Hereditary C1 Inhibitor Deficiency Research Articles

Hereditary C1-inhibitor deficiency angioedema (C1-INH-HAE) in children – practical considerations

Hereditary angioedema is a rare, autosomal dominant, potentially life-threatening disorder usually resulting from C1-esterase deficiency or dysfunction. Clinical manifestations include unpredictable, acute, recurrent episodes of well-demarcated oedema occurring without pruritus, most commonly affecting the face, trunk, extremities, but also, due to mucosal involvement, the respiratory and gastrointestinal systems. Although oedema resolves spontaneously within 2–5 days, the skin lesions are disfiguring, painful and disrupt daily functioning, while abdominal attacks are very painful and often lead to hospital admissions and unnecessary surgery. In addition, laryngeal oedema, which affects at least half of patients, is life-threatening and, in many cases, leads to fatal asphyxia. Therefore, early diagnosis and implementation of proper therapeutic management as soon as possible are crucial. In recent years, significant advances have been made in the treatment of hereditary angioedema. Initially, only intravenous drugs administered during attacks were available in medical facilities. Patient education has allowed for home therapy. The next step was the introduction of subcutaneous injections, which were more convenient for patients. Finally, long-term prophylactic treatment, which completely relieves symptoms and allows for a normal life, has gained importance. Unfortunately, the high cost of these therapies remains a problem. This paper reviews in detail the clinical picture and differential diagnosis of the disorder, as well as modern treatment approaches, with special focus on the distinctive features in children.

Diagnosing Pediatric Patients With Hereditary C1-Inhibitor Deficiency-Experience From the Hungarian Angioedema Center of Reference and Excellence.

BackgroundHereditary Angioedema with C1-inhibitor deficiency (C1-INH-HAE) is a rare disease characterized by recurrent subcutaneous and/or submucosal edematous (HAE) episodes, which may occur at any age. The mean age of the symptom onset is 10–12 years. Diagnostic protocols differ by age group and family history.MethodsWe retrospectively analyzed clinical and laboratory data (C4-, C1-INH concentration and function) from 49 pediatric patients diagnosed with C1-INH deficiency at our Angioedema Center between 2001 and 2020. Moreover, we analyzed the connection between complement parameters and symptom onset.ResultsFrom the 49 pediatric patients [boy/girl: 23/26, the average age of diagnosis: 6.7 years (min: 0-max: 18.84)], the majority (36/49, 73%) was diagnosed as the result of family screening. Of all the enrolled patients, 34% (17/49) experienced symptoms before the diagnosis. During the observational period, 33% (16/49) of the patients remained asymptomatic, while 33% (16/49) became symptomatic. The average age at symptom onset was 7.8 years (min: 0.5–max: 18). Only 27% (13/49) of pediatric patients were diagnosed after referrals to our center because of typical symptoms. From those patients diagnosed with family screening, 4/36 experienced symptoms at or before the time of the diagnosis. In the case of five newborns from the family screening group, umbilical cord blood samples were used for complement testing. In the case of 3/36 patients, the first complement parameters did not clearly support the disease, but the presence of the mutation identified in the family verified the diagnosis. Complement results were available from 11 patients who became symptomatic during the observational period. Complement parameters 1 year prior to and after the onset of symptoms were compared, and significantly lower concentrations of C1-INH (p = 0.0078) were detected after the onset of symptoms compared to the preceding (symptom-free) period.DiscussionThe majority of pediatric patients were diagnosed as a result of family screening before the onset of symptoms. Early diagnosis allows supplying the patients with special acute treatment for HAE attacks, which may occur at any time. Our results highlight the importance of DNA analysis in pediatric patients in case of a known mutation in the family, and an ambiguous result of complement testing.

