Medical Literature - 2009

Szema AM, Paz G, Merriam L, Stellaccio F, Jen J 5/2009 Allergy & Asthma Proceedings

Hereditary angioedema (HAE), deficiency of C1 esterase inhibitor, poses a risk of airway compromise during trauma, including surgery, due to activation of the complement cascade. Classical surgical management includes emergent/slash tracheostomy and cricothyrotomy, associated with high complication rates. We provide here an evidence-based review of available medical literature to construct guidelines for managing patients with HAE pre- and intra-operatively. We also describe our experience with a patient for whom we cared using these guidelines. Our objective was to explain new preventive measures to prevent airway compromise in HAE and their level of evidence for averting potential therapeutic misadventure. We analyzed PUBMED literature regarding airway management and etiology of angioedema and its prevention, followed by application of guidelines based on these data in a patient with HAE undergoing inguinal hernia repair. An analysis of contemporary literature yielded key points: (1) using a Cook Exchange catheter to facilitate re-intubation, (2) measuring cuff leak pressure to verify whether airway pressure had increased during surgery, (3) visualizing the airway directly using a fiberoptic laryngoscope connected to a digital flat-screen monitor for real-time assessment, (4) following conventional dictum to double stanozolol dosages 2 weeks before admission, (5) administering fresh frozen plasma pre- and intraoperatively, and (6) preparing recombinant C1 esterase inhibitor for instantaneous intraoperative use; and using FDA-approved human-derived C1-esterase inhibitor prophylactically. Biotechnology in the form of novel but currently available and in-practice medical devices, as well as new therapeutic agents, have expanded the armamentarium for safely managing patients with HAE pre- and intraoperatively. [References: 9].

May-Jun;30(3):338-342

Available online at: ingentaconnect.com/content/ocean/aap/2009/00000030/00000003/art00016

Kreuz W, Martinez-Saguer I, Aygoren-Pursun E, Rusicke E, Heller C, Klingebiel T 9/2009 Transfusion

BACKGROUND: Hereditary angioedema (HAE) caused by functional deficiency of C1-inhibitor (C1-INH) is a rare disease that manifests with recurrent spontaneous nonallergic edema of the subcutaneous tissues and mucous membranes. In cases of laryngeal edema that are not treated immediately, HAE is associated with high mortality rates. Attenuated androgens (e.g., danazol) are usually administered for prophylaxis, but associated side effects may limit their use. This study investigated the efficacy, safety, and quality of life (QoL) associated with a pasteurized plasma-derived C1-inhibitor (pC1-INH) concentrate for individual replacement therapy (IRT) in patients with severe HAE suffering from frequent attacks who were intolerant or not responding to danazol.

STUDY DESIGN AND METHODS: Twenty-two patients with severe HAE and danazol incompatibility or insufficient efficacy of danazol were recruited. Intraindividual comparisons of efficacy, safety, and QoL with pC1-INH concentrate IRT versus danazol treatment were made using retrospective and prospective patient data. Pharmacokinetic data were collected for 15 of the 22 patients.

RESULTS: In patients receiving pC1-INH regularly, the median number of attacks per year decreased significantly compared to danazol prophylaxis (p < 0.001), and the 24 laryngeal edema episodes per year ceased. Superior efficacy of pC1-INH was found for all QoL variables (e.g., general condition, social activities). No transmission of human immunodeficiency virus or hepatitis A, B, or C was observed.

CONCLUSION: In patients with severe HAE who experience severe side effects and/or lack of efficacy of danazol prophylaxis, very early substitution with pC1-INH can completely abolish the incidence of potentially fatal laryngeal edema and can reduce the incidence of acute attacks.

Sep;49(9):1987-1995

Available online at: onlinelibrary.wiley.com/doi/10.1111/j.1537-2995.2009.02230.x/full (small fee)

Weis M 11/2009 Postgrad.Med.

