Hereditary angioedema (HAE) caused by C1-esterase inhibitor deficiency is an
autosomal-dominant disease resulting from a mutation in the C1-inhibitor gene.
HAE is characterized by recurrent attacks of intense, massive, localized
subcutaneous edema involving the extremities, genitalia, face, or trunk, or
submucosal edema of upper airway or bowels. These symptoms may be disabling,
have a dramatic impact on quality of life, and can be life-threatening when
affecting the upper airways. Because the manifestations and severity of HAE are
highly variable and unpredictable, patients need individualized care to reduce
the burden of HAE on daily life. Although effective therapy for the treatment of
HAE attacks has been available in many countries for more than 30 years, until
recently, there were no agents approved in the United States to treat HAE
acutely. Therefore, prophylactic therapy is an integral part of HAE treatment in
the United States and for selected patients worldwide. Routine long-term
prophylaxis with either attenuated androgens or C1-esterase inhibitor has been
shown to reduce the frequency and severity of HAE attacks. Therapy with
attenuated androgens, a mainstay of treatment in the past, has been marked by
concern about potential adverse effects. C1-esterase inhibitor works directly on
the complement and contact plasma cascades to reduce bradykinin release, which
is the primary pathologic mechanism in HAE. Different approaches to long-term
prophylactic therapy can be used to successfully manage HAE when tailored to
meet the needs of the individual patient.
C1-esterase inhibitor; attenuated androgen; angioedema; HAE; prophylaxis
Hereditary angioedema (HAE) is a clinical disorder characterized by a deficiency of C1 esterase inhibitor (C1-INH). HAE has traditionally been divided into two subtypes. Unique among the inherited deficiencies of the complement system, HAE Types I and II are inherited as an autosomal dominant disorder. The generation of an HAE attack is caused by the depletion and/or consumption of C1-inhibitor manifested as subcutaneous or submucosal edema of the upper airway, face, extremities, or gastrointestinal tract. Attacks can be severe and potentially life-threatening, particularly with laryngeal involvement. Despite the availability of C1-INH for the treatment of HAE since the 1980s in Europe and other countries, HAE treatment in the United States was limited to androgen therapy. The human plasma-derived C1 esterase inhibitor (Cinryze™), distributed by Lev Pharmaceuticals, was approved in October 2008 for the prevention of HAE attacks based on the results of a phase III clinical trial. This review aims to describe the history of C1-INH replacement in HAE as well as the pharmacology, efficacy and safety of C1-INH, concentrating on Cinryze as the first approved chronic replacement treatment for the prophylaxis of HAE attacks.
hereditary angioedema; C1 esterase inhibitor; Cinryze; prophylaxis; angioedema
Hereditary angioedema (HAE) is a potentially fatal genetic disorder typified by a deficiency (type I) or dysfunction (type II) of the C1-inhibitor (C1-INH) and characterized by swelling of the extremities, face, trunk, abdominal viscera, and upper airway. Type III is normal estrogen-sensitive C1-INH HAE. Bradykinin, the main mediator of HAE, binds to endothelial B2 receptors, increasing vascular permeability and resulting in edema. HAE management includes short- and long-term prophylaxis. For treating acute episodes, C1-INH concentrate is recommended with regression of symptoms achieved in 30–90 min. Infusions of 500–1000 U have been used in Europe for years. Two plasma-derived C1-INH concentrates have been licensed recently in the United States: Berinert® for treating acute attacks and Cinryze® for prophylaxis in adolescent/adult patients. A recombinant C1-INH that is being considered for approval (conestat alfa) exhibited significant superiority versus placebo. Ecallantide (Kalbitor®) is a selective kallikrein inhibitor recently licensed in the United States for treating acute attacks in patients aged >16 years. It is administered in three 10-mg subcutaneous injections with the risk of anaphylactic reactions. Icatibant (Firazyr®) is a bradykinin B2 receptor competitor. It is administered subcutaneously as a 30-mg injection and approved in Europe but not in the United States.
hereditary angioedema; C1 esterase inhibitor; acute attacks
Attacks of hereditary angioedema (HAE) are unpredictable and, if affecting the upper airway, can be lethal. Icatibant is used for physician- or patient self-administered symptomatic treatment of HAE attacks in adults. Its mode of action includes disruption of the bradykinin pathway via blockade of the bradykinin B2 receptor. Early treatment is believed to shorten attack duration and prevent severe outcomes; however, evidence to support these benefits is lacking.
