF-alpha mRNA expression was analyzed by quantitative reverse transcription-polymerase chain reaction on total RNA extracted from the incubated alveolar macrophages. RESULTS In unstimulated alveolar macrophages, TNF-alpha levels were significantly reduced by incubation with BHT or NAC. When alveolar macrophages from patients with cytomegalovirus infection were incubated with BHT, TNF-alpha secretion was significantly lowered. A significant reduction of TNF-alpha levels in LPS-stimulated alveolar macrophages was obtained in the presence of BHT or NAC. Our data from quantitative reverse transcription-polymerase chain reaction showed that the observed decrease in protein levels of TNF-alpha was associated with a decrease in TNF-alpha mRNA expression. CONCLUSIONS Our results indicate that antioxidant treatment may be an effective step to lower the inflammatory process caused by cytomegalovirus infection or in endotoxin (LPS)-activated macrophages. The therapeutic use of antioxidant compounds could, therefore, be of interest in conditions such as lung transplantation, in which oxidative stress and inflammation can contribute significantly to the loss of allograft function.