Hereditary angioedema (HAE) is caused by a deficiency in C1 esterase inhibitor and is characterized by sudden attacks of edema associated with discomfort and pain. The disease places patients at risk for disability and death if left untreated. Symptom severity and frequency can be extremely variable even among affected members of the same family. Attacks are not associated with inflammation or allergy, with most occurring secondary to trauma or stress. Swelling can affect any part of the body or multiple sites at once. Commonly affected areas include the extremities, genitalia, trunk, gastrointestinal tract, face, and larynx. Swelling typically worsens over 24 to 36 hours and resolves within 48 hours in less severe cases. Attacks result in 15,000 to 30,000 emergency department visits each year. Many of these emergency cases will undergo unnecessary surgeries or medical procedures due to misdiagnosis. The hallmarks of HAE–recurrent episodes of swelling without urticaria, a family history of HAE, first attack in childhood, and worsening at puberty–can be identified by a thorough family history, and the diagnosis can be confirmed by laboratory studies. Nevertheless, diagnosis may be delayed by 2 decades. We review available therapies and clinical characteristics that will both help clinicians diagnose HAE and distinguish among emergencies and nonemergency cases. [References: 27].

Nov;121(6):113-120

Available online at: tandfonline.com/doi/abs/10.3810/pgm.2009.11.2071 (small fee)

Craig TJ, Levy RJ, Wasserman RL, Bewtra AK, Hurewitz D, Obtulowicz K, et al 10/2009 Journal of Allergy & Clinical Immunology

BACKGROUND: Hereditary angioedema caused by C1 esterase inhibitor deficiency is a rare disorder.

OBJECTIVE: To compare the efficacy of pasteurized C1 esterase inhibitor concentrate (Berinert, CSL Behring) at intravenous doses of 10 or 20 U/kg body weight with placebo in the treatment of single, acute abdominal or facial attacks in patients with hereditary angioedema.

METHODS: This was a randomized, double-blind, placebo-controlled study in 125 patients with type I or II hereditary angioedema. The primary outcome was time from start of treatment to onset of symptom relief. Secondary outcomes were time to complete resolution, proportion of patients with worsened intensity of angioedema symptoms between 2 and 4hours after treatment, and number of vomiting episodes within 4 hours.

RESULTS: Median time to onset of relief was significantly shorter with C1 esterase inhibitor concentrate at a dose of 20 U/kg than with placebo (0.5 vs 1.5 hours; P = .0025), whereas with 10 U/kg, the time to onset of relief was only slightly shorter than with placebo (1.2 vs 1.5 hours; P = .2731). Compared with placebo, the reduction in time to onset of relief was greatest for severe attacks (0.5 vs 13.5 hours). The secondary outcomes consistently supported the efficacy of the 20 U/kg dose. C1 esterase inhibitor concentrate was safe and well tolerated. No seroconversions were observed for HIV, hepatitis virus, or human B19 virus.

CONCLUSION: C1 esterase inhibitor concentrate given intravenously at a dose of 20 U/kg is an effective and safe treatment for acute abdominal and facial attacks in patients with hereditary angioedema, with a rapid onset of relief.

Oct;124(4):801-808

Available online at: jacionline.org/article/S0091-6749%2809%2901085-9/fulltext

Chinniah N, Katelaris CH 2/2009 Australian and New Zealand Journal of Obstetrics and Gynaecology (Aust.N.Z.J.Obstet.Gynaecol.)

BACKGROUND: Hereditary angioedema (HAE) is an autosomal dominant disease caused by a quantitative or functional defect in C1-esterase inhibitor (C1-INH). Patients with this deficiency present with episodes of angioedema which can be life-threatening. Studies examining HAE and pregnancy are scarce with little known about the interrelationship between the two.

OBJECTIVE: To examine the effect, and evaluate the clinical manifestations of HAE in pregnancy using retrospective interviews of affected women.

METHODS: Women with HAE who have undergone one of more pregnancies were identified throughout Australia using the national Australasian Society of Clinical Immunology and Allergy immunodeficiency database. Following informed consent, identified women were interviewed regarding their HAE status during pregnancy and the perinatal period using a questionnaire.