RECURRENT ANGIOEDEMA IN SLE PATIENT

TOPIC: Allergy and Airway TYPE: Medical Student/Resident Case Reports INTRODUCTION: The pathophysiology of angioedema is broad. It may be hereditary, idiopathic, or a reaction to a range of medications or allergens; there have been a few case reports describing recurrent angioedema in patients with autoimmune conditions such as systemic lupus erythematosus (SLE). We present the case of a patient with SLE who suffered from recurrent angioedema of the face, including lips, tongue, and throat, without urticaria, with normal C1-Inhibitor levels. CASE PRESENTATION: A 69-year-old female with a history of SLE and recurrent angioedema presented with progressive swelling of eyes, lips, and tongue for one week. She did not consume angiotensin-converting enzyme inhibitors and reported no medication changes or exposure to unknown substances. Physical examination revealed facial, periorbital, and tongue edema with respiratory distress. Initial lab work was unremarkable. Histamine blockers and steroids were immediately administered, and she was intubated due to respiratory compromise. Racemic epinephrine was also initiated, and tracheostomy was performed for definitive airway management. Workup for infection was unrevealing. C1-Inhibitor, CH50, and C4 levels were not deficit. Once her respiratory status was stabilized, she was discharged to a long-term care facility. DISCUSSION: Angioedema, defined as localized subcutaneous or submucosal swelling due to the extravasation of fluid into interstitial tissues, maybe mast cell-mediated or kinin-mediated. The former is often associated with urticaria and is triggered by an allergic reaction or medications. At the same time, the latter occurs in the absence of a specific trigger and is associated with hereditary C1-Inhibitor deficiency or dysfunction. Our patient had normal C1 esterase inhibitor levels, rendering the diagnosis of hereditary angioedema less likely. Furthermore, she reported taking no medications known to cause angioedema and had not been exposed to any new allergens before the presentation. Literature states that patients with SLE characteristically exhibit reduced levels of components of the classical complement pathway. The defect can either originate from a lymphoproliferative disease that catabolizes C1-Inhibitor or circulating antibodies that inactivate C1-Inhibitor. However, our patient did not fulfill the above-mentioned criteria. Even though similar cases have been reported in the literature, the occurrence is still scarce. CONCLUSIONS: SLE has rarely been associated with recurrent angioedema. The pathophysiology of such is unclear. Our patient's late age of presentation and lack of family history of angioedema favored SLE as the independent risk factor for angioedema. Cl-inhibitor dysfunction in SLE is heterogeneous and distinct from that reported in either hereditary or acquired angioedema. Hence, more work needs to be done for early recognition and prompt prevention. REFERENCE #1: Dunckley H, Gatenby PA, Hawkins B, Naito S, Serjeantson SW. Deficiency of C4A is a genetic determinant of systemic lupus erythematosus in three ethnic groups. J Immunogenet. 1987 Aug-Oct;14(4-5):209-18. doi: 10.1111/j.1744-313x.1987.tb00383.x. PMID: 3502648. REFERENCE #2: Alsenz J, Bork K, Loos M. Autoantibody-mediated acquired deficiency of C1 inhibitor. N Engl J Med. 1987 May 28;316(22):1360-6. doi: 10.1056/NEJM198705283162202. PMID: 3494945. REFERENCE #3: Thong BY, Thumboo J, Howe HS, Feng PH. Life-threatening angioedema in systemic lupus erythematosus. Lupus. 2001;10(4):304-308. doi:10.1191/096120301680417011 DISCLOSURES: No relevant relationships by Asim Amjad, source=Web Response No relevant relationships by Zamara Hamid, source=Web Response No relevant relationships by Dan Kazmierski, source=Web Response No relevant relationships by Si Li, source=Web Response No relevant relationships by Pius Ochieng, source=Web Response No relevant relationships by NISHANT SHARMA, source=Web Response

Analysis of Heart-Rate Variability during Angioedema Attacks in Patients with Hereditary C1-Inhibitor Deficiency.

