Laryngeal Attacks Research Articles

Human pasteurized C1-inhibitor concentrate for the treatment of hereditary angioedema due to C1-inhibitor deficiency

Hereditary angioedema is a relatively rare genetic disorder affecting between one in 10,000 and one in 50,000 individuals worldwide. The most common clinical symptoms observed are relapsing swelling of the skin and abdominal pain attacks. However, more serious and potentially fatal laryngeal attacks can also occur. Hereditary angioedema is most frequently caused by a deficiency of C1-inhibitor. Replacement therapy with Berinert®, an intravenous pasteurized C1-inhibitor concentrate derived from human plasma, is a recommended treatment for rapid resolution of acute attacks of hereditary angioedema due to C1-inhibitor deficiency. Prophylactic therapy with C1-inhibitor is also available. Future advances may improve morbidity and mortality associated with hereditary angioedema.

Randomized placebo-controlled trial of the bradykinin B 2 receptor antagonist icatibant for the treatment of acute attacks of hereditary angioedema: the FAST-3 trial

The For Angioedema Subcutaneous Treatment (FAST)-3 study was a phase III, randomized, double-blind, placebo-controlled study of icatibant (bradykinin B(2) receptor antagonist) in subjects with hereditary angioedema (HAE) resulting from C1-INH deficiency or dysfunction (type I/II). To investigate icatibant efficacy and safety in subjects with acute HAE attacks. Subjects with moderate to very severe cutaneous or abdominal symptoms received icatibant (n = 43) or placebo (n = 45). Five subjects with laryngeal (mild-to-moderate) first attacks received icatibant (n = 3) or placebo (n = 2), and 5 subjects with severe laryngeal first attacks received open-label icatibant. Cutaneous or abdominal attacks: icatibant significantly reduced median times (vs placebo) to 50% or more reduction in symptom severity (2.0 vs 19.8 hours; P < .001, primary endpoint), onset of primary symptom relief (1.5 vs 18.5 hours; P < .001, key secondary endpoint), or almost complete symptom relief (8.0 vs 36.0 hours; P = .012) and provided a shorter time to initial symptom relief (0.8 vs 3.5 hours; P < .001). For laryngeal attacks, median time to 50% or more reduction in symptom severity was 2.5 hours (icatibant) and 3.2 hours (placebo). No icatibant-treated subject required rescue medication before symptom relief occurred. The incidence of adverse events (AEs) was similar in icatibant- and placebo-treated subjects (41% and 52%, respectively). All icatibant-treated subjects experienced injection site reactions, but none reported clinically relevant changes in safety parameters or serious AEs. FAST-3 demonstrated that icatibant was effective and generally well tolerated in subjects with acute HAE attacks. Clinicaltrials.gov Identifier: NCT00912093.

C1 esterase inhibitor concentrate in 1085 Hereditary Angioedema attacks - final results of the I.M.P.A.C.T.2 study

The placebo-controlled study International Multicentre Prospective Angioedema C1-INH Trial 1 (I.M.P.A.C.T.1) demonstrated that 20 U/kg C1 esterase inhibitor (C1-INH) concentrate (Berinert®; CSL Behring, Marburg, Germany) is effective in treating acute abdominal and facial Hereditary Angioedema (HAE) attacks. I.M.P.A.C.T.2 was an open-label extension study of I.M.P.A.C.T.1 to evaluate the safety and efficacy of long-term treatment with 20 U/kg C1-INH for successive HAE attacks at any body location. Efficacy outcomes included patient-reported time to onset of symptom relief (primary) and time to complete resolution of all symptoms (secondary), analysed on a per-patient and per-attack basis. Safety assessments included adverse events, vital signs, viral safety and anti-C1-INH antibodies. During a median study duration of 24 months, 1085 attacks were treated in 57 patients (10-53 years of age). In the per-patient analysis, the median time to onset of symptom relief was 0.46 h and was similar for all types of attacks (0.39-0.48 h); the median time to complete resolution of symptoms was 15.5 h (shortest for laryngeal attacks: 5.8 h; 12.8-26.6 h for abdominal, peripheral and facial attacks). Demographic factors, type of HAE, intensity of attacks, time to treatment, use of androgens and presence of anti-C1-INH antibodies had no clinically relevant effect on the efficacy outcomes. There were no treatment-related safety concerns. No inhibitory anti-C1-INH antibodies were detected in any patient. A single dose of 20 U/kg C1-INH concentrate is safe and provides reliable efficacy in the long-term treatment of successive HAE attacks at any body location.