RESULTS: Seven women with a total of 16 pregnancies were identified. During the first trimester of pregnancy, more than ten attacks of angioedema were experienced in six of 16 pregnancies. During the second trimester only in three of 16 pregnancies did women experience greater than ten attacks. During the post-partum period, four of seven women experienced increased frequency and severity of attacks as compared to the pre-pregnancy state. For two of four patients, this impacted on their breast-feeding routine.

CONCLUSION: Our study showed that women with HAE have greatly reduced or absent attacks in the last two trimesters of pregnancy, although, during the post-partum period, the majority of women experienced increased frequency and severity of attacks.

Feb;49(1):2-5

Available online at: onlinelibrary.wiley.com/doi/10.1111/j.1479-828X.2008.00945.x/full (small fee)

Bork K, Wulff K, Hardt J, Witzke G, Staubach P 7/2009 Journal of Allergy & Clinical Immunology

BACKGROUND: Hereditary angioedema caused by mutations in the factor XII gene is a recently described disease entity that occurs mainly in women. It differs from hereditary angioedema caused by C1 inhibitor deficiency.

OBJECTIVE: To assess the clinical symptoms, factors triggering acute attacks, and treatments of this disease.

METHODS: Thirty-five female patients with hereditary angioedema and the factor XII mutations p.Thr309Lys and p.Thr309Arg who came from 13 unrelated families were studied. The observation period was 8.4 years on average (range, 2-26 years).

RESULTS: Patients had on average 12.7 +/- 7.9 angioedema attacks per year. Recurrent facial swellings occurred in all patients; skin swellings other than facial, abdominal pain attacks, tongue swellings, and laryngeal edema occurred less frequently. Some factors that triggered angioedema attacks were trauma, physical pressure, and emotional stress. Clinical symptoms started mainly after intake of oral contraceptives (17 women) or pregnancy (3 women). Exacerbation of the symptoms occurred after oral contraceptive use (8 women), pregnancy (7 women), hormone replacement therapy (3 women), intake of angiotensin-converting enzyme inhibitors (2 women), and an angiotensin 1 receptor blocker (1 woman). Effective treatments included C1 inhibitor concentrate for angioedema attacks (6 women) and, for prophylaxis, progesterone (8 women), danazol (2 women), and tranexamic acid (1 woman). No difference between mutation p.Thr309Arg and p.Thr309Lys was found.

CONCLUSIONS: Facial swelling is a cardinal symptom of this condition. Estrogens may have a great influence, but this influence is highly variable. Various treatment options are available.

Jul;124(1):129-134

Available online at: jacionline.org/article/S0091-6749%2809%2900548-X/fulltext?refuid=S1081-1206%2810%2960369-9&refissn=1081-1206&mobileUi=0

Bork K 7/2009 Current Allergy & Asthma Reports

Until recently, it was assumed that hereditary angioedema was a disease resulting exclusively from a genetic deficiency of the C1 inhibitor. In 2000, families with hereditary angioedema, normal C1 inhibitor activity, and protein in plasma were described. Since then, numerous patients and families with this condition have been reported. Most of the patients were women. In many of the affected women, oral contraceptives, hormone replacement therapy containing estrogens, and pregnancies triggered the clinical symptoms. In some families, mutations in the coagulation factor XII (Hageman factor) gene were detected in the affected persons.

Jul;9(4):280-285

Available online at: amjmed.com/article/S0002-9343%2807%2900802-9/abstract (small fee)

Bork K, Hardt J 8/2009 Am.J.Med.

OBJECTIVE: C1 inhibitor concentrate is regarded as effective and safe in treating acute attacks of hereditary angioedema caused by C1 inhibitor deficiency. This study investigated the course of disease in 3 women treated frequently with C1 inhibitor concentrate.

METHODS: Three women are described who received C1 inhibitor concentrate for the treatment of acute attacks of hereditary angioedema and experienced an increase in the frequency of attacks during that treatment period. In a control group of 24 patients aged more than 60 years with hereditary angioedema, the natural course of disease was determined.

