Application of a dried blood spot based proteomic and genetic assay for diagnosing hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is a rare disease caused by low level (type I) or dysfunction (type II) of the C1-inhibitor protein with subsequent reduction of certain complement protein levels. METHODS: To develop and test the reliability of a two-tier method based on C1-INH and C4 quantitation followed by genetic analysis from dried blood spot (DBS) for establishing the diagnosis of C1-INH-HAE. C1-INH and C4 proteins have been quantified in human plasma using a classical immuno-assay and in DBS using a newly developed proteolytic liquid chromatography-mass spectrometry method. Genetic analysis was carried out as reported previously (PMID: 35386643) and by a targeted next-generation sequencing panel, multiplex ligation-dependent probe amplification and in some cases whole genome sequencing. RESULTS: DBS quantification of C1-INH and C4 showed the same pattern as plasma, offering the possibility of screening patients with AE symptoms either locally or remotely. Genetic analysis from DBS verified each of the previously identified SERPING1 mutations of the tested C1-INH-HAE patients and revealed the presence of other rare variations in genes that may be involved in the pathogenesis of AE episodes. CONCLUSIONS: C1-INH/C4 quantification in DBS can be used for screening of hereditary AE and DNA extracted from dried blood spots is suitable for identifying various types of mutations of the SERPING1 gene.

C1-inhibitor/C1-inhibitor antibody complexes in acquired angioedema due to C1-inhibitor deficiency.

BACKGROUND: Autoantibodies against C1-inhibitor (C1-INH-Ab) have a diagnostic value in acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE), even though antibodies can circulate in complexes, which can be undetectable by proven methods. Our aim was to measure C1-INH/C1-INH-Ab complexes (CAC) and investigate their connection to C1-INH-Ab and the changes in their titer over time. RESULTS: 19 patients were diagnosed with C1-INH-AAE in the Hungarian Angioedema Center of Reference and Excellence; 79% of them had an underlying disease. Samples were examined with a newly developed in-house complex ELISA method. Patients with high C1-INH-Ab titer had a CAC titer which did not exceed the normal level and the ones with high CAC titer had a C1-INH-Ab titer which did not exceed the normal level. In case of those patients who had C1-INH-Ab and CAC of the same type of immunoglobulin, the increasing titer of C1-INH-Ab went together with the decreasing level of CAC and vice versa. CAC titer was already increased before the diagnosis of the underlying disease. CONCLUSIONS: Free circulating and complex antibodies are in a dynamically changing equilibrium. CAC measurements can help to predict the development of an underlying disease. The efficiency of the treatment for underlying disease can be monitored by the decreasing CAC titers. Our results show that the CAC can be of important additional information besides the complement panel examination in case of C1-INH-AAE. Measurement of CAC is recommended to be done parallelly with C1-INH-Ab, so as to detect both free and bound antibodies.

Long term follow-up of complement parameters to improve the management of acquired angioedema due to C1-inhibitor deficiency.

Acquired angioedema due to C1-inhibitor deficiency (C1-INH-AAE) is a rare disease that can be diagnosed via complement testing. It often accompanies lymphoproliferative underlying diseases. Our study aimed to examine if there is a connection between complement parameters and the clinical symptoms of C1-INH-AAE, and, in case of a known underlying disease, its activity. The other question is how a connection, if proven, could help in the development of the therapeutic strategy of C1-INH-AAE patients. In the past 30 years, out of the 3938 patients sent to the Angioedema Center with angioedema symptoms, we have diagnosed C1-INH-AAE in 19 cases. An underlying disease was diagnosed in 15 patients. Most often lymphoma (6/19 patients) and monoclonal gammopathy of undetermined significance (6/19 patients) were found. Angioedema specific long-term prophylaxis did not result in an improvement in neither the frequency of the attacks nor in the complement parameters. A connection has been found between the presence and activity of any underlying disease, the frequency of the angioedema attacks and the decreased level of proteins of the complement system. Decreasing complement parameters warn about the appearance or the worsening of the underlying disease. The treatment of the underlying disease brings improvement in the complement parameters. Rituximab treatment reduced the number of attacks or completely made them disappear, and we experienced positive changes in complement parameters. Complement parameters supported the long-term efficacy of rituximab treatment for C1-INH-AAE. The change in complement parameters predict the relapse of the underlying disease, and it is a good indicator for the prediction of angioedematous attacks. In C1-INH-AAE, it is essential to examine the patients for underlying diseases, and to regularly follow up the patient's complement parameters.

