Administration Of C1 Esterase Inhibitor Research Articles

C1 esterase inhibitor (C1-INH) for the off-label treatment of angiotensin-converting enzyme inhibitor induced angioedema

Introduction: Currently, C1 esterase inhibitor (C1-INH) is indicated for hereditary angioedema (HAE) but is utilized off-label for angiotensin- converting enzyme inhibitors (ACEi) induced angioedema (AAE). There is no standard of care for the treatment of AAE, however patients may receive a combination of epinephrine, corticosteroids, fresh frozen plasma (FFP), tranexamic acid (TXA), and histamine 1 and 2 receptor antagonists (H1RA, H2RA). C1-INH place is therapy is not well defined. Materials & Methods: A retrospective chart review was conducted from patients at a large academic medical center who received C1-INH for AAE between January 2012 and May 2022. Variables and outcomes of interest were receipt of alternative angioedema treatment prior to C1-INH, time of C1-INH administration, dose of C1-INH, need for intubation or surgical airway placement, duration of intubation, and hospital length of stay. Results: All patients received additional medications for angioedema prior to C1-INH administration. Steroids and H1RAs were most common. The dose of C1-INH ranged from 11.7 IU/kg to 23.2 IU/kg with an average dose of 19.3 IU/kg. Five patients required airway support with four requiring intubation (30.8%) and one requiring a surgical airway. Conclusions: This retrospective review of 13 patients showed mixed results for C1-INH to prevent intubation in AAE. Providers should consider limiting the use of C1-INH to patients who remain symptomatic after administering a combination of other therapies when there is an ongoing risk for airway compromise and adequate time for preparation, administration, and effect.

Mannan-Binding Lectin Promotes Murine Graft-versus-Host Disease by Amplifying Lipopolysaccharide-Initiated Inflammation

Conditioning regimens used for hematopoietic stem cell transplantation (HCT) can escalate the severity of acute T cell-mediated graft-versus-host disease (GVHD) by disrupting gastrointestinal integrity and initiating lipopolysaccharide (LPS)-dependent innate immune cell activation. Activation of the complement cascade has been associated with murine GVHD, and previous work has shown that alternative pathway complement activation can amplify T cell immunity. Whether and how mannan-binding lectin (MBL), a component of the complement system that binds mannose as well as oligosaccharide components of LPS and lipoteichoic acid, affects GVHD is unknown. In this study, we tested the hypothesis that MBL modulates murine GVHD and examined the mechanisms by which it does so. We adoptively transferred C3.SW bone marrow (BM) cells ± T cells into irradiated wild type (WT) or MBL-deficient C57Bl/6 (B6) recipients with or without inhibiting MBL-initiated complement activation using C1-esterase inhibitor (C1-INH). We analyzed the clinical severity of disease expression and analyzed intestinal gene and cell infiltration. In vitro studies assessed MBL expression on antigen-presenting cells (APCs) and compared LPS-induced responses of WT and MBL-deficient APCs. MBL-deficient recipients of donor BM ± T cells exhibited significantly less weight loss over the first 2 weeks post-transplantation weeks compared with B6 controls (P < .05), with similar donor engraftment in the 2 groups. In recipients of C3.SW BM+T cells, the clinical expression of GVHD was less severe (P < .05) and overall survival was better (P < .05) in MBL-deficient mice compared with WT mice. On day-7 post-transplantation, analyses showed that the MBL-deficient recipients exhibited less intestinal IL1b, IL17, and IL12 p40 gene expression (P < .05 for each) and fewer infiltrating intestinal CD11c+, CD11b+, and F4/80+ cells and TCRβ+, CD4+, CD4+IL17+, and CD8+ T cells (P < .05 for each). Ovalbumin or allogeneic cell immunizations induced equivalent T cell responses in MBL-deficient and WT mice, demonstrating that MBL-deficiency does not directly impact T cell immunity in the absence of irradiation conditioning. Administration of C1-INH did not alter the clinical expression of GVHD in preconditioned WT B6 recipients, suggesting that MBL amplifies clinical expression of GVHD via a complement-independent mechanism. WT, but not MBL-deficient, APCs express MBL on their surfaces. LPS-stimulated APCs from MBL-deficient mice produced less proinflammatory cytokines (P < .05) and induced weaker alloreactive T cell responses (P < .05) compared with WT APCs. Together, our data show that MBL modulates murine GVHD, likely by amplifying complement-independent, LPS-initiated gastrointestinal inflammation. The results suggest that devising strategies to block LPS/MBL ligation on APCs has the potential to reduce the clinical expression of GVHD.

