C1 esterase inhibitor in pediatric cardiac surgery with cardiopulmonary bypass plays a vital role in activation of the complement system.

Our prospective study was therefore designed to determine which part of the systemic inflammatory response after cardiac operations resulted from Cardiopulmonary bypass (CPB) in neonates and infants. After approval by the human ethical committee of the Gunma Children's Medical Center (GCMC) and informed consent of the parents, 40 consecutive term congenital heart disease patients aged until 1 year who underwent long CPB time (> 3 h) at surgery were included in the prospective study between January 2012 and December 2014. C1 esterase inhibitor (C1-inh) drug (@Berinert) was generously provided by CSL Behring (King of Prussia, PA). The C1-inh (20 IU/kg) was given intravenously 60 min after CPB. Blood samples for complement factors were obtained before and 48 h after administration of C1-inh. Six patients did not survive and their data were not included. Of 34 patients included, median age was 6.5 months, median body weight was 6050 g, and 16 (47%) were female. According to the Mann-Whitney U test, there were no differences between the two groups concerning demographic and intraoperative data, postoperative chemical data. C1q concentration was only significant lower in patients with C1-inh non-treated group than in patients with C1-inh treated group. But, the consumption of C1q, C3, C4, CH50, and C1-inh in patients with C1-inhibitor non-treated group was observed early postoperatively. There is a significant difference in the values before and after C1-inh treatment between the two groups. The lower value in the C1-inh-treated group is explained by the activation of the classical pathway through the replenishment of complements by C1-inh treatment. This study proposes the administration of C1-inh is an effective therapy to reduce the activation and improve the clinical capillary leak syndrome.

Engraftment Syndrome after Autologous Stem Cell Transplantation: An Update Unifying the Definition and Management Approach.

Engraftment syndrome (ES) encompasses a continuum of periengraftment complications after autologous hematopoietic stem cell transplantation. ES may include noninfectious fever, skin rash, diarrhea, hepatic dysfunction, renal dysfunction, transient encephalopathy, and capillary leak features, such as noncardiogenic pulmonary infiltrates, hypoxia, and weight gain with no alternative etiologic basis other than engraftment. Given its pleiotropic clinical presentation, the transplant field has struggled to clearly define ES and related syndromes. Here, we present a comprehensive review of ES in all documented disease settings. Furthermore, we discuss the proposed risk factors, etiology, and clinical relevance of ES. Finally, our current approach to ES is included along with a proposed treatment algorithm for the management of this complication.

Nivolumab-induced systemic capillary leak syndrome as an ultra rare life-threatening phenomenon of late toxicity and intravenous immunoglobulin efficacy.

Systemic capillary leak syndrome (SCLS) is a life-threatening disease. It is characterized by severe capillary hyperpermeability to proteins resulting in hemoconcentration, hypoalbuminemia and hypovolemic shock. Its treatment remains supportive, and the prognosis is generally poor. We report on a 51-year old male with melanoma treated with nivolumab for 1 year. 1 month following the completion of the treatment, the patient presented with signs of hypovolemic shock, anasarca, hemoconcentration and hypoalbuminemia. After excluding other diseases, a diagnosis of nivolumab-induced systemic capillary leak syndrome was made. A high dose of intravenous steroid therapy was promptly initiated without any significant clinical improvement. Intravenous immunoglobulin therapy was then administered with normalization of blood pressure, hemoconcentration and complete resolution of anasarca. Intravenous immunoglobulin should be considered a first-line treatment option for this rare phenomenon.

Lay abstract Systemic capillary leak syndrome (SCLS) is a life-threatening disease with a high fatality rate. Patients present with low blood pressure, widespread edema and rapid weight gain. Labs show low albumin levels with highly concentrated blood, seen as high hematocrit and hemoglobin levels. Current treatments aim to support the acute crisis. We are presenting on a 51-year old patient with melanoma, treated with nivolumab for 1 year who developed signs of SCLS 1-month following medication discontinuation. He was first treated with high-dose steroids without symptom resolution. He was then administered immune proteins called intravenous immunoglobulins, resolving all his symptoms. Due to the patient's complete response, we suggest intravenous immunoglobulins as the initial treatment in patients taking nivolumab presenting with SCLS.

Probable Mechanisms Involved in Immunotoxin Mediated Capillary Leak Syndrome (CLS) and Recently Developed Countering Strategies.