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

Background: Hereditary 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. Methods: We 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. Results: From 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. Discussion: The 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.

Overview of SERPING1 Variations Identified in Hungarian Patients With Hereditary Angioedema.

Background: Hereditary angioedema (HAE) due to C1-inhibitor (C1-INH) deficiency (C1-INH-HAE) is a rare autosomal dominant disorder, characterized by recurrent, unpredictable edematous symptoms involving subcutaneous, and/or submucosal tissue. C1-INH-HAE may be caused by more than 700 different mutations in the gene encoding C1-INH (SERPING1) that may lead to decreased protein synthesis or to functional deficiency. Methods: Concentrations of C1-INH, C4, C1q, and anti-C1-INH antibodies, as well as functional C1-INH activity were determined in subjects suffering from edematous symptoms and admitted to the Hungarian Angioedema Center of Reference and Excellence. In those patients, who were diagnosed with C1-INH-HAE based on the complement measurements, SERPING1 was screened by bidirectional sequencing following PCR amplification and multiplex ligation-dependent probe amplification. For detecting large deletions, long-range PCRs covering the entire SERPING1 gene by targeting 2-7 kb long regions were applied. Results: Altogether 197 individuals with C1-INH deficiency belonging to 68 families were identified. By applying Sanger sequencing or copy number determination of SERPING1 exons, 48 different mutations were detected in 66/68 families: 5 large and 15 small insertions/deletions/delins, 16 missense, 6 nonsense, and 6 intronic splice site mutations. Two novel variations (p.Tyr199Ser [c.596A>C] and the duplication of exon 7) were shown to cosegregate with deficient C1-inhibitor level and activity, while two other variations were detected in single patients (c.797_800delinsCTTGGAGCTCAAGAACTTGGAGCT and c.812dup). A series of long PCRs was applied in the remaining 2 families without an identified mutation and a new, 2606 bp long deletion including the last 91 bp of exon 6 (c.939_1029+2515del) was identified in all affected members of one pedigree. In the remaining one family, a deep intronic SERPING1 variation (c.1029+384A>G) was detected by a targeted next-generation sequencing panel as reported previously. Conclusions: Sequencing and copy number determination of SERPING1 exons uncover most pathogenic variants in C1-INH-HAE patients, and further methods are worth to be applied in cases with unrevealed genetic background. Since knowledge of the genetic background may support the establishment of the correct and early diagnosis of C1-INH-HAE, identification of causative mutations and reporting data supporting the interpretation on the pathogenicity of these variants is of utmost importance.

The characteristics of upper airway edema in hereditary and acquired angioedema with C1-inhibitor deficiency.