Hereditary angioedema: A case of near fatal laryngeal swelling in a 41-year-old woman

Hereditary angioedema (HAE) is characterized by nonpitting, nonpruritic subcutaneous, or submucosal edema that may be accompanied by a nonpruritic serpentine erythematous rash. The swelling in this autosomal dominantly inherited disorder is mediated by uncontrolled localized bradykinin production. The extremities, face, gastrointestinal tract, genitalia, larynx, and trunk are commonly involved. Nearly one-third of patients who are not treated may suffer asphyxiation from a laryngeal attack. HAE symptoms overlap with other conditions that cause swelling. An accurate diagnosis is therefore crucial when considering therapy. Recently approved treatments for HAE swelling attacks include C1 esterase inhibitor concentrate and ecallantide. This case describes a 41-year-old woman who was treated ineffectively for more than 20 years, was switched to an effective therapy, but suffered near fatal laryngeal edema due to a missed dose of the effective therapy. The case underscores the need for increased awareness of HAE among clinicians and the importance of good compliance to therapy among patients with HAE.

The Turkish Hereditary Angioedema Pilot Study (TURHAPS): The First Turkish Series of Hereditary Angioedema

Background: No published data presently exist concerning hereditary angioedema (HAE) in Turkey. The aim of the study was to initiate a preliminary multicentric evaluation about HAE and to determine the genetic properties of Turkish patients. Methods: Based on records drawn from four medical centers we identified a total of 70 subjects, belonging to 60 unrelated families, fulfilling clinical and laboratory criteria for diagnosis of HAE with C1 inhibitor deficiency. Ten type I patients, and their first-degree relatives, underwent genetic analysis for HAE. Results: The majority of patients were female (60%), the mean age was 37.7 ± 14.1 years. The mean age at the time of first angioedema symptom was 12.5 ± 9.2 years. Mean time lag between first symptom and diagnosis was 26 ± 14.4 years. All but 3 subjects had HAE type I. Family history of angioedema was present in 75.7% of the cases. Cutaneous swelling was reported by 87.1% of the patients, facial edema by 65%, abdominal symptoms by 74.3% and approximately one half (55.7%) had experienced one or more laryngeal attack. Genetic analysis of 10 families demonstrated that 5 carried a mutation that had never been previously described. Conclusion: We found that the clinical features of Turkish HAE patients were consistent with previously described patterns of this rare disease. The most noteworthy feature identified in the study was a significantly long duration between the first symptom appearance and final diagnosis. Our detection of different mutations in 10 patients confirms the allelic heterogeneity of the disease.

Home therapy with intravenous human C1‐inhibitor in children and adolescents with hereditary angioedema

C1-esterase inhibitor (C1-INH) replacement therapy is the treatment of choice for acute edema attacks in patients with hereditary angioedema (HAE). Our retrospective, observational study assessed the efficacy and safety of home therapy with a human plasma-derived C1-INH concentrate (pC1-INH) in 20 pediatric patients with HAE who had previously been treated with physician-based therapy. While on home therapy, 15 patients received on-demand treatment and five received individual replacement treatment (IRT). The switch to home therapy did not involve a significant increase in the dose of pC1-INH administered, but there was a significant increase in dosing frequency. Although only two patients were affected, the frequency of laryngeal attacks appeared to decrease on home therapy. All attacks, including laryngeal edema, were treated successfully during home therapy with pC1-INH. The mean annual number of days hospitalized was reduced from 3.8 during physician-based therapy to 0.11 during home therapy. No side effects or injection site complications were reported. The median time from onset of attack to administration of pC1-INH was reduced from 67.5 minutes during physician-based therapy to 15 minutes after switching to home therapy. The corresponding median time to initial symptom relief for all types of attack was reduced from 60 to 40 minutes. As in adults, home therapy with pC1-INH is effective and safe in the treatment of HAE attacks in pediatric patients; a larger, randomized study should ideally confirm our findings before this approach can be considered the standard of care for pediatric patients.

