C1 Esterase Inhibitor Deficiency Research Articles

Angioedema in the emergency department: clinical presentation and outcomes

was significantly longer in patients with urticaria (p<0.001), but the presence of urticaria did not predict admission. A probable cause was identified in 48.8% of visits. Periorbital angioedema was associated with environmental, contact, and insect sting allergy (p<0.001). 58.3% of patients with angioedema due to drug allergy had lip angioedema (p=0.032). C1 esterase inhibitor deficiency was most frequently associated with a history of previous episodes. Several factors were found to predict admission, including NSAID-induced angioedema (OR=15.3), epinephrine treatment (OR=8.34), hypotension (OR=15.7), multiple site angioedema (OR=4.25), pharyngeal angioedema (OR=1.23), and tongue angioedema (OR=4.62). Conclusions This large cohort retrospective review confirms causeclinical associations in angioedema and demonstrates novel predictors of morbidity, with implications in clinical practice.

Angioedema secondary to angiotensin converting enzyme inhibitors is not due to C1 esterase inhibitor deficiency

Angioedema secondary to angiotensin converting enzyme inhibitors is not due to C1 esterase inhibitor deficiency

C1-esterase inhibitor deficiency in pediatric heart transplant recipients: incidence and findings on ultrasound

Acquired angioedema of the bowel caused by a deficiency of C1-esterase inhibitor can lead to severe abdominal pain with sudden onset, mimicking an acute surgical abdomen. In contrast to hereditary angioedema, which usually manifests in childhood, acquired angioedema is broadly recognized to affect people older than 40years. To determine the incidence of acquired angioedema in a cohort of pediatric heart transplant recipients and assess imaging findings on ultrasonography. A cohort of 207 children and adolescents who had undergone heart transplantation were assessed at regular follow-up examinations for incidence of acquired angioedema. All patients received ACE inhibitors and immune inhibitors. Control examinations carried out in 3-month intervals included history, assessment of clinical symptoms, physical examination, US of the abdomen and laboratory blood analysis. In addition, if clinical symptoms were newly encountered, children were admitted between regularly scheduled intervals. We analyzed results of abdominal US for pathological findings of the bowel, and we assessed imaging findings in children diagnosed with acquired angioedema. Acquired angioedema was diagnosed in 3/207 patients (2 girls ages 16 and 17years and 1 boy age 9months). These children presented with sudden onset of severe abdominal pain. The bowel wall was thickened in the presence of ascites. After a mean of 72h, abdominal pains resolved. Thickening of bowel loops dissolved and ascites disappeared. Single episodes of acquired angioedema were encountered in 1.4% of our series of pediatric heart transplant recipients. Radiologists should be familiar with this disease so they can diagnose it on US imaging.

Pharmacokinetics of plasma‐derived C1‐esterase inhibitor after subcutaneous versus intravenous administration in subjects with mild or moderate hereditary angioedema: the PASSION study

BackgroundHereditary angioedema (HAE) is a rare disease caused by C1-esterase inhibitor (C1-INH) deficiency, characterized by periodic attacks of acute edema affecting subcutaneous (SC) tissues and mucous membranes. Human C1-INH concentrate given intravenously (IV) is effective and safe, but venous access may be difficult. We compared SC and IV administration of human pasteurized C1-INH concentrate with respect to pharmacokinetics, pharmacodynamics, and safety.Study Design and MethodsThis was a prospective, randomized, open-label, crossover study. Twenty-four subjects with mild or moderate HAE were randomly assigned during an attack-free interval to receive 1000 units of human pasteurized C1-INH concentrate IV or SC. Plasma levels of C1-INH activity and antigen, C4 antigen, cleaved high-molecular-weight kininogen (clHK), and C1-INH antibodies were measured.ResultsThe mean relative bioavailability of functional C1-INH after SC administration was 39.7%. Maximum C1-INH activity after SC administration occurred within 48 hours and persisted longer than after IV administration. C4 antigen levels increased and clHK levels decreased after IV and SC administration, indicating the pharmacodynamic action of C1-INH. The mean half-life of functional C1-INH was 62 hours after IV administration and 120 hours after SC administration (p = 0.0595). C1-INH concentrate was safe and well tolerated when administered via both routes. As expected, SC administration resulted in a higher incidence of injection site reactions, all of which were mild.ConclusionWith a relative bioavailability of 39.7%, SC administration of human pasteurized C1-INH yields potentially clinically relevant and sustained plasma levels of C1-INH and is safe and well tolerated.