An anesthetic experience of hereditary angioedema type I patient undertook total laparoscopic hysterectomy - A case report -

BackgroundHereditary angioedema (HAE) is an autosomal dominant disorder. The characteristic of HAE is recurrent angioedema episodes due to low C1 esterase inhibitor (C1-INH) level. HAE symptoms, especially those affecting oropharynx or larynx may develop respiratory distress syndrome due to impaired airway, which can be potentially fatal.Case We report a clinical case of a 57 year-old female patient, with type I HAE, scheduled for total laparoscopic hysterectomy under general endotracheal anesthesia, which was done successfully without inducing airway edema. Danazol, which increases liver synthesis of C1-INH, was administered and fresh frozen plasma (FFP), which contained C1-INH, was transfused after induction.ConclusionsFor HAE patients, the greatest concern is that general anesthesia can induces upper airway edema by direct mucosal irritation by the endotracheal tube. The perioperative management should include both prophylactic increase of C1-INH production and on-demand administration of C1-INH or FFP.

Effects of Ischemic Preconditioning and C1 Esterase Inhibitor Administration following Ischemia-Reperfusion Injury in a Rat Skin Flap Model.

Ischemia-reperfusion (I/R) injury is a serious condition that can affect the success rate of microsurgical reconstructions of ischemic amputated limbs and complex tissue defects requiring free tissue transfers. The purpose of this study was to evaluate the effects of ischemic preconditioning (IPC) and C1 esterase inhibitor (C1-Inh) intravenous administration following I/R injury in a rat skin flap model. Superficial caudal epigastric skin flaps (3 cm × 7 cm) were performed on 50 Wistar rats that were randomly divided into five groups. Ischemia was not induced in the control group. All other flaps underwent 8 hours of ischemia prior to revascularization: I/R control group (8-hour ischemia), IPC group (preconditioning protocol + 8-hour ischemia), C1-Inh group (8-hour ischemia + C1-Inh), and IPC + C1-Inh group (preconditioning protocol + 8-hour ischemia + C1-Inh). Survival areas were macroscopically assessed after 1 week of surgery, and histopathological and biochemical evaluations were also measured. There were no significant differences in flap survival between the treatment groups that were suffering 8 hours of ischemia and the control group. A significant increase in neovascularization and lower edema formation were observed in the IPC group compared with that in the I/R group. Biochemical parameters did not show any significant differences. Intravenous administration of C1-Inh did not significantly modulate I/R-related damage in this experimental model, but further research is needed. On the other hand, IPC reduces tissue damage and improves neovascularization, confirming its potential protective effects in skin flaps following I/R injury.

A Case of Prolonged Angioedema After Cardiac Surgery

Angioedema (AE) is a transient capillary leak syndrome, caused by either histamine or bradykinin, that presents as an acute nonpitting swelling of the skin, subcutaneous tissues, and mucous membranes of the face, lips, tongue, upper airways, and gastrointestinal tract, with or without a rash. A lack of response to antihistamines, steroids, and epinephrine suggests a bradykinin-mediated AE. Bradykinin-AE may be inherited, acquired, or drug related. Mechanism of increased bradykinin can include decreased C1-esterase inhibitor (C1-INH) levels or activity, increased bradykinin production, or decreased bradykinin breakdown, the latter occurring during angiotensin converting enzyme inhibitor (ACEi). A 65-year-old woman had coronary artery bypass grafting, which was complicated by prolonged bradykinin-AE owing to ACEi, requiring prolonged endotracheal tube intubation. Treatment with a C1-esterase inhibitor (Berinert) on postoperative day 7 resulted in a dramatic improvement in airway edema and tongue swelling within 7 hours, and the patient was subsequently extubated. The case is unusual because of the prolonged course of AE and the benefit of late administration of C1-INH concentrate.