To examine the impact of timing of icatibant administration on the duration and resolution of HAE type I and II attacks.
The Icatibant Outcome Survey is an international, prospective, observational study for patients treated with icatibant. Data on timings and outcomes of icatibant treatment for HAE attacks were collected between July 2009–February 2012. A mixed-model of repeated measures was performed for 426 attacks in 136 HAE type I and II patients.
Attack duration was significantly shorter in patients treated <1 hour of attack onset compared with those treated ≥1 hour (6.1 hours versus 16.8 hours [p<0.001]). Similar significant effects were observed for <2 hours versus ≥2 hours (7.2 hours versus 20.2 hours [p<0.001]) and <5 hours versus ≥5 hours (8.0 hours versus 23.5 hours [p<0.001]). Treatment within 1 hour of attack onset also significantly reduced time to attack resolution (5.8 hours versus 8.8 hours [p<0.05]). Self-administrators were more likely to treat early and experience shorter attacks than those treated by a healthcare professional.
Early blockade of the bradykinin B2 receptor with icatibant, particularly within the first hour of attack onset, significantly reduced attack duration and time to attack resolution.
Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.
C1-INH (C1 inhibitor, C1-esterase inhibitor); Hereditary angioedema; Consensus; Pediatric
Hereditary angioedema (HAE) is a rare, debilitating, and potentially life-threatening disease characterized by recurrent edema attacks. Important advances in HAE treatment have been made, including the development of new therapies for treating or preventing attacks. Nevertheless, the disease is still frequently misdiagnosed and inappropriately treated, potentially exposing patients with laryngeal attacks to the risk of asphyxiation.
The Icatibant Outcome Survey (IOS) is an international, observational study that documents the clinical outcome of HAE patients eligible for treatment with icatibant. Patient ages at first symptoms and at diagnosis were recorded at enrolment, and the delay between first symptoms and diagnosis was calculated.
The median [range] diagnostic delay in HAE type I and II patients across eight countries was 8.5 years [0–62.0]. The median delay in diagnosis was longer for HAE type II versus type I (21 versus 8 years, respectively), although this did not quite reach statistical significance.
Although it can be difficult to differentiate HAE symptoms from those of more common angioedema sub-types (e.g. idiopathic or acquired angioedema), our results show that HAE type I and II patients have an unacceptable delay in diagnosis, even those with a family history of the disease. Raising physician awareness of this disabling and potentially fatal disease may lead to a more accurate diagnosis and timely treatment.
Bradykinin; C1-inhibitor; Diagnosis; Hereditary angioedema; Icatibant
Current strategies for the treatment of hereditary angioedema (HAE) include
targeted inhibition or antagonism of the contact system, which is dysregulated
in HAE patients by a C1 esterase inhibitor deficiency. Ecallantide, a plasma
kallikrein inhibitor, and icatibant, a selective bradykinin-2 receptor
antagonist, have recently been evaluated in clinical studies for the treatment
of acute HAE attacks. Both drugs have demonstrated evidence of efficacy and
safety in treating acute HAE episodes, with ecallantide approved for use in the
United States and icatibant approved for use in Europe. As therapeutic options
for HAE expand for both for prophylactic and acute treatment strategies, a
number of patient-specific and drug-specific factors have emerged as important
considerations when developing individualized HAE management plans. Optimization
of HAE therapy will require further integration of new therapies into the
current treatment paradigm.