Les angiœdèmes bradykiniques héréditaires ou acquis

Bradykinin angioedema (AE) are characterized by acute recurrent episodes of localized swelling. They are not associated with pruritus or erythema, and are short-lived (24 to 72 hours), disappearing without any sequelae. Corticosteroids are useless. Skin or mucous membranes (upper respiratory and intestinal) could be affected. Bradykinin AE can be secondary to: (1) AE associated with C1 inhibitor deficiency (hereditary or acquired); (2) drug-induced AE (converting enzyme inhibitors…); (3) type III AE type (oestrogen dependant) without C1 inhibitor deficiency. These type III AE can be associated with a gain of function mutation that markedly increases factor XII activity. Prognosis depends on the laryngeal attacks (resulting in 25 % of death in the absence of specific treatment). In case of severe attacks, icatibant (bradykinin receptor antagonist) or C1 inhibitor concentrate can be used. In case of frequent attacks, long-term therapy with danazol or tranexamic acid is effective.

Safety and Efficacy of Nanofiltered C1 Esterase Inhibitor (Human) (Cinryze™) for the Treatment of Laryngeal Attacks in Subjects with Hereditary Angioedema (HAE)

Safety and Efficacy of Nanofiltered C1 Esterase Inhibitor (Human) (Cinryze™) for the Treatment of Laryngeal Attacks in Subjects with Hereditary Angioedema (HAE)

A delayed diagnosis: stridor secondary to hypocalcemia

Hypocalcemia with stridor is a well-known condition in the pediatric age group but has rarely been reported in the elderly. We report an elderly patient who presented with dyspnea and laryngeal stridor attack caused by hypocalcemia. The patient had been suffering from stridor and dyspnea episodes for 2 years, and the etiology had not been determined until the evaluation in our department. The cause of stridor was hypocalcemia secondary to thyroidectomy. Complete resolution of stridor was achieved by calcium replacement therapy.

Long-term efficacy of danazol treatment in hereditary angioedema

No systematic study has been published yet on the long-term efficacy of attenuated androgens in hereditary angioedema (HAE). Our aim was to conduct a follow-up study in two (German and Hungarian) cohorts of HAE patients (45 and 39 patients, respectively) undergoing uninterrupted treatment for 6 years with similar (starting dose 128 ± 78 mg per day and 136 ± 70 mg per day, respectively) and constant doses of danazol. The frequencies of subcutaneous, abdominal and laryngeal attacks were recorded each year. The annual frequency of all the three types of attacks was significantly lower during the first year of danazol treatment, compared to the last year before baseline. During subsequent years in Hungarian patients, the frequency of both subcutaneous and abdominal attacks - but not that of laryngeal attacks - increased significantly. In the case of abdominal attacks, a significant increase in the attack frequency was observed only in female patients. In the German cohort, by contrast, no change in the frequency of either type of attack was found during the 6-year study period. The differences observed between these cohorts cannot be related to drug dose, the age or gender distribution of subjects or the age at the onset of symptoms or the length of diagnostic delay in the patients. There were, however, marked differences in the baseline pattern of attacks: significantly - 3 times - more abdominal attacks were recorded in German patients. Further studies are necessary to clarify the mechanism of these findings.

Prospective Study of Rapid Relief Provided by C1 Esterase Inhibitor in Emergency Treatment of Acute Laryngeal Attacks in Hereditary Angioedema

IntroductionHereditary angioedema (HAE) is a rare disorder characterized by C1 esterase inhibitor (C1-INH) deficiency, resulting in periodic attacks of acute edema that can be life-threatening if they occur in the laryngeal region. We assessed the efficacy of C1-INH concentrate in the emergency treatment of rarely occurring acute laryngeal HAE attacks in a prospective, open-label clinical study.MethodsAcute laryngeal attacks were each treated with C1-INH concentrate (Berinert) at a single dose of 20 U/kg body weight. Efficacy endpoints included time to onset of symptom relief and time to complete resolution of all symptoms, each based on the patient's assessment.ResultsAll 39 laryngeal attacks in 16 patients were treated successfully. The median time to onset of symptom relief was 15 min. The median time to complete resolution of all symptoms was 8.25 h. No treatment-related serious adverse events occurred, and the treatment was well tolerated. The administration of C1-INH concentrate was not associated with any viral infections.ConclusionC1-INH concentrate is an effective and safe emergency treatment for providing reliable and rapid relief from the potentially life-threatening symptoms of laryngeal HAE attacks.