EXPLORATORY ANALYSIS REVEALS POSITIVE CORRELATION BETWEEN C1 ESTERASE INHIBITOR AND SERUM COMPLEMENT 4 ANTIGEN LEVELS

Introduction Low levels of C1-esterase inhibitor (C1-INH) and concomitant reduced complement 4 (C4) concentrations have been identified in patients with hereditary angioedema (HAE). C4 constitutes a promising candidate for a biomarker of disease activity. This investigation aims to determine the relationship between C1-INH functional activity levels (C1-INH[f]) and C4 antigen concentrations in patients with HAE treated with subcutaneous (SC) C1-INH, inferring significance for clinical practice. Methods C1-INH(f) and C4 antigen levels were assayed in three clinical studies (NCT01576523, NCT01912456, NCT02316353 [COMPACT Phase 2, 3 and open-label extension studies]). The relationship between these measurements was inspected in an exploratory manner. All measurements were performed at a central laboratory using validated assays and investigated with respect to time after C1-INH(SC) administration and HAE type. C4 antigen concentration over time after C1-INH(SC) administration was characterized, and the correlation with C1-INH(f) evaluated. Results C4 antigen concentration increased gradually following C1-INH(SC) administration until ∼100 hours post-administration when concentrations declined. A linear relationship was observed between C4 antigen concentrations and C1-INH(f) in patients with type I HAE, based on the Loess fit, until C1-INH(f) of ∼50%, at which point signs of saturability became apparent (example figure shown). The relationship in patients with type II HAE was not clear. Conclusions An exploratory analysis showed a linear relationship between C1-INH(f) and C4 antigen levels in patients with type I HAE, consistent with previous reports. The interplay between C1-INH(f) and C4 should be further explored to understand the potential role of C4 monitoring in treatment decision-making.

Practicalities of a reduced volume formulation of a C1-INH concentrate for the treatment of hereditary angioedema: real-life experience

BackgroundHereditary angioedema (HAE) due to C1 esterase inhibitor (C1-INH) deficiency is characterized by recurrent swelling attacks that can be life-threatening if left untreated. Prompt treatment is vital during acute attacks; plasma-derived C1-INH (Berinert®) is one treatment currently licensed for the intravenous treatment of acute HAE attacks in adults, adolescents and children. A new, volume-reduced formulation, of C1-INH is currently available which aims to reduce the time to treatment, and provide greater convenience to patients and healthcare professionals. Here we compare the clinical experience of the reduced volume 1500 IU vial with multiple 500 IU vials.MethodsHAE patients treated with C1-INH at the Royal London Hospital were selected to take part in this assessment. Included patients were aged 10–65 with moderate to severe HAE requiring high doses of C1-INH. The practicalities of the reduced 1500 IU vial compared with multiple 500 IU vials were assessed, including preparation and administration time, training to self-administer time and several quality of life aspects.ResultsTwenty-three patients participated in this study. Twenty-one patients were previously treated with C1-INH (Berinert®) 500 IU for 1–14 years prior to switching to the 1500 IU vial format, two patients were naïve to C1-INH (Berinert®). Preparation and administration of C1-INH (Berinert®) 1500 IU was faster than an equivalent dose with multiple 500 IU vials (11 and 17 min, respectively) and also required less time to train to self-administer (45 and 55 min, respectively). Overall, patients rated the 1500 IU vial format higher in all assessed aspects than the 500 IU format, including preparation, administration, training, travel and storage. Nonetheless, reconstitution of the 1500 IU vial was noted more difficult, requiring gentle mixing to fully dissolve prior to intravenous injection. Patients remained stable on C1-INH (Berinert®) 1500 IU; two patients switched back to multiple 500 IU vials due to headaches and preference for a larger volume.ConclusionsThe volume-reduced C1-INH concentrate (Berinert®) 1500 IU is a practical and convenient alternative to multiple 500 IU vials for the treatment of HAE, which provides patients with more control and independence over their disease owing to a simpler to administer treatment.