HAE; contact system; ecallantide; icatibant
Hereditary angioedema due to C1-inhibitor deficiency (HAE-C1-INH) is a life-threatening, rare disease characterized by recurrent edematous attacks. In 50% of cases, the initial onset of symptoms occurs between 5 and 11 years of age. There are limited data on the emergency treatment of acute episodes in pediatric patients. Our aim was to analyze the efficacy and safety of human plasma-derived C1-INH concentrate in our pediatric patient population with HAE-C1-INH.
50 pediatric patients (23 boys, 27 girls; 45 HAE type I, 5 HAE type II patients) were enrolled. The follow-up period began at the time of diagnosis and ended when the patient turned 18 years old. The indications for the use of C1-INH concentrate were upper airway oedema of any severity; moderate-to-severe abdominal edema; edema of face, neck, or lips and severe edema of the extremities and trunk. Clinical and laboratory data were entered into the Hungarian HAE Registry.
152 attacks out of 1392 experienced by 42 patients were treated with C1-INH concentrate (28% of attacks at home and 72% at the clinic). The distribution of C1-INH-treated attacks by location was as follows: 38% subcutaneous, 32% abdominal, 30% upper airway. In all locations, the clinical symptoms were consistently relieved by 500 IU C1-INH concentrate. An additional 500 IU dose of C1-INH concentrate was required in 4 cases only. The symptoms improved within 15 to 60 minutes of drug administration. Time to complete resolution was 24 to 48 hours in subcutaneous edema, 12 to 24 hours in abdominal attacks, and less than 12 hours when the edema involved the upper airways. No progression or recurrence of the attack was observed. Repeated administration did not reduce therapeutic efficacy of the drug. Adverse events did not occur. Transmission of viral infections (HIV, HBV, HBC, Parvo virus B19) was not detected. Comparing the first and last year of follow-up, anti-C1-INH antibodies (IgA, IgG, IgM types) did not show any relationship with the administration of C1-INH concentrate.
Our prospective study demonstrated that the administration of C1-INH concentrate is highly effective and safe for the treatment of edematous attacks – regardless their location – in pediatric patients with HAE-C1-INH.
Hereditary angioedema (HAE) is a clinical disorder characterized by a deficiency of C1 esterase inhibitor (C1-INH). HAE has traditionally been divided into two subtypes. Unique among the inherited deficiencies of the complement system, HAE Types I and II are inherited as an autosomal dominant disorder. The generation of an HAE attack is caused by the depletion and/or consumption of C1-inhibitor manifested as subcutaneous or submucosal edema of the upper airway, face, extremities, or gastrointestinal tract mediated by bradykinin. Attacks can be severe and potentially life-threatening, particularly with laryngeal involvement and treatment of acute attacks in the United States has been severely limited. In December 2009 the FDA approved ecallantide for the treatment of acute HAE attacks. Ecallantide is a small recombinant protein acting as a potent, specific and reversible inhibitor of plasma kallikrein which binds to plasma kallikrein blocking its binding site, directly inhibiting the conversion of high molecular weight kininogen to bradykinin. Administered subcutaneously, ecallantide was demonstrated in two clinical trials, EDEMA3 and EDEMA4, to decrease the length and severity of acute HAE attacks. Although there is a small risk for anaphylaxis, which limits home administration, ecallantide is a novel, safe, effective and alternative treatment for acute HAE attacks.
hereditary angioedema; ecallantide; Kalbitor®; acute; angioedema
Hereditary angioedema (HAE) is a rare disorder characterized by funcional deficiency of C1 inhibitor (C1-INH) resulting in unpredictable, acute swelling attacks at varied locations. Icatibant, a selective bradikinin B2 receptor antagonist, is a novel treatment for acute attacks of HAE. The aim of the present study was to compare the efficacy beteween icatibant and fresh frozen plasma (FFP) in the acute attacks of HAE.
We performed a retrospective analysis of acute attacks of HAE in a tertiary hospital. We compared the efficacy of icatibant with fresh frozen plasma as control group. Efficacy was measured as the median time to onset of symptoms relief and the improvement of HAE and the median time to end of the attacks. Safety was assessed in terms of adverse events. All participants gave written informed consent.