Antibody-toxin fused agents or immunotoxins, are a newly engineered class of cytotoxic agents consisting of a bacterial or plant toxin moiety hooked up either to a monoclonal antibody or a specific growth factor. Nevertheless, acquiring a full potency in clinic is mostly restricted due to the Capillary leak syndrome (CLS), a serious immune provoked, life-threatening side effect, subsequent to the endothelial damage, resulting in fluid escape from the bloodstream into tissues including lungs, muscle and brain, developing organ failure and eventually death. Proposed underlying mechanisms include direct damage to endothelial cells, acute inflammation, Lymphokine-activated killer (LAK) cells engagement, alteration in cell-cell/cell-matrix connectivities and cytoskeletal dysfunction. Very poor biodistribution and heterogeneous extravasation pattern in tumor site result in accumulation of ITs close to the extravasation site, gradual toxin release and initiation of nearby endothelial cells lysis, secretion of pro-inflammatory cytokines, development of acute inflammation and engagement of Lymphokine-activated killer (LAK) cells. Intrinsic immunogenicity of applied toxin moiety is another important determinant of CLS incidence. Toxins with more intrinsic immunogenicity possess more probability for CLS development. Recently, development of new generations of antibodies and mutated toxins with conserved cytotoxicity has partly tapered risk of CLS development. Here, we describe probable mechanisms involved in CLS and introduce some of the recently applied strategies for lessening incidence of CLS as much as possible.

Vascular biology in sepsis: pathophysiological and therapeutic significance of vascular dysfunction.

Sepsis is the leading cause of mortality in critically ill patients. In this pathological syndrome, septic shock and sequential multiple organ failure correlate with poor outcome. The pathophysiology of sepsis with acute organ dysfunction involves a highly complex, integrated response that includes activation of number of cell types, inflammatory mediators, and the hemostatic system. Central to this process may be alterations in vascular functions. This review article provides a growing body of evidence for the potential impact of vascular dysfunction on sepsis pathophysiology with a major emphasis on the endothelium. Furthermore, the role of apoptotic signaling molecules in the mechanisms underlying endothelial cell injury and death during sepsis and its potential value as a target for sepsis therapy will be discussed, which may help in the assessment of ongoing therapeutic strategies.

[Clarkson syndrome: a rare clinical condition characterized by generalized edema associated to monoclonal gammopathy]. / Sindrome di clarkson: una rara causa di edema associato a paraproteinemia.

Generalized edema is commonly due to cardiac failure, renal changes, hepatic and metabolic disturbances, or it can be idiopathic, i.e. primitive lymphedema. Here we describe a patient with several episodes of fluid extravasation characterized by hypotension, hemoconcentration and functional renal insufficiency. These findings, associated to a monoclonal gammopathy, lead to the diagnosis of systemic capillary leak syndrome or Clarkson Syndrome. This rare and perplexing disorder, characterized by a typical three-phase clinical feature, is due to an endothelium permeability alteration, rather responsible of these paroxysmal manifestations. Interleukin-2-pathway is considered as one of the underlying mechanisms. During acute phase the patient underwent therapy with plasma-expanders and glucocorticoids, although in quiescent phase we administered aminophylline, salbutamol and prednisone. After three months, the patient is asymptomatic.

Tolerability and side effects of anti-CD3-immunotoxin in preclinical testing in kidney and pancreatic islet transplant recipients.

INTRODUCTION: Anti-CD3-immunotoxin (alpha-CD3-IT) promotes allograft tolerance in nonhuman primates owing to efficient depletion of sessile and circulating T cells. Common side effects of vascular leak syndrome, hepatotoxicity, and nephrotoxicity have limited tolerability of other immunotoxins. We report on preclinical studies of alpha-CD3-IT-related side effects. METHODS: Normal rhesus monkeys received a kidney transplant and alpha-CD3-IT alone (on day -to +2) or in combination with brief peritransplant adjunctive immunosuppressive therapy. Some received donor CD34+ cells. Blood chemistries, complete blood count, weight, liver, and kidney biopsies were examined for immunotoxin-related changes. Five spontaneously diabetic primates also received alpha-CD3-IT, three of whom had a pancreas islet transplant. RESULTS: The main side effect of alpha-CD3-IT, vascular leak syndrome, was entirely prevented by adjunctive immunosuppressive therapy. Renal and liver function tests and biopsies revealed a lack of nephrotoxicity and hepatotoxicity. All had transient weight loss (14+/-5%). Without infusion of donor CD34+ cells, 97% had full weight recovery. Of those given donor CD34+ cells, 50% were euthanized for wasting. CONCLUSIONS: Side effects of alpha-CD3-IT are manageable and should not prevent therapeutic application.

[A case report of systemic capillary leak syndrome. Effective treatment with immunoadsorption and leukotriene antagonist]. / Fallbeskrivning av systemiskt kapillärläckage-syndrom. Behandling med immunadsorption och leukotrienantagonist hade god effekt.

Systemic capillary leak syndrome (SCLS) is an unusual condition characterized by periodic leakage of plasma proteins through the capillary wall, leading to hypoalbuminaemia, hypovolaemia, haemoconcentration and shock. The pathogenesis is unknown and the mortality high. Various prophylactic treatments have been tried but are difficult to evaluate because of the unpredictable course of the disease. We describe one patient with frequent attacks of SCLS, that did not respond to any kind of treatment regimens over a period of nine years. Subsequently, therapy with regular immunoadsorption of plasma proteins and a leukotriene receptor antagonist was attempted. This treatment has now been given for six years and only one episode of capillary leakage has occurred. The effect may be due to removal of pathogenic immunoglobulins or immune complexes and/or inhibition of leukotriene-induced capillary leakage.