Human plasma-derived C1 esterase inhibitor concentrate has limited effect on house dust mite-induced allergic lung inflammation in mice.

C1 esterase inhibitor (C1-INH) can inhibit multiple pathways (complement, contact-kinin, coagulation, and fibrinolysis) that are all implicated in the pathophysiology of asthma. We explored the effect of human plasma-derived C1-INH on allergic lung inflammation in a house dust mite (HDM) induced asthma mouse model by daily administration of C1-INH (15 U) during the challenge phase. NaCl and HDM exposed mice had comparable plasma C1-INH levels, while bronchoalveolar lavage fluid (BALF) levels were increased in HDM exposed mice coinciding with slightly reduced activation of complement (C5a). C1-INH treatment reduced Th2 response and enhanced HDM-specific IgG1. Influx of eosinophils in BALF or lung, pulmonary damage, mucus production, procoagulant response or plasma leakage in BALF was similar in both groups. In conclusion, C1-INH dampens Th2 responses during HDM induced allergic lung inflammation.

Antihistone Properties of C1 Esterase Inhibitor Protect against Lung Injury.

Acute respiratory distress syndrome is characterized by alveolar epithelial cell injury, edema formation, and intraalveolar contact phase activation. To explore whether C1 esterase inhibitor (C1INH), an endogenous inhibitor of the contact phase, may protect from lung injury in vivo and to decipher the possible underlying mechanisms mediating protection. The ability of C1INH to control the inflammatory processes was studied in vitro and in vivo. Here, we demonstrate that application of C1INH alleviates bleomycin-induced lung injury via direct interaction with extracellular histones. In vitro, C1INH was found to bind all histone types. Interaction with histones was independent of its protease inhibitory activity, as demonstrated by the use of reactive-center-cleaved C1INH, but dependent on its glycosylation status. C1INH sialylated-N- and -O-glycans were not only essential for its interaction with histones but also to protect against histone-induced cell death. In vivo, histone-C1INH complexes were detected in bronchoalveolar lavage fluid from patients with acute respiratory distress syndrome and multiple models of lung injury. Furthermore, reactive-center-cleaved C1INH attenuated pulmonary damage evoked by intravenous histone instillation. Collectively, C1INH administration provides a new therapeutic option for disorders associated with histone release.

Complement Blockade with C1 Esterase Inhibitor in Severe C3d Positive Autoimmune Hemolytic Anemia