RESULTS: The 3 women (ages 50, 69, and 72 years) had received C1 inhibitor concentrate for 27, 18, and 22 years, respectively, for acute abdominal and skin attacks. Before this treatment, all attacks were severe. The treatment was always effective: The attacks were mild, and the duration of the attacks was shortened. During the treatment period, the number of attacks increased slowly but continuously, starting at the onset of treatment and paralleling the course of treatment. At the end of the observation period, the number of attacks increased by 4-fold, 12-fold, and 5-fold in the 3 women, respectively. No factors known to increase the frequency of attacks in hereditary angioedema were found in these patients. The control group did not show a similar increase in attacks during a comparable period of time.

CONCLUSION: A possible explanation for the increase in the frequency of attacks may lie in the large number of injections of C1 inhibitor concentrate.

Aug;122(8):780-783

Available online at: amjmed.com/article/S0002-9343%2809%2900406-9/pdf (small fee)

Keating GM /2009 Biodrugs

Human C1-esterase inhibitor concentrate (C1-INH concentrate) is derived from human plasma and is indicated for the treatment of acute episodes of hereditary angioedema. Intravenous C1-INH concentrate provided rapid symptom relief in patients with acute abdominal or facial episodes associated with type I or II hereditary angioedema, according to the results of the randomized, double-blind, multicenter, placebo-controlled IMPACT-1 trial. The median time to the onset of symptom relief was significantly shorter with C1-INH concentrate 20 U/kg than with placebo (0.5 vs 1.5 hours). A subsequent noncomparative extension trial (IMPACT-2) showed the ongoing efficacy of ‘on-demand’ treatment with C1-INH concentrate; overall, the onset of symptom relief occurred in a median 30 minutes. Several additional studies demonstrated the efficacy of intravenous C1-INH concentrate in patients with laryngeal edema, skin swellings, or abdominal episodes associated with type I or II hereditary angioedema. Self-administered home therapy with intravenous C1-INH concentrate significantly improved health-related quality of life in patients with hereditary angioedema. Dermatology Life Quality Index and Short Form 36-item Health Survey scores were significantly improved from baseline by self-administered home therapy with C1-INH concentrate. Intravenous C1-INH concentrate was well tolerated in patients with hereditary angioedema, with no confirmed cases of viral transmission. [References: 28].

23(6):399-406

Available online at: link.springer.com/article/10.2165%2F11201100-000000000-00000 (small fee)

Gras J 12/2009 Drugs of Today

Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening disease, characterized by recurrent self-limiting bouts of edema mainly involving the extremities, genitalia, face, intestines and airways. The prevalence of HAE in the general population has been estimated to be in the range of 1:10,000 to 1:150,000. Currently, acute attacks of HAE are treated mainly symptomatically, with poor outcomes. Recently, it has been demonstrated that bradykinin (BK) is responsible for most of the symptoms of HAE. Icatibant (Firazyr, HOE 140, JE049) is a potent, specific and selective B2 BK receptor antagonist that has recently been approved by the EMEA for the treatment of HAE. In phase III clinical trials, 30 mg of subcutaneous icatibant demonstrated rapid and stable relief from symptoms in cutaneous, abdominal or laryngeal HAE attacks. Local site reactions after subcutaneous injection of icatibant were observed, however, these reactions were mild to moderate in severity and resolved spontaneously and quickly. Icatibant is a new, safe and effective treatment for acute attacks of HAE.Copyright 2009 Prous Science, S.A.U. or its licensors. All rights reserved. [References: 69].

Dec;45(12):855-864

Available online at: journals.prous.com/journals/servlet/xmlxsl/pk_journals.xml_summaryn_pr?p_JournalId=4&p_RefId=1424267 (small fee)

Hussar DA 6/2009 Nursing

In this article, you’ll learn about six new drugs, including:

• clevidipine, an I.V. antihypertensive for use when oral medication isn’t feasible
• romiplostim and eltrombopag olamine, new agents for chronic immune thrombocytopenic purpura
• C1 inhibitor (human) for hereditary angioedema.