C1-inhibitor hereditary angioedema (C1-INH-HAE) is a rare disease characterized by self-limiting edema associated with localized vasodilation due to increased levels of circulating bradykinin. C1-INH-HAE directly influences patients’ everyday lives, as attacks are unpredictable in frequency, severity, and the involved anatomical site. The autonomic nervous system could be involved in remission. The cardiac autonomic profile has not yet been evaluated during the attack or prodromal phases. In this study, a multiday continuous electrocardiogram was obtained in four C1-INH-HAE patients until attack occurrence. Power spectral heart rate variability (HRV) indices were computed over the 4 h preceding the attack and during the first 4 h of the attack in three patients. Increased vagal modulation of the sinus node was detected in the prodromal phase. This finding may reflect localized vasodilation mediated by the release of bradykinin. HRV analysis may furnish early markers of an impending angioedema attack, thereby helping to identify patients at higher risk of attack recurrence. In this perspective, it could assist in the timing, titration, and optimization of prophylactic therapy, and thus improve patients’ quality of life.

Hereditary C1 inhibitor deficiency is associated with high spontaneous amidase activity.

Angioedema diagnosis classically targets the complement system (via C1 inhibitor (C1Inh) function and antigenic C4 level) and contact phase activation (via amidase activity). Bradykinin is responsible for angioedema attacks and is produced from contact phase activation secondary to failed C1Inh control. We aimed to compare the diagnostic performances of spontaneous amidase activity and antigenic C4 level in C1Inh hereditary angioedema (C1Inh-HAE) patients. Samples from 185 C1Inh-HAE patients (81 men, 104 women; confirmed by SERPING1 gene mutations) and from 99 blood donors (50 men, 49 women) were tested for C1Inh function, antigenic C4 level and spontaneous amidase activity. In the C1Inh-HAE group, antigenic C4 level was decreased (n=135) and amidase activity was increased (n=181). Receiver operating characteristic analyses showed higher diagnostic performance values for the spontaneous amidase assay compared to those of antigenic C4. The spontaneous amidase activity assay should replace antigenic C4 level testing and should be tested alongside the C1Inh function for both AE screening and follow up of HAE patients.

Angio-Oedema Induced by Oestrogen Contraceptives Is Mediated by Bradykinin and Is Frequently Associated with Urticaria

Background: Hereditary C1-inhibitor (C1-Inh) deficiency is associated with ‘bradykinin-mediated angio-oedema’ (BK-AO) and is believed not to be associated with urticaria. Acquired AO has been related to oestrogen contraceptives. Objective: To demonstrate that AO precipitated by oestrogens and characterized by nonfunctional C1-Inh is mediated by BK and to evaluate the occurrence of urticaria in these patients. Methods: A retrospective evaluation of patients referred for AO related to oestrogen was undertaken. Circulating C1-Inh, high molecular weight kininogen (HK) and enzymes involved in the metabolism of bradykinin were investigated. Results: Fifteen patients were included. HK cleavage concurrent to oestrogen intake was demonstrated in 10 patients with available plasma. Eight patients reported recurrent or chronic urticaria. Discontinuation of the contraceptive resulted in a return to native C1-Inh and HK in all cases studied and to normal kininogenase activity in all but one. The clinical manifestations completely disappeared in 6 patients and improved in 7 after the withdrawal of oestrogen. Conclusion: Patients display extensive cleavage of HK in the plasma, which supports that AO precipitated by oestrogen contraception is BK-mediated. Recurrent urticaria may have been underestimated in this context. The presence of recurrent urticaria should not systematically rule out the diagnosis of BK-AO when the history is suggestive.