Autoimmune hemolytic anemia (AIHA) is defined as the development of autoantibodies against red blood cell (RBC) antigens. AIHA is diagnosed in the presence of hemolysis and a positive direct antiglobulin test (DAT) for IgG and/or complement C3d. AIHA is classified as warm, cold or mixed based on the temperature at which the autoantibody is most active. The most clinically severe anemia is usually associated with AIHA in which C3d is detected on DAT. The classical complement pathway is activated in AIHA when antigen-autoantibody complexes on the RBC surface bind to the complement protein C1q. This ultimately results in the generation of C3b. C3b is both an opsonin and an additional proteolytic enzyme. C3b deposition targets the RBC for phagocytosis by macrophages of the reticuloendothelial system resulting in extravascular hemolysis. C3b can also continue activation of complement on the RBC membrane resulting in formation of the membrane attack complex (MAC) and cell lysis. C3b is degraded into C3d, which is identified by the DAT (Bartolmas 2015). Severe anemia and its immediate consequences, the difficulty identifying suitable units for acute RBC transfusion, the likelihood of causing additional hemolysis as well as concerns for stimulating additional antibody production with transfusion make these patients particularly challenging to treat. Current standard treatment consists of steroids with or without rituximab. This treatment paradigm does not, however, address the acute and urgent management of life threatening anemia in many of these patients. C1 esterase inhibitor (C1-INH) is a member of the serine protease inhibitor family and interacts with C1 esterase to block activation of the classical pathway of complement. Case reports have demonstrated that C1-INH can prevent C3-mediated lysis of PNH erythrocytes (DeZern 2014) and augment survival of transfused RBCs in a patient with DAT C3d positive autoimmune hemolytic anemia (Wouters 2013). We hypothesized that minimizing or inhibiting the generation of C3b with C1-INH in patients with either severe cold autoantibody AIHA or a mixed AIHA would rapidly reduce acute hemolysis. We report our clinical experience using a novel approach in the acute management of severe AIHA using the commercially available C1-INH, Berinert. The four patients we identified with either cold or mixed AIHA (Table 1) were between the ages of 58 and 63. All patients presented with clinically severe anemia and required urgent management. Three of the 4 had a co-morbid condition associated with AIHA. All patients received prednisone (1mg/kg) and the commercially available C1-INH at a dose of 20mcg/kg daily from the day of admission for a minimum of 6 days to a maximum of 20 days. Patients 2, 3, and 4 also received 4 weekly doses of rituximab during the course of treatment. The average increase in mean hemoglobin was 79% (presentation mean 4.5gm/dL- end of C1-INH mean 7.95gm/dL) during C1-INH administration. An average of 1.25(0-2) units of packed RBC per patient were transfused during C1-INH administration. Additional measures of ongoing hemolysis including mean LDH which decreased by an average of 72% (presentation mean 1358u/L to end of C1-INH mean 356u/L) and mean haptoglobin which increased in all patients from &lt; 8mg/dL to 111mg/dL after C1-INH. Of note, patient 1 had cold agglutinin titers measured prior to C1-INH administration at 1:128 and repeated after two days of C1-INH administration revealed a decrease to 1:32. This retrospective review of patients demonstrates that utilizing C1-INH in conjunction with standard therapy is safe and results in rapid improvement of hemoglobin levels in patients with DAT/C3d positive AIHA. We hypothesize the inhibition of C1q-C4 interaction rapidly reduces C3b deposition on the RBC membrane decreasing both extra and intravascular RBC destruction. CI-INH therapy allowed successful management of these acutely ill patients with minimal RBC transfusions. We hypothesize that decreasing the exposure to additional antigenic stimulation may shorten the acute exacerbation of hemolysis. The optimal form and schedule of C1-INH therapy for AIHA remains to be determined. Based on these observations the role of inhibitors of the classical pathway of complement as both a single modality and in conjunction with standard therapy in the management of AIHA deserves further investigation. Table Table. Disclosures Broome: Alexion Pharmaceuricals: Honoraria; True North Therapeutics: Honoraria.

P085 Perioperative prophylaxis using weight-based C1-esterase inhibitor dosing in pediatric patients with hereditary angioedema

Perioperative C1-esterase inhibitor administration is associated with successful prophylaxis in adults with hereditary angioedema (HAE). In children with HAE, there is a paucity of data related to short-term prophylaxis. There are currently no universal consensus guidelines regarding dosing strategies for C1-esterase inhibitor as short-term prophylaxis in the perioperative setting. We identify outcomes related to pediatric patients with HAE who received weight-based dosing of C1-esterase inhibitor in the perioperative period.

C1 Inhibitor Limits Organ Injury and Prolongs Survival in Swine Subjected to Battlefield Simulated Injury.

Complement system activation is recognized as a deleterious component of the mammalian physiological response to traumatic injury with severe hemorrhage (TH). Female Yorkshire swine were subjected to a simulated austere prehospital battlefield scenario. Each animal underwent controlled hemorrhage of 22 mL/kg at 100 mL/min rate for approximately 10 min followed by soft tissue injury, femur fracture, and spleen injury. Subsequent blood loss was uncontrolled. Twenty-eight minutes postinjury the animals were randomized into treatment or no treatment with recombinant human C1 esterase inhibitor (C1INH) (500 IU/kg, n = 11) and into receiving or not permissive hypotensive resuscitation (n = 14) with infusion of 45 mL/kg lactated Ringer's solution (2× blood lost). Observation and animal maintenance continued for 6 h at which time the animals had either expired or were euthanized. Heart, lung, and small intestine tissue samples were collected. Pharmacokinetic, hemodynamic, and metabolic parameters as well as survival time, plasma complement activity and tissue deposition, cytokine levels, and tissue injury were determined. We found that administration of C1INH protected tissues from damage, reduced the levels of inflammatory cytokines, and improved blood chemistry. Immunohistochemical analyses revealed that C1INH administration following TH markedly reduced complement activation and deposition in tissues. Importantly, C1INH administration prolonged survival of animals particularly in those which received resuscitation fluid infusion. Our data urge early administration of C1INH to limit organ damage and prolong survival of those injured in the battlefield.