BACKGROUND: Angioedemas localized in the upper airway are potentially life threatening, and without proper treatment, they may lead to death by suffocation. Upper airway edemas (UAE) in bradykinin-mediated angioedemas can even be the first symptoms of the disease. METHODS: Our survey was performed with a retrospective long-term follow-up method from the medical history of 197 hereditary (C1-INH-HAE) and 20 acquired C1-inhibitor deficiency (C1-INH-AAE), 3 factor XII and 3 plasminogen gene mutation (FXII-HAE, PLG-HAE) patients treated at our center between 1990 and 2020. The UAE group included edemas localized to the mesopharynx, hypopharynx, and larynx, as narrowing of these anatomical regions can lead to suffocation. RESULTS: 98/197 C1-INH-HAE (47 families) and 13/20 C1-INH-AAE, 1/3 PLG-HAE, 1/3 FXII-HAE patients had experienced UAE at least once according to their medical history. In case of C1-INH-HAE patients, in 6/47 families who had undiagnosed ancestors had 13 members who died of suffocation. After the diagnosis, 1-1 member of two families died of UAE. 44/64 C1-INH-HAE patients did not smoke, 20/64 did. The occurrence of UAE was significantly higher in smoker patients. We analyzed 7607 HAE attacks of 56/98 patients. Out of all attacks, the incidence of UAE in the C1-INH-HAE group was 4%, and 9.5% in the C1-INH-AAE group, respectively. CONCLUSION: Early diagnosis is key in bradykinin-mediated angioedemas cases, since the patient must be provided with adequate treatment; and also it is essential to inform patients about the importance of avoiding the trigger factors and the early symptoms of UAE, as these measures could significantly decrease the incidence of lethal UAEs.

The Global Registry for Hereditary Angioedema due to C1-Inhibitor Deficiency.

Hereditary angioedema (HAE) is a rare condition, mostly due to genetic deficiency of complement C1 inhibitor (C1-INH). The rarity of HAE impedes extensive data collection and assessment of the impact of certain factors known to affect the course of this disabling and life-threatening disease. Establishing a global registry could assist to overcome such issues and provides valuable patient data from different countries. The HAE Global Registry is a disease-specific registry, with web-based electronic support, where data are provided by physicians and patients through a dedicated application. We collected data between January 1, 2018, and August 31, 2020. Data on 1297 patients from 29 centers in 5 European countries were collected. At least one attack was recorded for 497 patients during the study period. Overall, 1182 patients were diagnosed with HAE type 1 and 115 with type 2. At the time of database lock, 389 patients were taking long-term prophylactic medication, 217 of which were on danazol. Most recorded attacks affected the abdomen, were generally moderate in severity, and occurred in patients who were not on prophylactic treatment (70.6%, 6244/8848). The median duration of attacks was 780 min (IQR 290-1740) in patients on prophylactic medication and 780 min (IQR 300-1920) in patients not on continuous prophylactic medication. In conclusion, the establishment of a registry for C1-INH-HAE allowed collection of a large amount of data that may help to better understand the clinical characteristics of this disease. This information may enhance patient care and guide future therapeutic decisions.

Screening for Plasminogen Mutations in Hereditary Angioedema Patients.

Hereditary angioedema (HAE) is a rare disease belonging to the group of bradykinin-mediated angioedemas, characterized by recurring edematous episodes involving the subcutaneous and/or submucosal tissues. Most cases of HAE are caused by mutations in the SERPING1 gene encoding C1-inhibitor (C1-INH-HAE); however, mutation analysis identified seven further types of HAE: HAE with Factor XII mutation (FXII-HAE), with plasminogen gene mutation (PLG-HAE), with angiopoietin-1 gene mutation (ANGPT1-HAE), with kininogen-1 gene mutation (KNG1-HAE), with a myoferlin gene mutation (MYOF-HAE), with a heparan sulfate-glucosamine 3-sulfotransferase 6 (HS3ST6) mutation, and hereditary angioedema of unknown origin (U-HAE). We sequenced DNA samples stored from 124 U-HAE patients in the biorepository for exon 9 of the PLG gene. One of the 124 subjects carried the mutation causing a lysine to glutamic acid amino acid exchange at position 330 (K330E). Later, the same PLG mutation was identified in the patient's son. The introduction of new techniques into genetic testing has increased the number of genes identified. As shown by this study, a biorepository creates the means for the ex-post analysis of recently identified genes in stored DNA samples of the patients. This makes the diagnosis more accurate with the possibility of subsequent family screening and the introduction of appropriate therapy.