Unless otherwise specified, the information in the following summaries applies to adults, not children. Consult the package insert for information about each drug’s safety during pregnancy and breast-feeding. Also consult a pharmacist, the package insert, or a comprehensive drug reference for more details on precautions, drug interactions, and adverse reactions* for all these drugs

Jun;39(6):33-39

Available online at: journals.lww.com/psnjournalonline/pages/articleviewer.aspx?year=2009&issue=10000&article=00014&type=abstract (small fee)

Bossi F, Fischetti F, Regoli D, Durigutto P, Frossi B, Gobeil F Jr, et al 12/2009 Journal of Allergy & Clinical Immunology

BACKGROUND: Activation of bradykinin-mediated B2 receptor has been shown to play an important role in the onset of angioedema associated with C1 inhibitor deficiency. This finding has led to the development of novel therapeutic drugs such as the B2 receptor antagonist icatibant. However, it is unclear whether other receptors expressed on endothelial cells contribute to the release of kinins and vascular leakage in these patients. The recognition of their role may have obvious therapeutic implications.

OBJECTIVE: Our aim was to investigate the involvement of B1 and gC1q receptors in in vitro and in vivo models of vascular leakage induced by plasma samples obtained from patients with C1 inhibitor deficiency.

METHODS: The vascular leakage was evaluated in vitro on endothelial cells by a transwell model system and in vivo on rat mesentery microvessels by intravital microscopy.

RESULTS: We observed that the attack phase plasma from C1 inhibitor-deficient patients caused a delayed fluorescein-labeled albumin leakage as opposed to the rapid effect of bradykinin, whereas remission plasma elicited a modest effect compared with control plasma. The plasma permeabilizing effect was prevented by blocking the gC1q receptor-high-molecular-weight kininogen interaction, was partially inhibited by B2 receptor or B1 receptor antagonists, and was totally prevented by the mixture of the 2 antagonists. Involvement of B1 receptor was supported by the finding that albumin leakage caused by attack phase plasma was enhanced by IL-1beta and was markedly reduced by brefeldin A.

CONCLUSION: Our data suggest that both B1 receptor and gC1q receptor are involved in the vascular leakage induced by hereditary and acquired angioedema plasma.

Dec;124(6):1303-10.e4

Available online at: europepmc.org/articles/PMC2798851;jsessionid=6al6ZU49LschTHx0ZtAX.0

Vernon MK, Rentz AM, Wyrwich KW, White MV, Grienenberger A 9/2009 Quality of Life Research

PURPOSE: Hereditary angioedema (HAE) is a rare disorder characterized by highly variable, acute attacks of swelling at various anatomical locations. Clinical measures do not adequately assess the diversity of symptoms characteristic of an attack. Two disease-specific, patient-reported outcome measures were developed to comprehensively capture symptom severity and change: the Treatment Outcome Score (TOS) and the Mean Symptom Complex Severity (MSCS) score.

METHODS: This study comprised a secondary analysis of pooled data from a randomized controlled trial to evaluate the psychometric properties, including reliability and validity, and minimally important difference (MID) of the TOS and MSCS score.

RESULTS: HAE patients (n = 73) had a mean age of 33 years, and 60% were female. Test-retest evaluation demonstrated moderate to substantial agreement (ICCs = 0.53 for TOS; 0.62 for MSCS score). The TOS and change in MSCS score were moderately to highly correlated with a Global Improvement Measure at 4 h (TOS: r = 0.90; MSCS: r = -0.59). Anchor- and distribution-based analyses suggested that conservative estimates for MID are 30 points for TOS and -0.30 points for 4-h change in MSCS score.

CONCLUSIONS: The psychometric tests performed here provide evidence of the reliability and validity of the TOS and MSCS for evaluating symptom severity and change in HAE patients. The TOS and MSCS score provide an example of measurement methodology that may be used to precisely capture symptom severity and change in a disease characterized by acute attacks.