Plasma-derived human C1-esterase inhibitor does not prevent mechanical ventilation-induced pulmonary complement activation in a rat model of Streptococcus pneumoniae pneumonia.

Mechanical ventilation has the potential to cause lung injury, and the role of complement activation herein is uncertain. We hypothesized that inhibition of the complement cascade by administration of plasma-derived human C1-esterase inhibitor (C1-INH) prevents ventilation-induced pulmonary complement activation, and as such attenuates lung inflammation and lung injury in a rat model of Streptococcus pneumoniae pneumonia. Forty hours after intratracheal challenge with S. pneumoniae causing pneumonia rats were subjected to ventilation with lower tidal volumes and positive end-expiratory pressure (PEEP) or high tidal volumes without PEEP, after an intravenous bolus of C1-INH (200 U/kg) or placebo (saline). After 4 h of ventilation blood, broncho-alveolar lavage fluid and lung tissue were collected. Non-ventilated rats with S. pneumoniae pneumonia served as controls. While ventilation with lower tidal volumes and PEEP slightly amplified pneumonia-induced complement activation in the lungs, ventilation with higher tidal volumes without PEEP augmented local complement activation more strongly. Systemic pre-treatment with C1-INH, however, failed to alter ventilation-induced complement activation with both ventilation strategies. In accordance, lung inflammation and lung injury were not affected by pre-treatment with C1-INH, neither in rats ventilated with lower tidal volumes and PEEP, nor rats ventilated with high tidal volumes without PEEP. Ventilation augments pulmonary complement activation in a rat model of S. pneumoniae pneumonia. Systemic administration of C1-INH, however, does not attenuate ventilation-induced complement activation, lung inflammation, and lung injury.

Evaluating the efficacy of subcutaneous C1-esterase inhibitor administration for use in rat models of inflammatory diseases

Context: C1-esterase inhibitor (C1-inh) therapy is currently administered to patients with C1-inh deficiency through intravenous injections. The possibility of subcutaneous administration is currently being explored since this would alleviate need for hospitalization and increase mobility and well-being of patients. Recently, it was observed in pigs that C1-inh indeed can effectively be applied by subcutaneous injection. For studies on the effectiveness of C1-inh therapy for other indications than acquired and hereditary angioedema, rats are commonly used as model animal. For rats, however, subcutaneous C1-inh administration has never been investigated.Objective: To evaluate the efficacy of subcutaneous C1-inh administration in rats.Materials and methods: Three boli of 100 U/kg human plasma-derived C1-inh were administered to Wistar rats on three consecutive days through subcutaneous injection or intravenous injection. Blood samples were collected from the tail veins 3, 4.5 or 6 h after C1-inh administration for measurement of C1-inh plasma levels. Antigen and activity levels of C1-inh of each plasma sample were determined by means of a specific ELISA.Results: For both C1-inh antigen and C1-inh activity, 21- to 119-fold higher plasma levels were measured after intravenous administration compared with subcutaneous administration. Subcutaneous administration also resulted in C1-inh plasma levels that were less stable and with decreased relative activity.Conclusion: These combined results indicate that in rats, subcutaneous injections in the present formulation are not effective as alternative administration route for C1-inh.

Anaesthesia Management of a Patient with Hereditary Angioedema with Prophylactic Administration of C1 Esterase Inhibitor : Case Report and Literature Review

Hereditary angioedema (HAE) is a rare disorder caused by a deficiency of C1 esterase inhibitor. Minor trauma and emotional stress are the most common initiating events leading to contact system activation and excessive uncontrolled bradykinin release. This manifests as angioedema, a vascular reaction of the deeper layers of the skin and mucous membranes, with vasodilatation and increased permeability resulting in tissue swelling. Severe angioedema can occur in the perioperative period, leading to fatal airway obstruction. We describe the anaesthetic management of a child with HAE for dental rehabilitation and provide an review of the relevant literature.