There were 21 acute attacks, 14 for icatibant and 7 for FFP. The median time to onset of symptoms relief was 27 and 45 minutes for icatibant and FFP respectively (P = 0.106). The median time to complete resolution of all simptoms was 240 and 2880 minutes respectively for icatibant and FFP (P = 0.002). All patients with Icatibant experienced generally mild transient injection-site reactions (erythema and swelling, and pain) wich resolved spontaneously without intervention. No drug-related serious adverse events were observed with icatibant and administration of FFP was not associated with infections of human inmunodeficiency virus, or hepatitis virus.
Icatibant was effective and generally well tolerated, providing rapid regression of symptoms associated with acute HAE attacks at all anatomic sites.
Hereditary 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.
We 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).
Twenty-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.
Home 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.
Manifestation of acute edema in hereditary angioedema (HAE) is characterized by interindividual and intraindividual variability in symptom expression over time. Flexible therapy options are needed.
We describe and report on the outcomes of the highly individualized approach to HAE therapy practiced at our HAE center in Frankfurt (Germany).
The HAE center at the Frankfurt University Hospital currently treats 450 adults with HAE or AAE and 107 pediatric HAE patients with highly individualized therapeutic approaches. 73.9% of the adult patients treat HAE attacks by on-demand therapy with pasteurized pd C1-INH concentrate, 9.8% use additional prophylaxis with attenuated androgens, 1% of the total patient population in Frankfurt has been treated with Icatibant up to now. In addition adult and selected pediatric patients with a high frequency of severe attacks are instructed to apply individual replacement therapy (IRT) with pasteurized pd C1-INH concentrate. Improvement on Quality of Life items was shown for these patients compared to previous long-term danazol prophylaxis. Home treatment of HAE patients was developed in the Frankfurt HAE center in line with experiences in hemophilia therapy and has so far been implemented over a period of 28 years. At present 248 (55%) of the adult patients and 26 (24%) of the pediatric patients are practicing home treatment either as on demand or IRT treatment.
In conclusion, the individualized home therapies provided by our HAE center, aim to limit the disruption to normal daily activities that occurs for many HAE patients. Furthermore, we seek to optimize the economic burden of the disease while offering a maximum quality of life to our patients.
Urticaria (hives) is a common disorder that often presents with angioedema (swelling that occurs beneath the skin). It is generally classified as acute, chronic or physical. Second-generation, non-sedating H1-receptor antihistamines represent the mainstay of therapy for both acute and chronic urticaria. Angioedema can occur in the absence of urticaria, with angiotensin-converting enzyme (ACE) inhibitor-induced angioedema and idiopathic angioedema being the more common causes. Rarer causes are hereditary angioedema (HAE) or acquired angioedema (AAE). Although the angioedema associated with these disorders is often self-limited, laryngeal involvement can lead to fatal asphyxiation in some cases. The management of HAE and AAE involves both prophylactic strategies to prevent attacks of angioedema (i.e., trigger avoidance, attenuated androgens, tranexamic acid, and plasma-derived C1 inhibitor replacement therapy) as well as pharmacological interventions for the treatment of acute attacks (i.e., C1 inhibitor replacement therapy, ecallantide and icatibant). In this article, the authors review the causes, diagnosis and management of urticaria (with or without angioedema) as well as the work-up and management of isolated angioedema, which vary considerably from that of angioedema that occurs in the presence of urticaria.