Fast 3: a phase III randomized double-blind, placebo-controlled multicenter study of Icatibant for subcutaneous injection in patients with acute Attacks of Hereditary Angioedema (HAE)

Background Herditary Angioedema (HAE) is a rare disorder (1:10,000 – 1:50,000) characterized by episodic, localized edema of skin or mucosa of airway, genitourinary tract or gastrointestinal tract. It is due to inherited deficiency of the serpin known as C1 Inhibitor leading to unopposed kallikrein, producing excess bradykinin which binds to G-protein coupled receptors known as B1 and B2 receptors. Icatabant, a ten amino acid peptide analogue of bradykinin is an effective blocker of the B2 receptor and has been shown to provide rapid and complete relief of symptoms compared to Tranexamic acid (Fast1) or placebo (Fast-2). Rapid relief of laryngeal edema was confirmed in the open label arm. A new trial (Fast3) has begun. Primary Objective are to compare icatibant vs placebo on the time to symptom relief using a 3 symptom Visual Analog Scale (VAS) score during moderate to very severe acute cutaneous and/or abdominal attacks in patients with type I or type II hereditary angioedema (HAE). Secondary Objectives are to compare the global outcome following treatment with icatibant vs placebo using patient-reported (single symptom and 8 symptom composite score) and physician-reported outcome measures at 4 and 8 hours; to compare the time to almost complete symptom relief following treatment with icatibant vs placebo during moderate to very severe acute cutaneous and/or abdominal attacks; to assess safety and tolerability of icatibant vs placebo; and to assess the efficacy and safety of open-label icatibant treatment in patients experiencing laryngeal edema attacks. 88 patients, aged 18 or older, with an attack of at least moderate severity os skin, abdomen or larynx/ pharynx will be randomized to double-blind treatment with either 30 mg of Icatabant SC or placebo.

Clinical Outcomes with Icatibant in the Open-Label Treatment of 45 Laryngeal Attacks of Hereditary Angioedema

Clinical Outcomes with Icatibant in the Open-Label Treatment of 45 Laryngeal Attacks of Hereditary Angioedema

Icatibant for hereditary angioedema

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.

Treatment of Hereditary Angioedema: Current Perspectives

Hereditary angioedema (HAE) is a rare familial disease characterized by recurrent self-limiting episodes of soft tissue swelling affecting different parts of the body. Acute HAE attacks range from benign, but disfiguring skin edema, to painful abdominal, and even life-threatening laryngeal attacks. The disease is caused by an aberrant C1 esterase inhibitor (C1-INH), which regulates complement, fibrinolytic, and contact pathways. Elevated serum level of bradykinin as a result of contact pathway activation is thought to be the major mediator of pain and edema formation in HAE. Current therapy of acute HAE attacks is limited and mainly offers symptom control. In the United States only fresh frozen plasma provides some reconstitution of C1-INH, but the efficacy and safety of this treatment is controversial. In some European countries two human derived C1-INH concentrates have been used successfully. Prophylactic therapy for patients with frequent HAE attacks is confined to attenuated androgens and in some countries anti-fibrinolytics and C1-INH are also used. To satisfy the unmet needs, investigation of one recombinant C1-INH, two drugs working on bradykinin pathway and two human derived C1-INH concentrates are underway. This review article also discusses some recent patents related to the filed.

CLINICAL NEWS

Firazyr (icatibant), a selective bradykinin-B2-receptor antagonist which can be administered subcutaneously, is now available in the UK for treating patients with hereditary angioedema, including those with life-threatening laryngeal attacks.

Appraisal of danazol prophylaxis for hereditary angioedema

Hereditary angioedema (HAE) is an autosomal dominant disease characterized by painful, recurrent attacks of inflammation affecting the hands, feet, face, abdomen, urogenital tract, and the larynx. The inflammation can be disfiguring, debilitating, quite painful, and, in the case of laryngeal attacks, life-threatening. Attacks are frequently the source of unnecessary exploratory abdominal procedures, extended hospital stays affecting a patient's ability to retain employment, and severe compromise of the patient's quality of life. HAE is estimated to affect 10,000 people in the US and is caused by deficient or dysfunctional C1-inhibitor, a naturally occurring molecule that is known to inhibit kallikrein, bradykinin, and other serine proteases in plasma. The treatment and management of HAE have been hampered by the dearth of safe and effective therapies. In the United States, there are currently no approved therapies for the treatment of acute HAE attacks. Although prophylactic HAE therapies do exist, they are often viewed as suboptimal due to moderate degrees of efficacy and the existence of adverse effects associated with therapy. Danazol, an attenuated androgen, is the most commonly prescribed prophylaxis treatment for HAE in the United States. Although it has demonstrated moderate efficacy in the prevention of HAE attacks, danazol's side-effect profile can be problematic because there is a correlation between frequency and severity of adverse events and dosage and duration of therapy.