How Angioedema Quality of Life Questionnaire Can Help Physicians in Treating C1-Inhibitor Deficiency Patients?

The Angioedema Quality of Life Questionnaire (AE-QoL) is an angioedema (AE)-specific validated questionnaire, which surveys the quality of life of diagnosed patients. The questionnaire has been used in multiple clinical trials. Our aim was to investigate how the questionnaire can assist physicians in the everyday practice of following up and managing C1-inhibitor deficiency patients. In a prospective trial conducted in our center between 2016 and 2018, 125 hereditary angioedema and 10 diagnosed with acquired angioedema completed an AE-QoL during their annual follow-up visit. Laboratory indices (i.e., complement levels) were obtained for each patient. Statistical analysis comparing clinical data with QoL parameters was performed. Results of the analysis show that AE-QoL total score and number of AE attacks per year correlated well (r = 0.47; p < 0.0001). Women reached higher AE-QoL total score values than men, over a 3-year period (p = 0.0014). The highest AE-QoL total scores were reached by the 41-60-year age group; we obtained a similar result, when analyzing the four domains. No correlation was found between the AE-QoL total score and complement parameters. Patients with a negative correlation between AE-QoL total score and number of AE attacks had a positive correlation with psychologic attributes like fatigue/mood and fears/shame domains. Patients that acquired HAE showed a significant correlation between the annual number of AE attacks and the AE-QoL total scores (r = 0.46; p < 0.0001). The study establishes the use of AE-QoL as a clinical tool for follow-up which can help in the complex assessment of both hereditary and acquired HAE patients, and help to develop better therapeutic strategies.

Pathways of Neutrophil Granulocyte Activation in Hereditary Angioedema with C1 Inhibitor Deficiency.

Hereditary angioedema (HAE) with C1-inhibitor deficiency belongs to bradykinin-mediated angioedemas. It is characterized by recurrent subcutaneous and/or submucosal swelling episodes (HAE attacks) and erythema marginatum skin rash as a pre-attack (prodromal) phase. HAE attacks were shown to be accompanied by peripheral blood neutrophilia. We aimed to find molecular mechanisms that may explain the distinct role of neutrophil granulocytes in HAE. Plasma levels of blood cells and factors related to neutrophil activation (cytokines, chemokines, chemotactic factors, enzymes, and neutrophil extracellular trap) were measured in plasma samples obtained from patients during symptom-free periods (n = 77), during prodromal phase (n = 8) and attacks (n = 14), during a spontaneously resolved attack (n = 1), and in healthy controls (n = 79). Higher counts of white blood cells, lymphocytes, and neutrophil granulocytes were found in symptom-free patients compared with controls; these cell counts were elevated further during HAE attacks. The level of chemokine (C-C motif) ligand 5, monocyte chemoattractant protein-1, and myeloperoxidase were also higher in the symptom-free patients than in the controls. Levels of monocyte chemoattractant protein-1, leukotriene B4, neutrophil elastase, and myeloperoxidase were elevated during attacks. During erythema marginatum, white blood cells and monocyte count and levels of interleukin 8 were elevated compared with symptom-free period. Similar changes were detected during the attack follow-up. We conclude that the activation of NGs in symptom-free periods and a further increase observed during attacks suggests that NGs may be involved in the pathomechanism of HAE with C1-INH deficiency.

The Role of Mannose-binding Lectin in Infectious Complications of Pediatric Hemato-Oncologic Diseases.