Hereditary angioedema (HAE) is an autosomal dominant, potentially life-threatening condition, manifesting as recurrent and self-limiting episodes of facial, laryngeal, genital, or peripheral swelling with abdominal pain secondary to intra-abdominal edema. The estimated prevalence of HAE in the general population is one individual per 50,000, with reported ranges from 1:10,000 to 1:150,000, without major sex or ethnic differences. Various treatment options for acute attacks and prophylaxis of HAE are authorized and available in the market, including plasma-derived (Berinert®, Cinryze®, and Cetor®) and recombinant (Rhucin® and Ruconest™) C1 inhibitors, kallikrein inhibitor-ecallantide (Kalbitor®), and bradykinin B2 receptor antagonist-icatibant (Firazyr®). Some of these drugs are used only to treat HAE attacks, whereas others are only approved for prophylactic therapies and all of them have improved disease outcomes due to their different mechanisms of action. Bradykinin and its binding to B2 receptor have been demonstrated to be responsible for most of the symptoms of HAE. Thus icatibant (Firazyr®), a bradykinin B2 receptor antagonist, has proven to be an effective and more targeted treatment option and has been approved for the treatment of acute attacks of HAE. Rapid and stable relief from symptoms of cutaneous, abdominal, or laryngeal HAE attacks has been demonstrated by 30 mg of icatibant in Phase III clinical trials. Self-resolving mild to moderate local site reactions after subcutaneous injection of icatibant were observed. Icatibant is a new, safe, and effective treatment for acute attacks of HAE. HAE has been reported to result in enormous humanistic burden to patients, affecting both physical and mental health, with a negative impact on education, career, and work productivity, and with substantial economic burdens. The timely and proper use of disease-specific treatments could improve patients’ quality of life, reduce the disease-specific morbidity and mortality, and, last but not least, reduce costs associated with hospitalizations and emergency room visits. Therefore, the paradigm of HAE treatment has the potential to evolve significantly, thereby exponentially improving a patient’s quality of life.
hereditary angioedema; icatibant; C1 inhibitor; bradykinin
Hereditary angioedema (HAE) causes recurrent episodes of angioedema that may be very severe and are frequently associated with significant morbidity and even mortality. Understanding the pathophysiology of this disease is crucial for proper diagnosis and management of these patients. HAE is caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1 inhibitor. A large number of different mutations have been described that result in HAE. About 15% of patients have a mutation at or near the active site of the reactive mobile loop, resulting in a protein that lacks functional activity (type II HAE). Type I HAE is caused by a diverse range of mutations, some of which cause the nascent protein to misfold and thus to be unable to enter the secretory pathway. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system. Bradykinin induces increased vascular permeability by activating the bradykinin B2 receptor, which results in phosphorylation of vascular endothelial cadherin. The regulation of both the bradykinin B2 receptor and peptidases that degrade bradykinin may influence HAE disease severity. HAE results from mutations in the SERPING1 gene that lead to a loss of functional C1 inhibitor. Attacks of angioedema result from generation of bradykinin, which acts on bradykinin B2 receptors to enhance vascular permeability.
HAE; C1 inhibitor; contact system; bradykinin; plasma kallikrein; Hageman factor
Recombinant human C1 Inhibitor (rhC1INH) has been approved in Europe for the treatment of acute hereditary angioedema attacks. The efficacy of rhC1INH was demonstrated in 2 randomized-controlled trials. Open-label extension studies, where patients could be treated for subsequent HAE attacks, demonstrated continued efficacy for repeated rhC1INH treatments.
To review the integrated efficacy data of rhC1INH for treatment of acute HAE attacks.
Efficacy was assessed using patient-reported HAE-specific visual analog scales. The primary endpoint was time to onset of relief of symptoms (VAS decrease ≥20 mm), and the secondary efficacy endpoint was time to minimal symptoms (VAS <20 mm at all locations). Other endpoints included clinical response (relief achieved within 4 hours) and relapse (recurrence of symptoms within 24 hours following initial improvement). Subgroup analyses by attack location were also performed.