C1 esterase inhibitor (C1-INH) - Standard of Care for the Treatment of Acute Attacks in Hereditary Angioedema (HAE): Initial Results of an Ongoing, Prospective, Open Label Study in North America (I.M.P.A.C.T.2)

C1-inhibitor replacement therapy, available in most countries except the US, for many years is regarded as the gold standard treatment of acute attacks of hereditary angioedema (HAE) especially for laryngeal, facial and abdominal attacks. We studied the efficacy and safety of multiple treatments with C1-INH for HAE attacks at any body site.

Hereditary angioedema due to C1 inhibitor deficiency: patient registry and approach to the prevalence in Spain

Hereditary angioedema (HAE) is a rare disease caused by C1 inhibitor mutations. Although more than 100 mutations have been described, epidemiologic data are lacking; therefore, we developed a Spanish HAE patient registry. To study the prevalence of HAE and the current state of diagnosis and treatment of this disease in Spain. Epidemiologic data were obtained by direct contact with physicians who treat patients with HAE and with patients themselves. Diagnosis was evaluated by measuring C1 inhibitor levels and function, and most families also underwent genetic studies. We registered 444 patients (minimal prevalence, 1.09 per 100,000 inhabitants), many of whom are asymptomatic (never having symptoms) (n = 61, 13.7%). Most symptomatic patients (62.9%) receive long-term prophylaxis with attenuated androgens (80.9%) and antifibrinolytic agents (22.8%), alone or in combination, but no patients are receiving long-term prophylaxis with C1 inhibitor. There is a long delay in diagnosis (mean, 13.1 years). Nine patients underwent a tracheotomy as a consequence of a laryngeal attack, and 30 families recalled a total of 38 relatives who died of HAE, which underlines the severity of the illness. The detected minimal prevalence of HAE in Spain is 1.09 per 100,000 inhabitants. Because this is a rare disease and some patients may be misdiagnosed, this prevalence could be higher.

A phase I study of recombinant human C1 inhibitor (RHC1INH) in asymptomatic patients with hereditary angioedema (HAE)

HAE patients experience recurrent episodes of localized swelling of submucosal and/or subcutaneous tissue. An attack is life-threatening when occurring in the larynx. HAE is caused by deficiency of functional C1INH. IV administration of human plasma-derived C1INH is the preferred treatment of severe abdominal, facial and laryngeal attacks. However, this product has limited availability for reasons relating to its origin, supply and cost. A preparation of recombinant human C1INH (rhC1INH) was developed from the milk of transgenic rabbits. In an open study, the tolerability, PK and biological effects of ascending iv doses of rhC1INH (range 6.25–100 U/kg) were investigated in 12 asymptomatic HAE patients, who received 2 infusions of rhC1INH after a washout of at least 5 weeks. Modelling of the rhC1INH concentration-time profile taking into account the endogenous production for 100 U/kg dose showed a clearance of 13 mL/min, a half-life of 3 h, a volume of distribution of 3 L, and an endogenous 'infusion rate' of 2 U/min. Clearance decreased dose-dependently indicating a saturable mechanism of elimination. At 100 U/kg the functional C1INH level was above the presumed protective level of 0.4 U/ml for about 9 h. The effects of rhC1inh were assessed by the inhibition of plasma C4bc formation that results from C4 cleavage. The magnitude and duration of the decrease in C4bc was dose-dependent. There was no indication that anti-C1 inh and anti-HRI increased or formation of neutralizing antibodies. rhC1inh was well tolerated (no allergic reactions) and showed the desired biological activity (C4 increases and inhibition of C4b/c formation) and will be tested in phase II studies in patients with severe attacks of angioedema. Clinical Pharmacology & Therapeutics (2004) 75, P52–P52; doi: 10.1016/j.clpt.2003.11.198