The complement system is essential for protection against infections in oncologic patients because of the chemotherapy-induced immunosuppression. One of the key elements in the activation of the complement system via the lectin pathway is the appropriate functioning of mannose-binding lectin (MBL) and mannose-binding lectin-associated serine protease 2 (MASP2) complex. The objective of our study was to find an association between polymorphisms resulting in low MBL level and activation of the MBL-MASP2 complex. Also, we aimed at finding a connection between these abnormalities and the frequency and severity of febrile neutropenic episodes in children suffering from hemato-oncologic diseases. Ninety-seven patients had been enrolled and followed from the beginning of the therapy for 8 months, and several characteristics of febrile neutropenic episodes were recorded. Genotypes of 4 MBL2 polymorphisms (-221C/G, R52C, G54D, G57E) were determined by real-time polymerase chain reaction. Activation of the MBL-MASP2 complex was evaluated by enzyme-linked immunosorbent assay at the time of diagnosis and during an infection. The number of febrile neutropenic episodes was lower, and the time until the first episode was longer in patients with normal MBL level than in patients with low MBL level coding genotypes. The MBL-MASP2 complex activation level correlated with the MBL genotype and decreased significantly during infections in patients with low MBL level. Our results suggest that infections after immunosuppression therapy in children suffering from hemato-oncologic diseases are associated with the MBL2 genotype. Our results may contribute to the estimation of risk for infections in the future, which may modify therapeutic options for individuals.

The Importance of Complement Testing in Acquired Angioedema Related to Angiotensin-Converting Enzyme Inhibitors.

BACKGROUND: Angiotensin-converting enzyme inhibitors may cause angioedema. Currently, no laboratory method is available for identifying acquired angioedema related to angiotensin-converting enzyme inhibitors. However, establishing the diagnosis is possible from the medical history and the preexisting angiotensin-converting enzyme inhibitor therapy, as well as by excluding other angioedema types. OBJECTIVE: To evaluate the results of complement testing in patients experiencing angioedema while taking angiotensin-converting enzyme inhibitors. METHODS: Between 2005 and 2019, a total of 149 patients taking angiotensin-converting enzyme inhibitors were referred to our Angioedema Center for the diagnostic evaluation of recurrent angioedema episodes. Complement measurement was performed on these patients. RESULTS: The mean age of the 149 patients treated with angiotensin-converting enzyme inhibitors at the onset of the index angioedema episode was 55.8 years. The mean interval between the introduction of angiotensin-converting enzyme inhibitor therapy and the occurrence of the initial symptoms of angioedema was 43 months. The most commonly used angiotensin-converting enzyme inhibitor was perindopril (32.9% of the patients). The initial angioedema episode involved the face in 50.3%, the lips in 40.9%, and the tongue in 33.5% of the patients. Angiotensin-converting enzyme inhibitors were discontinued in all 149 patients, and at the same time, a complement test was performed. The complement tests confirmed hereditary angioedema with C1-inhibitor deficiency in 2 patients and an additional 12 family members. Acquired angioedema with C1-inhibitor deficiency was found in 3 patients. CONCLUSIONS: Excluding hereditary angioedema and acquired angioedema with C1-inhibitor deficiency is indispensable for establishing the diagnosis of acquired angioedema related to angiotensin-converting enzyme inhibitors.

Patterns of C1-Inhibitor/Plasma Serine Protease Complexes in Healthy Humans and in Hereditary Angioedema Patients.