Nanofiltered C1 Esterase Inhibitor for Treatment of Laryngeal Attacks in Patients with Hereditary Angioedema

Laryngeal edema is a life-threatening manifestation of hereditary angioedema (HAE), an autosomal-dominant disorder caused by quantitative or functional C1 esterase inhibitor (C1 INH) deficiency. The preparation of nanofiltered C1 INH (C1 INH-nf) used in this study is indicated for routine prophylaxis against angioedema attacks in the United States and for treatment, preprocedure prevention, and routine prevention of HAE in Europe. The objective of this analysis was to evaluate the effectiveness and tolerability of C1 INH-nf when used for the treatment of laryngeal attacks. A post hoc analysis of an open-label treatment study evaluated the effectiveness of C1 INH-nf in the treatment of laryngeal attacks in patients with HAE. Outcomes included unequivocal or clinical relief rates and time from treatment to onset of relief. Data were compiled from this and three other studies for post hoc dosing and tolerability analyses. In all studies, C1 INH-nf at 1000 U was administered i.v., with a second 1000-U dose given after 60 minutes if indicated. In the open-label treatment study, 60 (50/84) and 77% (65/84) of attacks achieved unequivocal relief within 1 and 4 hours, respectively, after treatment. Time to unequivocal relief was shorter with prompt treatment. When C1 INH-nf was administered within 4 hours of symptom onset, clinical relief was achieved in 94% (45/48) of attacks within 4 hours after treatment. Of 265 attacks from the four studies, 62% received two 1000-U doses of C1 INH-nf. No serious adverse events occurring within 7 days after treatment were attributed to study drug, and only one patient required intubation after receiving C1 INH-nf (14.5 hours after symptom onset). This analysis supports that C1 INH-nf is an effective and well-tolerated therapy for laryngeal angioedema attacks.

Cardiac Surgery and C1-Inhibitor Deficiency

HEREDITARY ANGIOEDEMA (HAE) is a rare autosomal dominant disease (prevalence ≈ 1/100,000) caused by a deficiency in C1-esterase inhibitor (C1-inh) level (Type I HAE) or functional activity (Type II HAE).1–3 C1-inh regulates the activation of the classical complement pathway. In its absence, fraction C4 consumption occurs by autoactivation. C1-inh deficiency induces unregulated factor XII activation, which in turn activates the kallikrein-kinin system and plasmin. This results in excess bradykinin and increased capillary permeability with resultant local edema.

Ongoing Contact Activation in Patients with Hereditary Angioedema

Hereditary angioedema (HAE) is predominantly caused by a deficiency in C1 esterase inhibitor (C1INH) (HAE-C1INH). C1INH inhibits activated factor XII (FXIIa), activated factor XI (FXIa), and kallikrein. In HAE-C1INH patients the thrombotic risk is not increased even though activation of the contact system is poorly regulated. Therefore, we hypothesized that contact activation preferentially leads to kallikrein formation and less to activation of the coagulation cascade in HAE-C1INH patients. We measured the levels of C1INH in complex with activated contact factors in plasma samples of HAE-C1INH patients (N=30, 17 during remission and 13 during acute attack) and healthy controls (N=10). We did not detect differences in enzyme-inhibitor complexes between samples of controls, patients during remission and patients during an acute attack. Reconstitution with C1INH did not change this result. Next, we determined the potential to form enzyme-inhibitory complexes after complete in vitro activation of the plasma samples with a FXII trigger. In all samples, enzyme-C1INH levels increased after activation even in patients during an acute attack. However, the levels of FXIIa-C1INH, FXIa-C1INH and kallikrein-C1INH were at least 52% lower in samples taken during remission and 70% lower in samples taken during attack compared to samples from controls (p<0.05). Addition of C1INH after activation led to an increase in levels of FXIIa-C1INH and FXIa-C1INH (p<0.05), which were still lower than in controls (p<0.05), while the levels of kallikrein-C1INH did not change. These results are consistent with constitutive activation and attenuated depletion of the contact system and show that the ongoing activation of the contact system, which is present in HAE-C1INH patients both during remission and during acute attacks, is not associated with preferential generation of kallikrein over FXIa.