Evidence‐based recommendations for the therapeutic management of angioedema owing to hereditary C1 inhibitor deficiency: consensus report of an International Working Group

Angioedema owing to hereditary deficiency of C1 inhibitor (HAE) is a rare, life-threatening, disabling disease. In the last 2 years, the results of well-designed and controlled trials with existing and new therapies for this condition have been published, and new treatments reached the market. Current guidelines for the treatment for HAE were released before the new trials and before the new treatments became available and were essentially based on observational studies and expert opinion. To provide evidence-based HAE treatment guidelines supported by the new studies, a conference was held in Gargnano del Garda, Italy, from September 26 to 29, 2010. The meeting hosted 58 experienced HAE expert physicians, representatives of pharmaceutical companies and representatives of HAE patients' associations. Here, we report the topics discussed during the meeting and evidence-based consensus about management approaches for HAE in adult/adolescent patients.

Standard care impact on angioedema because of hereditary C1 inhibitor deficiency: a 21-month prospective study in a cohort of 103 patients

Hereditary angioedema (HAE) due to the deficiency of C1 inhibitor (C1-INH) causes chronically recurrent cutaneous, abdominal and laryngeal angioedema that are disabling and potentially life-threatening. We designed a prospective study to quantify the residual disease in patients with HAE treated according to the existing consensus documents. Data were collected from diaries recording occurrence, duration, location and treatment of acute angioedema attacks. A total of 386 semesters properly completed were analyzed. Forty-seven of 103 patients were on prophylactic treatment, 41 with attenuated androgens and six with tranexamic acid. A total of 1532 angioedema attacks (one every 45.3 days) were registered. Peripheral attacks were the most frequent (698), followed by abdominal (503) and combined locations (232), laryngeal edema was less common (99). Patients on prophylaxis with attenuated androgens had 7.7 attacks/year lasting 1.47 days, those on tranexamic acid had 8.1 attacks/year lasting 1.59 days, and those without prophylaxis had 8.9 attacks/year lasting 1.68. Plasma-derived C1-INH was used by 44 patients to treat a total of 376 acute attacks that resolved faster (1.1 day) than those not treated (1.85 day) or treated with tranexamic acid (1.79 day). No adverse events related to C1-INH infusion were reported. Our data demonstrate that tranexamic acid is not effective in the treatment of acute attacks and indicate that under the current therapeutic approach, the HAE related disability is effectively but partially reduced. Incomplete success does not appear to depend on limited efficacy of the drugs but on their limited use that can be overcome by implementing specific treatment strategies.

Residual disease in patients with angioedema due to hereditary C1 inhibitor deficiency and access to established therapy: A 21 months prospective study in a cohort of 103 patients

Residual disease in patients with angioedema due to hereditary C1 inhibitor deficiency and access to established therapy: A 21 months prospective study in a cohort of 103 patients

Replacement therapy with C1 esterase inhibitors for hereditary angioedema

Angioedema due to hereditary C1 inhibitor deficiency (HAE) is a highly disabling and potentially lethal disease with an estimated prevalence of 1:50,000 in the general population worldwide. Treatment of this condition by replacing the deficient protein started shortly after discovery of the underlying genetic defect. Along with other therapeutic approaches developed over the years, C1 inhibitor replacement therapy maintains a central role for the treatment of angioedema attacks in patients with HAE. Two plasma-derived C1 inhibitors and a recombinant form, produced in transgenic rabbits, have successfully completed controlled trials that reinforced the evidence of the safety and efficacy of this treatment.

Usefulness of abdominal ultrasonography in the follow-up of patients with hereditary C1-inhibitor deficiency

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. 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. 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. 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. 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.

Disseminated Tuberculosis in a Patient with Hereditary C1-inhibitor Deficiency

Disseminated Tuberculosis in a Patient with Hereditary C1-inhibitor Deficiency

The impact of hereditary C1-inhibitor deficiency on the development of atherosclerosis

The impact of hereditary C1-inhibitor deficiency on the development of atherosclerosis