C1-inhibitor (C1-INH) is an important regulator of the complement, coagulation, fibrinolytic and contact systems. The quantity of protease/C1-INH complexes in the blood is proportional to the level of the in vivo activation of these four cascade-like plasma enzyme systems. Parallel determination of C1-INH-containing activation complexes could be important to understand the regulatory role of C1-INH in diseases such as hereditary angioedema (HAE) due to C1-INH deficiency (C1-INH-HAE). We developed in-house ELISAs to measure the concentration of complexes of C1-INH formed with active proteases: C1r, C1s, MASP-1, MASP-2, plasma kallikrein, factor XIIa, factor XIa, and thrombin, as well as to determine total and functionally active C1-INH. We measured the concentration of the complexes in EDTA plasma from 6 healthy controls, from 5 with type I and 5 with type II C1-INH-HAE patients during symptom-free periods and from five patients during HAE attacks. We also assessed the concentration of these complexes in blood samples taken from one C1-INH-HAE patient during the kinetic follow-up of a HAE attack. The overall pattern of complexed C1-INH was similar in controls and C1-INH-HAE patients. C1-INH formed the highest concentration complexes with C1r and C1s. We observed higher plasma kallikrein/C1-INH complex concentration in both type I and type II C1-INH-HAE, and higher concentration of MASP-1/C1-INH, and MASP-2/C1-INH complexes in type II C1-INH-HAE patients compared to healthy controls and type I patients. Interestingly, none of the C1-INH complex concentrations changed significantly during HAE attacks. During the kinetic follow-up of an HAE attack, the concentration of plasma kallikrein/C1-INH complex was elevated at the onset of the attack. In parallel, C1r, FXIIa and FXIa complexes of C1-INH also tended to be elevated, and the changes in the concentrations of the complexes followed rather rapid kinetics. Our results suggest that the complement classical pathway plays a critical role in the metabolism of C1-INH, however, in C1-INH-HAE, contact system activation is the most significant in this respect. Due to the fast changes in the concentration of complexes, high resolution kinetic follow-up studies are needed to clarify the precise molecular background of C1-INH-HAE pathogenesis.

Clinical Characteristics and Safety of Plasma-Derived C1-Inhibitor Therapy in Children and Adolescents with Hereditary Angioedema-A Long-Term Survey.

BACKGROUND: Plasma-derived C1-inhibitor (pdC1-INH) is a first-line therapy for hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) in pediatric patients. OBJECTIVE: We intended to study the clinical characteristics and safety of treatment with pdC1-INH in this population. METHODS: In the prospective, long-term survey, real-world data on pdC1-INH (Berinert, CSL Behring) use in pediatric patients, diagnosed and followed up at our Angioedema Reference Center, were analyzed for the period from 1986 to 2018. RESULTS: A total of 70 pediatric patients (31 boys and 39 girls) experienced a total of 3009 HAE attacks. The most common location of HAE attacks was subcutaneous. HAE attacks of any location were more frequent in girls versus boys, except for genital edema. Among the 70 patients, 37 received pdC1-INH for 456 HAE attacks, or as prophylaxis (69 vials). On average, 14.2 vials were administered per patient. The distribution of pdC1-INH use in the different age groups was as follows: no use (0-1 years), 0.11 vials/year (1-3 years), 0.7 vials/year (3-6 years), 1.26 vials/year (6-12 years), and 1.28 vials/year (12-18 years). No systemic allergic reactions, viral transmission, development of anti-C1-INH antibodies, or thromboembolic events occurred in relation to treatment with this drug. CONCLUSION: We confirmed that the clinical manifestations and the use of pdC1-INH are different in the various age groups of pediatric patients with C1-INH-HAE. Our long-term survey shows that the use of pdC1-INH is safe in this patient population.

Changes of coagulation parameters during erythema marginatum in patients with hereditary angioedema.

BACKGROUND: Hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE) is characterized by recurrent episodes of subcutaneous/submucosal edema, which may be preceded by erythema marginatum (EM) as a prodromal symptom. Our aim was to analyze the changes occurring in the parameters of the coagulation system during the development of EM and HAE attacks. MATERIALS AND METHODS: Eight C1-INH-HAE patients (1 male, 7 females, median age: 41.7 years) were studied. Blood samples were obtained from all patients (during symptom-free periods, EM, and HAE attacks), as well as from 20 sex- and age-matched healthy controls. Prothrombin time (PT), activated partial thromboplastin time (aPTT), fibrinogen, D-dimer, Factor V, Factor VII, Factor X, Factor XI, and Factor XII levels were measured. RESULTS: D-dimer levels were significantly lower, whereas aPTT was significantly prolonged in healthy controls vs. the values measured during the symptom-free period (p = 0.0497; p = 0.0043), in the presence of EM (p = 0.002; p = 0.0002), or during HAE attacks (p < 0.0001; p = 0.0002). We observed the following differences between samples taken during HAE attacks vs. in symptom-free periods: D-dimer levels were significantly elevated (p = 0.0391), while aPTT was significantly shorter during HAE attacks (p = 0.0159). D-dimer levels were significantly higher during EM than in symptom-free periods (p = 0.0078). Comparing the samples drawn during EM or during HAE attacks, there were no significant differences in the study parameters. CONCLUSIONS: D-dimer levels were elevated during EM and this suggests that EM may be part of the HAE attack. Nevertheless, further research into the complement and kinin-kallikrein systems is needed in more patients for a better understanding of the pathomechanism of EM.