C1 esterase inhibitor deficiency and SLE: A case report and review of the literature

C1 esterase inhibitor deficiency and SLE: A case report and review of the literature

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.

Treatment with C1-esterase inhibitor concentrate in type I or II hereditary angioedema: a systematic literature review.

Hereditary angioedema (HAE) due to C1 esterase inhibitor (HAE-C1-INH) deficiency is a rare genetic disorder presenting with recurrent episodes of skin swellings, abdominal pain attacks, and potentially fatal laryngeal edema. This study was designed to review the efficacy and safety of pasteurized, human, plasma-derived C1-INH concentrate for the treatment of patients with HAE-C1-INH. A systematic search of electronic databases up to December 2011 was performed without language or date restrictions. Two reviewers completed the study selection using predefined inclusion criteria, tabulated, and analyzed the data. The data were inappropriate for meta-analysis; thus, a qualitative synthesis was performed. We identified 89 studies (≍2000 patients) that investigated C1-INH. Replacement therapy with C1-INH significantly shortened time to onset of symptom relief in HAE attacks compared with placebo in a randomized controlled trial, and similar improvements were consistently reported in observational and descriptive studies, accompanied by improvements in patients' quality of life. C1-INH has been shown to be effective for patients receiving home therapy and short- and long-term prophylaxis. Treatment with C1-INH was generally well tolerated. Administration of C1-INH was not associated with transmission of viruses or development of autoantibodies irrespective of treatment duration. This research provides additional confirmation of the efficacy of C1-INH in the treatment and prevention of HAE attacks. C1-INH is generally safe and well tolerated and has an excellent safety record for over 25 years of clinical use.

Cysteine Proteinase from Streptococcus pyogenes Enables Evasion of Innate Immunity via Degradation of Complement Factors

Streptococcus pyogenes is an important human pathogen that causes invasive diseases such as necrotizing fasciitis, sepsis, and streptococcal toxic shock syndrome. We investigated the function of a major cysteine protease from S. pyogenes that affects the amount of C1-esterase inhibitor (C1-INH) and other complement factors and aimed to elucidate the mechanism involved in occurrence of streptococcal toxic shock syndrome from the aspect of the complement system. First, we revealed that culture supernatant of a given S. pyogenes strain and recombinant SpeB degraded the C1-INH. Then, we determined the N-terminal sequence of the C1-INH fragment degraded by recombinant SpeB. Interestingly, the region containing one of the identified cleavage sites is not present in patients with C1-INH deficiency. Scanning electron microscopy of the speB mutant incubated in human serum showed the abnormal superficial architecture and irregular oval structure. Furthermore, unlike the wild-type strain, that mutant strain showed lower survival capacity than normal as compared with heat-inactivated serum, whereas it had a significantly higher survival rate in serum without the C1-INH than in normal serum. Also, SpeB degraded multiple complement factors and the membrane attack complex. Flow cytometric analyses revealed deposition of C9, one of the components of membrane the attack complex, in greater amounts on the surface of the speB mutant, whereas lower amounts of C9 were bound to the wild-type strain surface. These results suggest that SpeB can interrupt the human complement system via degrading the C1-INH, thus enabling S. pyogenes to evade eradication in a hostile environment.

Inhibition of Vascular Permeability by Antisense-Mediated Inhibition of Plasma Kallikrein and Coagulation Factor 12

Hereditary angioedema (HAE) is a rare disorder characterized by recurrent, acute, and painful episodes of swelling involving multiple tissues. Deficiency or malfunction of the serine protease inhibitor C1 esterase inhibitor (C1-INH) results in HAE types 1 and 2, respectively, whereas mutations in coagulation factor 12 (f12) have been associated with HAE type 3. C1-INH is the primary inhibitor of multiple plasma cascade pathways known to be altered in HAE patients, including the complement, fibrinolytic, coagulation, and kinin-kallikrein pathways. We have selectively inhibited several components of both the kinin-kallikrein system and the coagulation cascades with potent and selective antisense oligonucleotides (ASOs) to investigate their relative contributions to vascular permeability. We have also developed ASO inhibitors of C1-INH and characterized their effects on vascular permeability in mice as an inducible model of HAE. Our studies demonstrate that ASO-mediated reduction in C1-INH plasma levels results in increased vascular permeability and that inhibition of proteases of the kinin-kallikrein system, either f12 or prekallikrein (PKK) reverse the effects of C1-INH depletion with similar effects on both basal and angiotensin converting enzyme (ACE) inhibitor-induced permeability. In contrast, inhibition of coagulation factors 11 (f11) or 7 (f7) had no effect. These results suggest that the vascular defects observed in C1-INH deficiency are dependent on the kinin-kallikrein system proteases f12 and PKK, and not mediated through the coagulation pathways. In addition, our results highlight a novel therapeutic modality that can potentially be employed prophylactically to prevent attacks in HAE patients.