Recombinant human C1‐inhibitor in the treatment of acute angioedema attacks

Patients with hereditary C1-inhibitor deficiency have recurrent attacks of angioedema, preferably treated with C1-inhibitor concentrate. A recombinant human C1-inhibitor (rHuC1INH) was developed, derived from milk from transgenic rabbits. This study was undertaken to investigate the effects of rHuC1INH in the treatment of acute angioedema attacks in patients with a hereditary C1-inhibitor deficiency. Patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH (at a dose of 100 U/kg) within 8 hours after onset of an acute attack. Time to initiation of relief and time to minimal symptoms were reported by both the patient and the treating physician. Thirteen severe angioedema attacks in 9 patients with hereditary C1-inhibitor deficiency were treated with rHuC1INH. There was rapid improvement of clinical conditions for all attacks, with approximately 80 percent of treated patients experiencing symptom relief within 2 hours and minimal symptoms within 12 hours. There were no drug-related adverse events or immunogenic reactions to C1-inhibitor or rabbit proteins. The transgenically produced rHuC1INH was successfully used in the treatment of acute angioedema attacks in patients with hereditary C1-inhibitor deficiency.

Angioedema without urticaria in 929 patients: Description and proposal for a diagnostic approach

Rationale Angioedema without major urticaria flares is poorly characterized and few data exist on the underlying etiopathogenetic mechanisms. Here we report our experience on this condition and propose a diagnostic-therapeutic approach. Methods 929 consecutive patients were examined at our outpatient clinic for recurrent angioedema without urticaria between 1993 and 2002. Known causes of angioedema were identified by clinical history with detailed information about personal and familial allergies, relationship of angioedema to potential causative agents, complete physical examination, routine laboratory tests (blood cell count, protein electrophoresis, erythrosedimentation rate, stool for ova and parasites, pharyngeal and urine cultures, sinus and dental film, anti-tissue autoantibodies, rheumatoid factor), complement parameters (C1 inhibitor, C4, C1q). Further testing was done when pertinent. When all was negative, response to H1-antihistamine was considered. Results According to our testing angioedema were classified as follow: related to external agents (drugs, insect stings, food) 209 (22.5%) (85 of them were related to treatment with an ACE-inhibitor); associated to autoimmune diseases or infections 77 (8.2%); hereditary C1 inhibitor deficiency 183 (19.6%); acquired C1 inhibitor deficiency 14 (1.5%); idiopathic histaminergic 253 (27.2%), idiopathic non histaminergic 40 (4%). 153 patients (16.4%) dropped out from the study and could not be classified. Conclusions Based on the frequency of the different diagnosis we propose the following progression of testing: 1. anamnestic identification of causative agents, 2. testing for complement abnormalities, 3. H1 antagonist treatment, 4. complete diagnostic workup.

Bradykinin and the pathophysiology of angioedema

Angioedema has different causes and different clinical presentations. Some types of angioedema may be mediated by bradykinin. We measured plasma levels of bradykinin-(1–9)nonapeptide by radioimmunoassay after high-performance liquid chromatography in patients with different types of angioedema during acute attacks and/or in remission, i.e. hereditary C1-inhibitor deficiency, angiotensin converting enzyme (ACE) inhibitor treatment, idiopathic non histaminergic and responders to antihistamines. Eleven patients with the deficiency of C1-inhibitor had very high levels of bradykinin during acute attacks of angioedema (18.0–90.0 pM) (normal range 0.2–7.1 pM). In three patients with history of ACE inhibitor-related angioedema, plasma bradykinin was high during ACE inhibitor treatment (62.0, 8.9 and 27.0 pM) and in a fourth patient was 47.0 pM during an acute attack and decreased by 93% to 3.2 pM after withdrawal of the ACE inhibitor. The patient with idiopathic angioedema, during an acute attack involving the right arm, had high levels of bradykinin in the venous blood refluent from the angioedematous arm (20.0 pM) while in the contralateral arm bradykinin levels were normal (6.6 pM), similarly to what we previously observed in cases of brachial angioedema due to C1-inhibitor deficiency. The four patients with angioedema responsive to antihistamines had normal levels of bradykinin even during acute attacks (5.7, 3.4, 4.7 and 1.2 pM). In one of these patients who had a brachial angioedema, bradykinin levels were normal in the venous blood refluent from both arms. Bradykinin is involved in hereditary C1-inhibitor deficiency angioedema, in ACE inhibitor-related angioedema, and in idiopathic non-histaminergic angioedema, while bradykinin is not related to allergen-dependent or idiopathic angioedema that are responsive to antihistamines.