Evaluation of the efficacy and safety of home treatment with the recombinant human C1-inhibitor in hereditary angioedema resulting from C1-inhibitor deficiency.

OBJECTIVE: Conestat alpha, a C1-inhibitor produced by recombinant technology (rhC1-INH) is an acute treatment for edematous attacks occurring in hereditary angioedema (HAE) with C1-inhibitor deficiency (C1-INH-HAE). Our study evaluated the efficacy and safety of rhC1-INH administered during HAE attacks, and for short-term prophylaxis (STP). MATERIALS & METHOD: Our prospective study analyzed the course of 544 HAE attacks experienced by the 21 C1-INH-HAE patients treated, as well as the outcome of 97 instances of STP implemented with rhC1-INH. Using a purpose-designed questionnaire, the patients recorded relevant, treatment-related information. RESULTS: Time to the administration of rhC1-INH was 90.0 min (median) after the onset of HAE attacks. The symptoms started to improve as early as 60 min after the injection of rhC1-INH, and the attack resolved 730.0 min after treatment. The interval between the onset of the HAE attack and the administration of rhC1-INH correlated with time until the onset of improvement (R = 0.2053 p < 0.0001), and with time to the complete resolution of symptoms (R = 0.2805, p < 0.0001). Nine patients received STP with rhC1-INH in 97 instances. STP successfully prevented the HAE attack within 72 h of the event on 93/97 occasions. No local and serious systemic adverse events/effects were observed. CONCLUSIONS: Treatment with rhC1-INH is effective and safe both for acute management, and for STP. Following the onset of an HAE attack, early administration of rhC1-INH may reduce time to the improvement and to the complete resolution of symptoms. Repeated administration of rhC1-INH does not impair its efficacy.

[Analysis of the relationship between vitamin D3 level and disease severity in hereditary angioedema]. / A D3-vitamin-szint és a betegség súlyossága közötti kapcsolat vizsgálata herediter angioödémában.

Introduction: In recent years, many papers analyzed the relationship between serum vitamin D3 level and the frequency and activity of various diseases at least partially attributed to immune mechanisms. Aim: We looked for correlations among the number and location of edematous episodes occurring in patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) and the quantity of the C1-inhibitor used for supplementation as well as the vitamin D3 levels of patients. Method: We measured vitamin D3 levels in 118 of the 175 C1-INH-HAE patients of the National Angioedema Reference Center during the winter-spring (n = 111) and the summer-autumn periods (n = 105) in 2013-2014. Complement levels and clinical data were extracted from the National Angioedema Registry and from patient diaries. Results: The proportion of vitamin D3 deficient patients (serum level <20 ng/ml) was approximately 59.5% during winter-spring, 27.6% in summer-autumn, and 23.5% during both periods. There was a significant difference between vitamin D3 serum levels measured in the winter-spring or in the summer-autumn months (p<0.0001). The same applies to the number of the vials of C1-inhibitor concentrate administered as acute treatment for angioedema attacks (p = 0.01). In any season, vitamin D3 level did not correlate with the number of attacks experienced by the patients during the given period or of the vials of C1-inhibitor concentrate administered. Conclusions: We could not demonstrate a relationship between vitamin D3 level and the frequency or location of edematous episodes in HAE patients. The need for treatment (as reflected by the number of the vials administered) was higher in the winter-spring period. As vitamin D3 deficiency was more severe than expected in our patients, supplementation is clearly necessary. Orv Hetil. 2019; 160(25): 987-993.