The dataset included 141 HAE patients treated for 403 attacks. Median times to the onset of symptom relief for attacks treated with 100 U/kg, 50 U/kg and 2100 U rhC1INH were 66, 60, and 61 minutes, respectively, compared to 495 minutes in the placebo-treated group. Median times for time to minimal symptoms were 266, 240 and 241 minutes for the 100 U/kg, 50 U/kg, and 2100 U rhC1INH-treated attacks respectively compared to 1210 minutes for the placebo-treated attacks. High clinical response rates were observed for the rhC1INH-treated groups (93, 96 and 88% for the 100 U/kg, 50U/kg, and 2100 U respectively) compared to the placebo group (41%). None of the rhC1INH-treated attacks relapsed. Subgroup analysis by attack location showed that abdominal attacks had the fastest median time to onset of symptom relief (50, 36 and 60 minutes for 100 U/kg, 50 U/kg and 2100 U doses respectively), followed by oro-facial-pharyngeal-laryngeal attacks (70, 65 and 120 minutes), and peripheral attacks (75, 84 and 121 minutes). No drug-related serious adverse events or hypersensitivity reactions were observed.
RhC1INH has demonstrated efficacy for the treatment of repeated HAE attacks for all doses tested (100 U/kg, 50 U/kg and 2100 U). Controlled studies did not show additional benefit with doses greater than 50 U/kg. RhC1INH was generally safe and well tolerated.
Hereditary angioedema (HAE) is a rare autosomal dominant disease characterized by swelling of the face, lips, tongue, larynx, genitalia, or extremities, with abdominal pain caused by intra-abdominal edema. HAE is caused by mutations affecting the C1 inhibitor gene, SERPING1, resulting in low levels of C1 inhibitor (Type I HAE) or normal levels of ineffective C1 inhibitor (Type II HAE). A nationwide survey identified nine unrelated families with HAE in Slovenia, among whom 17 individuals from eight families were recruited for genetic analyses. A diagnosis of HAE was established in the presence of clinical and laboratory criteria (low C1 inhibitor antigenic levels and/or function), followed up by a positive family history. Genetic studies were carried out using PCR and sequencing to detect SERPING1 mutations in promoter, noncoding exon 1, the 7 coding exons, and exon-intron boundaries. Multiplex ligation-dependent probe amplification was performed in order to search for large deletions/duplications in SERPING1 gene. A mutation responsible for HAE was identified in patients from seven families with the disease. In HAE type I families, one previously reported substitution (Gln67Stop, c.265C>T) and four novel mutations were identified. The new mutations included two missense substitutions, Ser128Phe (c.449C>T), and Glu429Lys (c.1351G>A), together with two frameshift mutations, indel (c.49delGinsTT) and deletion (c.593_594delCT). Both families with HAE type II harbored the two well-known substitutions affecting the arginyl residue at the reactive center in exon 8, Arg444Cys (c.1396C>T) and Arg444His (c.1397G>A), respectively. In one patient only the homozygous variant g.566T>C (c.-21T>C) was identified. Our study identified four novel mutations in the Slovenian HAE population, highlighting the heterogeneity of mutations in the SERPING1 gene causing C1 inhibitor deficiency and HAE. In a single patient with HAE a homozygous variant g.566T>C (c.-21T>C) might be responsible for the disease.
Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor (C1-INH) is a rare, life-threatening disorder. It is characterized by attacks of angioedema involving the skin and/or the mucosa of the upper airways, as well as the intestinal mucosa. In approximately 50 per cent of cases, clinical manifestations may appear during childhood. The complex management of HAE in pediatric patients is in many respects different from the management of adults. Establishing the diagnosis early, preferably before the onset of clinical symptoms, is essential in cases with a positive family history. Complement studies usually afford accurate diagnosis, whereas molecular genetics tests may prove helpful in uncertain cases. Appropriate therapy, supported by counselling, suitable modification of lifestyle, and avoidance of triggering factors (which primarily include mechanical trauma, mental stress and airway infections in children) may spare the patient unnecessary surgery and may prevent mortality. Prompt control of edematous attacks, short-term prophylaxis and intermittent therapy are recommended as the primary means for the management of pediatric cases. Medicinal products currently used for the treatment of children with hereditary angioedema include antifibrinolytics, attenuated androgens, and C1-INH replacement therapy. Current guidelines favour antifibrinolytics for long-term prophylaxis because of their favorable safety profile but efficacy may be lacking. Attenuated androgens administered in the lowest effective dose are another option. C1-INH replacement therapy is also an effective and safe agent for children. Regular monitoring and follow-up of patients are necessary.