Study of the effect of C1-esterase inhibitor administration to the sepsis pig model

Study of the effect of C1-esterase inhibitor administration to the sepsis pig model

Treatment response after repeated administration of C1 esterase inhibitor for successive acute hereditary angioedema attacks

Placebo-controlled studies established the efficacy of replacement therapy with C1 esterase inhibitor (C1-INH) concentrate for treating single acute hereditary angioedema (HAE) attacks, but only limited data from prospective studies are available on repeated treatment of successive HAE attacks. This study evaluates the association between repeated treatments with 20 U/kg of C1-INH concentrate (Berinert; CSL Behring, Marburg, Germany) for HAE attacks at any body location and treatment response. In a post hoc analysis of an open-label extension study (International Multicenter Prospective Angioedema C1-INH Trial [I.M.P.A.C.T.2]), the association between repeated treatment with C1-INH and times to onset of symptom relief and complete resolution of HAE symptoms was assessed in patients who were treated for at least 15 attacks by linear regression on the ordinal attack number. Eighteen patients received C1-INH concentrate for at least 15 HAE attacks over a mean duration of 34 months. Demographic and baseline characteristics of these patients were similar to those of all patients in the study. The distribution of body locations and the intensity of HAE attacks were similar for each of the first 15 attacks and subsequent attacks. The extent of previous use of C1-INH concentrate had no effect on the time to onset of symptom relief, the time to complete resolution of HAE symptoms, or the time between attacks treated with C1-INH concentrate; the median of individual linear regression coefficients was not statistically significantly different from 0. Treatment with 20 U/kg of C1-INH concentrate provided consistent treatment response in patients treated for multiple successive HAE attacks at any body location. (Clinicaltrials.gov identifier: NCT00292981).

C1-esterase inhibitor infusion increases survival rates for patients with sepsis*

Systemic inflammatory response variability displays differing degrees of organ damage and differing outcomes of sepsis. C1-esterase inhibitor, an endogenous acute-phase protein, regulates various inflammatory and anti-inflammatory pathways, including the kallikrein-kinin system and leukocyte activity. This study assesses the influence of high-dose C1-esterase inhibitor administration on systemic inflammatory response and survival in patients with sepsis. Open-label randomized controlled study. Surgical and medical intensive care units of nine university and city hospitals. : Sixty-one patients with sepsis. Patients were randomized to receive either 12,000 U of C1-esterase inhibitor infusions in addition to conventional treatment or conventional treatment only (n = 41 C1-esterase inhibitor, 20 controls). Blood samples for measurement of C1-esterase inhibitor, complement components C3 and C4, and C-reactive protein concentrations were drawn on days 1, 3, 5, 7, 10, and 28. Quartile analysis of C1-esterase inhibitor activity in sepsis subjects revealed that the lowest quartile subgroup had similar activity levels (0.7-1.2 U/L), when compared to healthy volunteers (p > .05). These normal-level C1-esterase inhibitor sepsis patients nevertheless displayed increased C-reactive protein (p = .04) production and higher likelihoods of a more severe sepsis (p = .001). Overall, infusion of C1-esterase inhibitor increased C1-esterase inhibitor (p < .005 vs. control on days 2, 3, and 5) functional activity, resulted in higher C3 levels (p < .05 vs. control on days 2 and 3), followed by decreased C-reactive protein (p < .05 vs. control on days 3 and 10). Simultaneously, C1-esterase inhibitor infusion in sepsis patients was associated with reduced all-cause mortality (12% vs. 45% in control, p = .008) as well as sepsis-related mortality (8% vs. 45% in control, p = .001) assessed over 28 days. The highest absolute reduction risk of 70% was achieved in sepsis patients with Simplified Acute Physiology Score II scores >27. In the present study, patients in the lowest quartile of C1-esterase inhibitor activity in combination with high C-reactive protein demonstrated a higher risk of developing severe sepsis. In general, high-dose C1-esterase inhibitor infusion down-regulated the systemic inflammatory response and was associated with improved survival rates in sepsis patients, which could have important treatment and survival implications for individuals with C1-esterase inhibitor functional deficiency.

