Intravenous Immunoglobulin for Hypogammaglobulinemia after Lung Transplantation: A Randomized Crossover Trial

Background We aimed to determine the effects of treatment with intravenous immunoglobulin on bacterial infections in patients with hypogammaglobulinemia (HGG) after lung transplantation. Methods We performed a randomized, double-blind, placebo-controlled two-period crossover trial of immune globulin intravenous (IVIG), 10% Purified (Gamunex, Bayer, Elkhart, IN) monthly in eleven adults who had undergone lung transplantation more than three months previously. We randomized study participants to three doses of IVIG (or 0.1% albumin solution (placebo)) given four weeks apart followed by a twelve week washout and then three doses of placebo (or IVIG). The primary outcome was the number of bacterial infections within each treatment period. Results IVIG had no effect on the number of bacterial infections during the treatment period (3 during IVIG and 1 during placebo; odds ratio 3.5, 95% confidence interval 0.4 to 27.6, p = 0.24). There were no effects on other infections, use of antibiotics, or lung function. IVIG significantly increased trough IgG levels at all time points (least square means, 765.3 mg/dl during IVIG and 486.3 mg/dl during placebo, p<0.001). Four serious adverse events (resulting in hospitalization) occurred during the treatment periods (3 during active treatment and 1 during the placebo period, p = 0.37). Chills, flushing, and nausea occurred during one infusion of IVIG. Conclusions Treatment with IVIG did not reduce the short-term risk of bacterial infection in patients with HGG after lung transplantation. The clinical efficacy of immunoglobulin supplementation in HGG related to lung transplantation over the long term or with recurrent infections is unknown

Platelet activation in the postoperative period after lung transplantation

Objective During lung transplantation, cells in the pulmonary parenchyma are subjected to ischemia, hypothermic storage, and reperfusion injury. Platelets, whose granular contents include adhesion receptors, chemokines, and coactivating substances that activate inflammatory and coagulant cascades, likely play a critical role in the lung allograft response to ischemia and reperfusion. The platelet response to the pulmonary allograft, however, has never been studied. Here we report significant platelet activation immediately after lung transplantation. Methods We performed a prospective cohort study comparing markers of platelet activation in patients undergoing lung transplantation and patients undergoing nontransplant thoracotomy. Plasma levels of soluble P-selectin, soluble CD40 ligand, and platelet–leukocyte conjugates were measured before surgery, after skin closure, and at 6 postoperative hours. Results Both soluble P-selectin and soluble CD40 ligand levels increased significantly after lung transplantation but not after thoracotomy. Additionally, platelet–monocyte conjugate fluorescence was significantly higher after lung transplantation than after thoracotomy alone. Conclusion These findings suggest that platelet activation is significantly increased after lung transplantation beyond that expected from the postoperative state. The increase in circulating platelet–monocyte conjugates suggests an important interaction between platelets and inflammatory cells. Further research should examine whether platelet activation affects early graft function after lung transplantation

Multifocal pleomorphic dermal sarcoma and the role of inflammation and immunosuppression in a lung transplant patient: a case report

Background Pleomorphic dermal sarcoma is the cutaneous variant of undifferentiated pleomorphic sarcoma. It is a rare malignancy of unclear histogenesis; it is a diagnosis of exclusion that requires extensive use of immunohistochemistry to rule out other malignancies. Pleomorphic dermal sarcoma typically presents as a solitary tumor in sun-exposed areas and may have unpredictable clinical behavior, with some tumors associated with metastasis and death. Case presentation We present an unusual case of multifocal pleomorphic dermal sarcoma arising in the areas of alpha-1-antitrypsin deficiency panniculitis in a lung transplant patient. Our patient was a 58-year-old white woman whose initial presentation was consistent with alpha-1-antitrypsin deficiency panniculitis. She then developed extensive multifocal, bleeding, and ulcerated nodules in the areas of the panniculitis. A skin biopsy was consistent with a diagnosis of pleomorphic dermal sarcoma. Her immunosuppressive regimen was decreased, and she was treated with liposomal doxorubicin 40 mg/m2 every 3 weeks with some initial improvement in the size of her tumors. However, soon after beginning therapy, she developed pneumonia and septic shock and ultimately died from multi-organ failure. Conclusions We hypothesize that chronic, multifocal inflammation in the skin in the setting of immunosuppression led to simultaneous, malignant transformation in numerous skin lesions. We discuss the challenges of diagnosing pleomorphic dermal sarcoma, therapeutic options, and stress the need for multidisciplinary management of these cases