Consumption of C4b-binding protein (C4BP) during in vivo activation of the classical complement pathway.

C4BP has a central role in regulating the classical complement (C') pathway, but it is still uncertain whether or not it is consumed during in vivo complement activation. Attempts to demonstrate changes in C4BP plasma levels in systemic lupus erythematosus and essential mixed cryoglobulinaemia have failed, probably due to up-regulation of this protein during the inflammatory reaction. We have studied one patient with severe post-transfusion complement-mediated anaphylaxis (CMA), and 67 patients with hereditary C1 inhibitor deficiency (hereditary angioedema (HAE)). The first of these two conditions is characterized by the absence of systemic inflammatory reaction and the second by acute and chronic activation of the C' classical pathway. C4BP, C4BP-C4b complex, and soluble terminal C' complex (sC5b-9) were measured in the patients' plasmas by ELISA techniques and C3a and C4a by radioimmunoassays. In CMA, 15 min after the transfusion, there was a massive C' activation, with increases in C4a, C3a, sC5b-9, C4BP-C4b complexes and decreases in C4, C3 and C4BP. All parameters reverted to preinfusion values within 24 h. Depletion of C4 was correlated with that of C4BP. In patients with HAE, the median value of C4BP (83% range 54-165) was significantly lower (P < 0.0001) than in normal controls (99% range 70-159), with no difference between patients in remission or during acute attacks. C4BP-C4b complexes could not be detected in HAE patients. The results of this study indicate that C4BP is consumed in vivo during acute, and possibly during chronic activation of the C' classical pathway, and that this protein, after interaction with C4b, not longer circulates in plasma.

Hereditary C1 inhibitor deficiency increases the risk for renal diseases

Hereditary C1 inhibitor deficiency increases the risk for renal diseases

A novel ELISA for the evaluation of the classical pathway of complement

Assessment of the overall function of the classical pathway of complement is traditionally performed by the hemolytic titration assay CH50. In the present study, we established a novel method for the quantitation of complement activity by measuring the deposition of C1q, C4, C3 and C9 on solid-phase IgM by an enzyme-linked immunosorbent assay (ELISA). Using the CH50 method as the reference, C9 deposition values displayed a sensitivity of 96.3% and a specificity of 99.4% in sera from patients with a variety of diseases. For C3, the sensitivity was 91.3% and the specificity 100%, for C4, the values were 95% and 100%, and for C1q, the corresponding values were 52.9% and 98.9%. A close correlation was found between CH50 values below 30 U/ml and the deposition of C9 ( r=0.92), C3 ( r=0.91) and C4 ( r=0.92). In two patients with postinfectious glomerulonephritis normal C4 and C1q deposition was accompanied by decreased C3 and C9 deposition reflecting complement activation predominantly through the alternative pathway. In contrast, in two patients with complete C2 deficiency the deposition of C3 and C9 was undetectable together with normal C4 deposition values. Furthermore, in two patients with hereditary C1-inhibitor deficiency distinctly increased C1q deposition was accompanied by decreased C4 deposition values. In conclusion, the determination of complement deposition by ELISA represents a novel, quantitative method for the evaluation of complement activity. The measurement of C9 deposition alone or in combination with further complement proteins makes this ELISA a valuable tool for assessing the degree and level of complement consumption as well as localizing the missing protein in the case of complement deficiencies.

P236 Subacute cutaneous lupus erythematosus associated with hereditary C1 inhibitor deficiency

P236 Subacute cutaneous lupus erythematosus associated with hereditary C1 inhibitor deficiency