Intravenous immunoglobulin in systemic capillary leak syndrome: a case report and review of literature.

The systemic capillary leak syndrome (SCLS) is a rare condition characterized by unexplained episodic attacks of systemic capillary hyperpermeability accompanied by hypoalbuminemia, hemoconcentration and edema. Treatment of the acute phase is supportive, focusing on adequate fluid resuscitation. Many agents have been used to prevent acute attacks, including corticosteroids, ß2-agonists (aminophylline, theophylline, or terbutaline), infliximab, thalidomide and intravenous immunoglobulin (IVIg). ß2-agonists were the first-line maintenance therapy until a few years ago. In more recent years, IVIg became common first-line prophylactic therapy in most patients with benefits at the dose of 2 g/kg once a month. We report the case of a 49-year-old man with SCLS treated successfully with a lower dose of IVIg (1 g/kg monthly) in the maintenance phase. He presented no acute episodes in a follow-up of 28 months. We describe prophylactic treatments for SCLS in literature and compare our patient to another 18 who received IVIg in follow-up.

Invasive pulmonary aspergillosis in a patient presenting with idiopathic systemic capillary leak syndrome.

A 54-year-old man presented to our emergency department with fever and dyspnoea. He required vigorous haemodynamic support and mechanical ventilation for hypotensive distributive shock with hypoalbuminaemia, haemoconcentration, rhabdomyolysis and acute renal failure, consistent with idiopathic systemic capillary leak syndrome. Left lung consolidation and hypoxaemia were observed 6 days after admission. Sputum smear revealed the presence of acute angled branching hyphae, consistent with a diagnosis of invasive pulmonary aspergillosis. Antifungal therapy was administered and mechanical ventilation discontinued on day 66. The patient recovered and was discharged from the hospital on day 185.

[Microvascular effects of burn plasma transfer and therapeutic options in a rat model]. / Mikrovaskuläre Effekte des Verbrennungsplasma-transfers und therapeutische Optionen im Tiermodell.

INTRODUCTION: Thermal injuries with more than 20% of burned body surface area (BSA) lead to systemic shock with generalised oedema in addition to local tissue destruction. This condition, known as burn injury, is caused by immunmodulative mediators whose individual significance is not known in detail. We present an experimental model where plasma of burned animals (burn plasma) is transmitted to healthy animals, to trigger burn iniury without performing direct burn trauma. MATERIAL AND METHODS: The systemic oedema is measured by extravasation of fluorescent albumin in mesenterial venules of Wistar rats. In addition, leukocyte-endothelial interactions ("leukocyte rolling and sticking") is examined. RESULTS: The systemic capillary leak is induced by both direct thermal trauma as well as by infusion of burn plasma. This is evident even after plasma dilution (1% in Ringer's lactate) of the burn plasma. In addition, topical therapy for burned animals (donors) with cerium nitrate led to a significant reduction of plasma extravasation in receiver animals. In addition, systemic antioxidant therapy with high-dose vitamin C of receiver animals, led to a significant reduction of the capillary leak. Leukocyte-endothelial interactions are not significantly affected in either case. CONCLUSION: In summary, for the first time a reliable model of burn injury has been established, which eliminates mediator-independent effects. In addition, our studies show that antioxidant therapy with high doses of vitamin C and topical treatment with cerium nitrate both reduce the systemic capillary leak in receiver animals. Their positive influence could therefore soon be integrated in clinical treatment algorithms.

Suppression of endotoxin-induced inflammation by taxol.

The pathogenesis of acute lung injury includes transendothelial diapedesis of leukocytes into lung tissues and disruption of endothelial/epithelial barriers leading to protein-rich oedema. In vitro studies show that the microtubule network plays a role in the regulation of endothelial permeability as well as in neutrophil locomotion. It was hypothesised that the microtubule-stabilising agent, taxol, might attenuate inflammation and vascular leak associated with acute lung injury in vivo. The effect of intravenously delivered taxol was assessed using a model of murine lung injury induced by intratracheal lipopolysaccharide (LPS) administration. Parameters of lung injury and inflammation were assessed 18 h after treatment. Intravenously delivered taxol significantly reduced inflammatory histological changes in lung parenchyma and parameters of LPS-induced inflammation: infiltration of proteins and inflammatory cells into bronchoalveolar lavage fluid, lung myeloperoxidase activity, and extravasation of Evans blue-labelled albumin into lung tissue. Taxol alone (in the absence of LPS) had no appreciable effect on these parameters. In addition to lung proteins, intravenous taxol reduced accumulation of leukocytes in ascitic fluid in a model of LPS-induced peritonitis. Taken together, the present data demonstrate that microtubule stabilisation with taxol systemically attenuates lipopolysaccharide-induced inflammation and vascular leak.