Administration of Conestat Alfa, Human C1 Esterase Inhibitor and Icatibant in the Treatment of Acute Angioedema Attacks in Adults with Hereditary Angioedema Due to C1 Esterase Inhibitor Deficiency. Treatment Comparison Based on Systematic Review Results

Introduction: Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH) and icatibant in the treatment of acute angioedema attacks in adults with HAE. Materials and methods: A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate or synonyms OR icatibant). Only randomized clinical studies were selected. Results: Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in a shorter time to the start of symptom relief and the time to reduce symptoms, the probability of treatment response after 4 hours is increased and the safety profile is comparable to placebo. Conclusions: Due to the significant heterogeneity of the identified trials, the scientific evidence available was insufficient to identify the most effective therapeutic option in the treatment of acute oedemas in HAE.

Social costs of icatibant self-administration vs. health professional-administration in the treatment of hereditary angioedema in Spain

BackgroundIcatibant is the only subcutaneous treatment for acute Type I and Type II hereditary angioedema with C1-esterase inhibitor deficiency (HAE-C1-INH) licensed for self-administration in Europe.AimTo compare the economic impact of two icatibant administration strategies: health professional-administration only (strategy 1) versus including the patient self-administration option (strategy 2).MethodsEconomic evaluation model based on the building of a decision tree. Both strategies are assumed to have equivalent effectiveness. The payer (Spanish National Health System) and the social perspectives were considered. All relevant cost-generating factors were taken into account. The time horizon was one year. Sources of information included scientific evidence, official data and experts’ opinion. A deterministic sensitivity analysis was carried out to quantify the underlying uncertainty in the model.ResultsFrom the social perspective, which considers both direct (health care costs) and indirect costs (productivity losses), strategy 2 would result into average savings of €121.30 per acute attack compared to strategy 1. For Spain, this would achieve in an annual savings of €551,371. The reduction in direct costs accounts for 74% of the savings and lower indirect costs account for the remaining 26%. Savings per acute attack may range from €79.50 to €169.80; accordingly, the annual savings in Spain may vary between €90,319 and €2,315,360.ConclusionCosts related to the management of acute HAE attacks with C1 inhibitor deficiency may be substantially reduced through interventions targeting home treatment by training patients to self-administer icatibant.

Ecallantide for treatment of acute attacks of acquired C1 esterase inhibitor deficiency

Acquired C1 inhibitor (C1-INH) deficiency exposes patients to angioedema recurrences (acquired angioedema [AAE]) mediated by bradykinin pathway activation. C1-INH replacement and specific inhibition of plasma kallikrein with ecallantide have been successful in the treatment of hereditary angioedema (HAE), a more common related disorder. C1-INH replacement has also been used in the treatment of AAE, but because of the underlying mechanism of rapid catabolism, some patients may not respond. As part of preclinical investigation of ecallantide, a potent bradykinin pathway inhibitor, we evaluated three AAE patients treated successfully with that agent. This study was designed to assess ecallantide for treatment of attacks in AAE. Three patients with AAE were treated a total of 12 times with various dosing regimens of ecallantide based on the protocols established for the studies using ecallantide in HAE (Evaluation of DX-88's Effects in Mitigating Angioedema trials). Response to therapy was also based on outcome measures determined by these protocols. Ecallantide effectively relieved symptoms in three patients with various manifestations of AAE over 12 acute episodes. Kallikrein inhibition with ecallantide appears effective in the treatment of AAE and may be an alternative for patients with resistance to C1-INH replacement therapy.