The relationship between plasma lipid peroxidation products and primary graft dysfunction after lung transplantation is modified by donor smoking and reperfusion hyperoxia

BACKGROUND: Donor smoking history and higher fraction of inspired oxygen (FIO2) at reperfusion are associated with primary graft dysfunction (PGD) after lung transplantation. We hypothesized that oxidative injury biomarkers would be elevated in PGD, with higher levels associated with donor exposure to cigarette smoke and recipient hyperoxia at reperfusion. METHODS: We performed a nested case-control study of 72 lung transplant recipients from the Lung Transplant Outcomes Group cohort. Using mass spectroscopy, F2-isoprostanes and isofurans were measured in plasma collected after transplantation. Cases were defined in 2 ways: grade 3 PGD present at day 2 or day 3 after reperfusion (severe PGD) or any grade 3 PGD (any PGD). RESULTS: There were 31 severe PGD cases with 41 controls and 35 any PGD cases with 37 controls. Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (28.6 pg/ml vs 19.8 pg/ml, p = 0.03). Plasma F2-isoprostane levels were higher in severe PGD cases compared with controls (29.6 pg/ml vs 19.0 pg/ml, p = 0.03) among patients reperfused with FIO2 >40%. Among recipients of lungs from donors with smoke exposure, plasma F2-isoprostane (38.2 pg/ml vs 22.5 pg/ml, p = 0.046) and isofuran (66.9 pg/ml vs 34.6 pg/ml, p = 0.046) levels were higher in severe PGD compared with control subjects. CONCLUSIONS: Plasma levels of lipid peroxidation products are higher in patients with severe PGD, in recipients of lungs from donors with smoke exposure, and in recipients exposed to higher Fio2 at reperfusion. Oxidative injury is an important mechanism of PGD and may be magnified by donor exposure to cigarette smoke and hyperoxia at reperfusion

General Anesthetics Inhibit Erythropoietin Induction under Hypoxic Conditions in the Mouse Brain

Background: Erythropoietin (EPO), originally identified as a hematopoietic growth factor produced in the kidney and fetal liver, is also endogenously expressed in the central nervous system (CNS). EPO in the CNS, mainly produced in astrocytes, is induced under hypoxic conditions in a hypoxia-inducible factor (HIF)-dependent manner and plays a dominant role in neuroprotection and neurogenesis. We investigated the effect of general anesthetics on EPO expression in the mouse brain and primary cultured astrocytes. Methodology/Principal Findings: BALB/c mice were exposed to 10 % oxygen with isoflurane at various concentrations (0.10–1.0%). Expression of EPO mRNA in the brain was studied, and the effects of sevoflurane, halothane, nitrous oxide, pentobarbital, ketamine, and propofol were investigated. In addition, expression of HIF-2a protein was studied by immunoblotting. Hypoxia-induced EPO mRNA expression in the brain was significantly suppressed by isoflurane in a concentration-dependent manner. A similar effect was confirmed for all other general anesthetics. Hypoxia-inducible expression of HIF-2a protein was also significantly suppressed with isoflurane. In the experiments using primary cultured astrocytes, isoflurane, pentobarbital, and ketamine suppressed hypoxia-inducible expression of HIF-2a protein and EPO mRNA. Conclusions/Significance: Taken together, our results indicate that general anesthetics suppress activation of HIF-2 an

Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

Six-Minute-Walk Distance Predicts Waiting List Survival in Idiopathic Pulmonary Fibrosis

Rationale: Functional studies may be useful to predict survival in idiopathic pulmonary fibrosis (IPF). Various cutoffs of 6-min-walk distance (6MWD) have been suggested to identify patients at a high risk of death

Adverse events.

<p>*AEs with more than 1 occurrence during the study (except for infusion related AEs, acute kidney injury, pancreatitis, and vitreous hemorrhage).</p