Agents for prophylaxis of hereditary angioedema (HAE) have been available in the United States for several decades, but their usefulness is limited by side effects and they cannot be used at all in some patients. No agents have been available in the United States to specifically treat acute attacks. HAE types I and II are associated with low functional levels of C1 inhibitor, and evidence accumulated over decades suggests that intravenous infusion of C1 inhibitor is useful for terminating angioedema attacks and for prophylaxis.
C1 inhibitor derived from pooled human plasma has been available for decades in Europe, and 2 preparations have been recently introduced into the United States. Both have been efficacious in carefully controlled double-blind studies. One preparation, Cinryze, was approved by the U.S. Food & Drug Administration (FDA) for prophylaxis of HAE attacks in October 2008, and the second, Berinert, was approved by the FDA for treatment of acute attacks in October 2009. A third preparation, the recombinant human C1 inhibitor Rhucin, is completing clinical trials. Although not yet approved by the FDA, preliminary results made available suggest that Rhucin, too, is effective in terminating attacks of HAE.
Americans will now have access to effective acute and prophylactic treatments with C1 inhibitor for hereditary angioedema.
HAE; contact system; C1INH
Backgroud. Hereditary angioedema (HAE) is characterized by recurrent swelling of the skin, the abdomen (causing severe acute pain), and the airways. A recently discovered type caused by mutations in the factor XII gene (designated as HAE type III) occurs mainly in women. Estrogens may play an important role, but few obstetrical complications have been reported. Case. We report the symptoms and obstetrical complications of women in two families with HAE attributable to the p. Thr328Lys mutation in the F12 gene. Clinical manifestations included acute and severe maternal abdominal pain, with transient ascites, laryngeal edema, and fetal and neonatal deaths. Patients had normal C4 levels and a normal C1 inhibitor gene. Administration of C1-inhibitor concentration twice monthly decreased the attack rate in one mother, and its predelivery administration (1000 U) led to the delivery of healthy girls. Conclusions. Obstetricians and anesthesiologists should be aware of this rare cause of unexplained maternal ascites and in utero or fetal death associated with edema.
Although the biochemistry of hereditary angioedema (HAE) is fairly well understood today, the lag in diagnosis of a decade or more suggests that clinicians have low awareness of this disease. This lag in diagnosis and hence treatment certainly stems from the rarity and complexity of the presentation which can be easily mistaken for allergic and non-allergic reactions alike. The symptoms of the disease include acute swelling of any or multiple parts of the body. The attacks may be frequent or rare, and they may vary substantially in severity, causing stomach discomfort or periorbital swelling in mild cases and hypovolemic shock due to abdominal fluid shift or asphyxiation in the most severe cases. Given that these patients are at significant risk for poor quality of life and death, greater awareness of this disease is needed to ensure that newly available, effective medications are used in these patients. These new medications represent significant advances in HAE therapy because they are targeted at the plasma cascades implicated in the pathophysiology of this disease. The clinical presentation of HAE, overlapping symptoms with other angioedemas, and available therapies are reviewed.
Management of hereditary angioedema (HAE) comprises the prophylaxis and emergency treatment of edematous attacks. Our aim was to appraise the wide variety of the prophylactic use of plasma-derived human C1-inhibitor concentrate in HAE type I and type II patients.
125 patients with HAE (54 males, 71 females) were included in our study. Classical short-term prophylaxis (STP) was administered before surgical or diagnostic interventions in the head and neck region and other types of major surgery, as well as before endotracheal intubation. Alternatively, STP was introduced before the expected and unavoidable onset of triggering factors.