A unique case of delayed diagnosis of early onset acquired angioedema

Abstract Acquired angioedema (AAE) is a very rare condition caused by an acquired deficiency in C1 esterase inhibitor (C1 INH). Pathogenesis of AAE can entail abnormal B cell lymphoproliferation ranging from benign monoclonal gammopathy

C1-Esterase Inhibitor: Biological Activities and Therapeutic Applications

Human C1-esterase inhibitor (C1-INH) is a unique anti-inflammatory multifunctional plasma protein best known for its key role in regulation of the classical complement pathway, contact activation system and intrinsic pathway of coagulation. By sequence homology and mechanism of protease inhibition it belongs to the serine proteinase inhibitor (serpin) superfamily. However, in addition to its inhibitory capacities for several proteases, it also exhibits a broad spectrum of non-inhibitory biological activities. C1-INH plays a key role in the regulation of vascular permeability, best demonstrated in Hereditary Angioedema (HAE) which is triggered by the deficiency of functional C1-INH in plasma? Since 1963, when the link between HAE and C1-INH was first identified, considerable progress has been made in the investigation of C1-INH structure and biological activities, understanding its therapeutic potential, and in the research and development of C1-INH-based therapies for the treatment of HAE and several other clinical conditions. However, augmentation therapy with C1-INH concentrates for patients with HAE is currently the only approved therapeutic application of C1-INH. This manuscript provides an overview of the structure and functions of human C1-INH, its role in HAE, summarizes published data available for recently approved C1-INH therapeutic products, and considers possible use of C1-INH for other applications.

Post partum flare in a patient with hereditary angioedema

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder due to dysfunctional or deficiency of C1 esterase inhibitor (C1INH). This leads to episodic subcutaneous and submucosal oedema involving the upper respiratory and gastrointestinal tracts which can be life threatening. Stress and trauma are known to trigger angioedema attack1. As a result of hormonal changes in pregnancy some women may experience increase angioedema attacks. This is a case report of a 34 year old woman who developed life threatening post partum complications with a background history of HAE. DOI: <a href="http://dx.doi.org/10.4038/sljog.v33i4.4806">http://dx.doi.org/10.4038/sljog.v33i4.4806</a> <em>Sri Lanka Journal of Obstetrics and Gynaecology </em>2011; <strong>33</strong>: 166-167

A Case of Hereditary Angioedema in a 7-Year-Old Korean Girl

Hereditary angioedema (HAE) is a rare autosomal dominant disease that usually occurs in adolescence and early adulthood. It is characterized by recurrent non-pitting edema involving the skin and intestinal tract, especially the extremities and face. It is not associated with urticaria and pruritus. The cause is known to be the deficiency of C1 inhibitor. We herein report a 7-year-old girl with HAE who had recurrent episodes of swelling of the extremities and face without urticaria and pruritus. Her great grandmother had suffered from the same symptoms. The level of serum C4 was 8.01 mg/dL (normal: 10-40 mg/dL). The level of C1 inhibitor was 5.0 mg/dL (normal: 18-40 mg/dL). To our knowledge, this is the first pediatric case with typical clinical symptoms of HAE and C1 esterase inhibitor deficiency in Korea.

Efficacy Assessments in Randomized Controlled Studies of Acute Therapy for Hereditary Angioedema

Hereditary angioedema (HAE) is a rare disorder caused by a deficiency of C1 esterase inhibitor, characterized by recurrent, highly variable attacks of subcutaneous or submucosal edema that may affect multiple body sites. Clinical studies of acute HAE therapies have required the use of assessment tools to evaluate both pretreatment attack severity (baseline severity) and changes in symptom severity following treatment (treatment response). This article reviews the range of assessment tools used for efficacy determination of acute HAE therapies, based on a review of relevant clinical studies. Because the goal is relief of symptoms (rather than cure), patient-reported outcomes (PROs) form the basis of these tools. Tools used to evaluate baseline severity typically employ location-specific assessment of symptom severity, using either categorical descriptions (which may be converted into numerical variables) or a visual analog scale (VAS). Some studies define the initial or most symptomatic site as an "index" site for purposes of efficacy determination, while others (such as the Mean Symptom Complex Severity score used in clinical studies of ecallantide) use a composite score that reflects all sites. Assessment of treatment response typically employs the same tool(s) to evaluate baseline severity, and may be either time-based (e.g., time to achievement of minimal or no symptoms) or symptom-based (e.g., degree of symptom relief at predetermined time points). Although it is unlikely that therapies will be compared using identical assessment tools, prospective or retrospective validation ensures the adequacy and relevance of such tools, which should be taken into consideration when therapies are compared.