549 Management of Twenty-Five Pediatric Patients with Hereditary Angioedema (Hae) Undergoing Home Treatment—A Clinical Surveillance Program

BackgroundHereditary angioedema (HAE) is a rare disorder characterized by C1 esterase inhibitor (C1-INH) deficiency. Clinically, HAE is characterized by relapsing episodes of edema at various body sites followed by disease-free intervals of variable duration. Episodes of upper airway obstruction (usually laryngeal edema) are potentially life-threatening and many patients died by asphyxiation in the families. In literature Longhurst et al, Buygun et al and Levi et al showed improvement of quality of life in patients with hereditary angioedema due to home treatment with C1-inhibitor-concentrate.MethodsWe investigated in a cohort study the integration of a clinical surveillance program into home treatment of pediatric patients suffering from hereditary angioedema. Parameters investigated were overall coping of the pediatric patient with home treatment, documentation of efficacy/safety of C1-INH concentrate (Berinertâ P, CSL Behring, Marburg), regular control of laboratory parameters (C1-inhibitor (INH) activity, C1-INH antigen, C4, hepatitis A, -B, -C-, HIV-1/2-, and parvovirus B19 serology) and quality of life parameters (hospitalization, absence from school).ResultsTwenty-five pediatric HAE patients (6 male, 19 female) have so far been investigated. Twenty-one patients suffer from HAE type I, 4 patients from HAE type II. Median age is 13.7 years (range: 2.8–17.4 years), first diagnosis of HAE took place at the median age of 5 years (range: 0.1–15.9 years) and first manifestation of HAE at the median age of 3.9 years (range: 0.3–11.7 years). Plasma C4 complement was reduced in nearly all patients (median: 2.4 mg/dL; range: <1.4–10 mg/dL) except one patient. All patients coped well with home treatment, compliance was excellent, clinical findings during regular medical control remained in the normal range and all parameters confirmed an improved quality of life, e.g., patients had not been hospitalized nor had they been absent from school. There were no adverse drug reactions due to administration of C1-INH concentrate.ConclusionsHome treatment might be also a valuable option for pediatric HAE patients not affecting compliance negatively and providing a significant positive impact on health-related quality of life.

The effect of C1-esterase inhibitor on systemic inflammation in trauma patients with a femur fracture - The CAESAR study: study protocol for a randomized controlled trial

BackgroundSystemic inflammation in response to a femur fracture and the additional fixation is associated with inflammatory complications, such as acute respiratory distress syndrome and multiple organ dysfunction syndrome. The injury itself, but also the additional procedure of femoral fixation induces a release of pro-inflammatory cytokines such as interleukin-6. This results in an aggravation of the initial systemic inflammatory response, and can cause an increased risk for the development of inflammatory complications. Recent studies have shown that administration of the serum protein C1-esterase inhibitor can significantly reduce the release of circulating pro-inflammatory cytokines in response to acute systemic inflammation.ObjectiveAttenuation of the surgery-induced additional systemic inflammatory response by perioperative treatment with C1-esterase inhibitor of trauma patients with a femur fracture.MethodsThe study is designed as a double-blind randomized placebo-controlled trial. Trauma patients with a femur fracture, Injury Severity Score ≥ 18 and age 18-80 years are included after obtaining informed consent. They are randomized for administration of 200 U/kg C1-esterase inhibitor intravenously or placebo (saline 0.9%) just before the start of the procedure of femoral fixation. The primary endpoint of the study is Δ interleukin-6, measured at t = 0, just before start of the femur fixation surgery and administration of C1-esterase inhibitor, and t = 6, 6 hours after administration of C1-esterase inhibitor and the femur fixation.ConclusionThis study intents to identify C1-esterase inhibitor as a safe and potent anti-inflammatory agent, that is capable of suppressing systemic inflammation in trauma patients. This might facilitate early total care procedures by lowering the risk of inflammation in response to the surgical intervention. This could result in increased functional outcomes and reduced health care related costs.Trial registrationclinicaltrials.gov NCT01275976 (January 12th 2011)