Before diagnosis of HAE, 128 interventions performed on 43 out of 125 patients induced edema: dental procedures (99 interventions in forty patients), ENT interventions (13/9 patients), surgery in the head and neck region (2/2 patients), surgery under general anesthesia (3/3 patients), gastroduodenoscopy (2/2 patients), delivery (6/6 patients) and artificial abortion (3/2 patients). After diagnosis of HAE, 500 IU of C1-INH concentrate was administered for STP, one hour before dental intervention (to 14 patients in 26 cases), surgery on the head or neck (to 7 patients in 7 cases), surgery under ETN (to 11 patients in 12 cases), diagnostic procedures (1 colonoscopy, 2 bronchoscopy, 4 gastroduodenoscopy, 1 cardiovascular catheterization), artificial abortion (to 4 patients in 6 cases), or childbirth (to 11 patients in 11 cases). Thirty-three of the 125 patients received prophylactic treatment on 70 occasions altogether. The medical history was positive for oedema provoked by medical interventions in 20 of the 33 patients undergoing STP with C1-INH concentrate. Eight patients received alternative prophylaxis: 2 patients during airway infections, 5 others before stressful life events, and one patient on the first day of the menstrual cycle over 4 months. In all cases, C1-INH concentrate prevented the occurrence of attacks.
STP with C1-INH concentrate was effective in preventing angioedematous attacks in all cases. After interventions, during 48 hours observation period, edematous attacks did not occur. Repeated administration did not diminish its efficacy. C1-INH concentrate was well tolerated, and it was never associated with potentially treatment-related adverse effects.
The diagnosis of hereditary angioedema (HAE) is often delayed due to the low awareness of this condition. In patients with undiagnosed HAE, abdominal symptoms often create the risk of unnecessary surgical operation and/or drug therapy. To explore the cause of misdiagnosis, we compared the laboratory findings of HAE patients under normal conditions with those during abdominal attacks.
Patient medical histories were analyzed and laboratory data at the first consultation with no symptoms and no medication were compared with those at visits to the emergency department during severe attacks.
Fourteen HAE patients were enrolled. Initial HAE symptoms occurred at 20.2 ± 9.4 years of age. The correct diagnosis of HAE was made 22.7 ± 14.2 years after the initial symptoms. A common site of angioedema was the extremities. Half of the patients experienced a life-threatening laryngeal attack and/or severe abdominal pain. In the patients with severe abdominal pain, significant leukocytosis with neutrophilia along with increased levels of hematocrit were observed while levels of C-reactive protein (CRP) remained low. All severe attacks were alleviated with an infusion of C1-inhibitor concentrate.
Consideration of the likelihood of a HAE attack is important when patients present with acute abdominal pain and leukocytosis without elevation of CRP.
Hereditary angioedema; C1-inhibitor; C1-inhibitor concentrate; Acute abdomen; Leukocytosis; Hemoconcentration
Hereditary angioedema (HAE) resulting from the deficiency of the C1 inhibitor protein is a rare disease, characterized by paroxysms of edema formation in the subcutis and in the submucosa. Edema can cause obstruction of the upper airway, which may lead to suffocation. Prompt elimination of edema is necessary to save patients from this life-threatening condition. Essentially, these edematous attacks are related to the activation of the kinin-kallikrein system and the consequent release of bradykinin. Ecallantide (known as DX-88 previously), a potent and specific inhibitor of plasma kallikrein is an innovative medicinal product. This is the only agent approved recently by the FDA for all localizations of edematous HAE attacks. Its advantages include no risk of viral contamination, high selectivity, very rapid onset of action, good tolerability, and straightforward subcutaneous administration. Owing to the risk of anaphylaxis, ecallantide should be administered by a health care professional. A postmarketing survey to improve risk-assessment and risk-minimization has been launched. The results of these studies may lead to the approval of ecallantide for self-administration.
hereditary angioedema; C1-inhibitor deficiency; treatment; bradykinin; kallikrein inhibitor; subcutaneous administration
Hereditary 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.
Acute 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.
All 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.
C1-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.
C1 inhibitor concentrate; hereditary angioedema; laryngeal attack; C1 inhibitor replacement therapy