Sep;18(7):929-939

Available online at: link.springer.com/article/10.1007%2Fs11136-009-9509-8 (small fee)

Bygum A, Andersen KE, Mikkelsen CS 3/2009 European Journal of Dermatology

Hereditary angioedema (HAE) is often debilitating with a serious effect on quality of life (QOL). Treatment of acute HAE attacks is usually with C1 esterase inhibitor (C1-INH) concentrates; however, treatment can be delayed by patients’ travel time for attending emergency units. We assessed the impact of self-administered home therapy with intravenous C1-INH concentrate on QOL in patients with HAE. Nine patients experiencing frequent or severe debilitating HAE attacks were offered self-administration of C1-INH concentrate. QOL was assessed prior to and following home therapy using the Dermatology Life Quality Index (DLQI) and 36-Item Short Form Survey (SF-36) questionnaires. Seven patients were recruited into the study. QOL was assessed at baseline and after 3 to 48 months of home therapy. The mean DLQI score fell from 12.6 +/- 4.65 to 2.7 +/- 1.38 (P < 0.001). Mean SF-36 scores for the individual and combined components also improved significantly. No serious complications were documented during a follow-up period of 27 to 72 months. Self-administration of C1-INH improved QOL on both physical and psychological parameters. Patients were able to resume a normal life without restrictions caused by the condition.

Mar-Apr;19(2):147-151

Available online at: researchgate.net/publication/24180431_Self-administration_of_intravenous_C1-inhibitor_therapy_for_hereditary_angioedema_and_associated_quality_of_life_benefits

Christiansen SC, Zuraw BL 9/2009 Allergy & Asthma Proceedings

Remarkable progress has been made in understanding the molecular mechanisms underlying attacks of swelling in hereditary angioedema (HAE). Treatment options in the United States for this potentially life-threatening disease had remained essentially static, however, over the past 40 years. Prophylactic therapy had relied on attenuated androgens or antifibrinolytic agents. Although demonstrably effective, these drugs have been fraught with side effects. Acute therapy has been largely relegated to supportive care. In this article we discuss emerging treatments that have evolved from the recognition that kinin generation is the fundamental abnormality leading to attacks of angioedema. We will review the newly approved replacement therapy for prophylaxis of HAE attacks with C1 inhibitor (C1INH). Potential options for the acute treatment of HAE will be discussed including purified C1INH, recombinant C1INH, an inhibitor of plasma kallikrein, and a B2-receptor antagonist. The arrival of these novel therapies promises to transform the future management of HAE. [References: 44].

Sep-Oct;30(5):500-505

Available online at: ingentaconnect.com/content/ocean/aap/2009/00000030/00000005/art00006 (small fee)

Pedrosa M, Caballero T, Gomez-Traseira C, Olveira A, Lopez-Serrano C 6/2009 Annals of Allergy, Asthma, & Immunology

BACKGROUND: Hereditary angioedema (HAE) is caused by the deficiency of functional C1 inhibitor. Symptoms of this disease include cutaneous angioedema, abdominal pain, and even laryngeal edema.

OBJECTIVE: To evaluate the usefulness of abdominal ultrasonography in patients with hereditary C1-inhibitor deficiency in diagnosing acute abdominal edema attacks and possible adverse effects of long-term prophylaxis with attenuated androgens.

METHODS: Fifty-nine adult patients with HAE regularly observed in our department were included whether they were symptomatic or not and whether they received long-term androgen prophylaxis or not. We evaluated the ultrasonographic findings in the assessments performed routinely or in the moment of an acute abdominal attack.

RESULTS: Of the 59 patients, 55 ever had any symptom due to HAE (abdominal location, 78% of the symptomatic patients); 4 patients were asymptomatic. In 11 cases, ultrasonography was performed during acute attacks. Ascites and intestinal wall swelling were found in 7 of these 11 cases and, thus, diagnosis was confirmed. Of the 59 patients, 33 were or had been receiving androgen prophylaxis. Abdominal ultrasonographic assessments were performed routinely in 31 of these patients. Four cases of angiomas, 4 of steatosis, and 1 each of portal hypertension, hepatic cysts, and hepatomegaly were found. Assessments were also performed in 17 patients who did not receive androgen prophylaxis; there were no findings in any of these patients.

CONCLUSION: Abdominal ultrasonography has been proved useful as an early tool for diagnosing the adverse effects of therapy and for confirming diagnosis in the case of an acute abdominal attack.

Jun;102(6):483-486

Available online at: annallergy.org/article/S1081-1206%2810%2960121-4/fulltext (small fee)