Idiopathic Nonhistaminergic Acquired Angioedema Versus Hereditary Angioedema.

BACKGROUND: The mechanism of idiopathic nonhistaminergic acquired angioedema (InH-AAE) has not yet been precisely elucidated. This condition is characterized by recurrent angioedema without wheals. OBJECTIVE: To study the clinical features of InH-AAE, and to make, for the first time, independent comparisons with hereditary angioedema of unknown origin (U-HAE), as well as with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE). METHODS: We compared the clinical parameters of 46 patients with InH-AAE with those of 27 patients suffering from U-HAE, as well as of 73 patients with C1-INH-HAE. RESULTS: The mean age at the onset of symptoms was 36 years in InH-AAE, 13 years in C1-INH-HAE, and 29 years in U-HAE. More than 12 edematous episodes occurred over a year in 56% of patients with InH-AAE, in 59% of those with C1-INH-HAE, and in 48% of those with U-HAE. Edema of the extremities, of the upper airways, and of the gastrointestinal tract was more common in patients with C1-INH-HAE (92%, 51%, and 75%, respectively). These manifestations occurred less frequently in patients with InH-AAE (54%, 28%, and 20%) and in patients with U-HAE (37%, 29%, and 20%). By contrast, facial edema occurred in only 15% of patients with C1-INH-HAE, but in 67% of patients with InH-AAE and in 59% of patients with U-HAE. CONCLUSIONS: The clinical manifestations of patients with InH-AAE were different from those of patients with C1-INH-HAE. This may indicate different processes underlying edema formation in these disease forms. The close resemblance of the clinical manifestations in InH-AAE and U-HAE might suggest a similarity between the pathophysiology of these conditions.

[Effect of danazol treatment on growth in pediatric patients with hereditary angioedema due to C1-inhibitor deficiency]. / A danazolkezelés hatása C1-inhibitor-hiány okozta hereditaer angiooedemás gyermekek növekedésére.

INTRODUCTION: Attenuated androgens are used for the prevention of angioedema attacks of hereditary angioedema with C1-inhibitor deficiency. After prepuberty, their use can lead to growth retardation. AIM: We assessed the effect of danazol on the growth of pediatric patients with hereditary angioedema. METHOD: In the retrospective study on 42 patients diagnosed with hereditary angioedema, we calculated the deviation from the mid-parental target height, and analyzed it against the gender, the dose and duration of danazol treatment administered before the age of 21 years and before the age of 16 years. RESULTS: Regarding the deviation from the mid-parental target height, we did not find any significant difference between patients taking vs. not taking danazol, males vs. females taking danazol. The dose and the duration of danazol treatment did not influence that value neither before 21, nor before 16 years of age. CONCLUSIONS: Our findings suggest that treatment with the lowest effective doses of danazol does not influence growth. Orv Hetil. 2017; 158(32): 1269-1276.

The role of the complement system in hereditary angioedema.

Hereditary angioedema (HAE) is a rare, but potentially life-threatening disorder, characterized by acute, recurring, and self-limiting edematous episodes of the face, extremities, trunk, genitals, upper airways, or the gastrointestinal tract. HAE may be caused by the deficiency of C1-inhibitor (C1-INH-HAE) but another type of the disease, hereditary angioedema with normal C1-INH function (nC1-INH-HAE) was also described. The patient population is quite heterogeneous as regards the location, frequency, and severity of edematous attacks, presenting large intra- and inter-individual variation. Here, we review the role of the complement system in the pathomechanism of HAE and also present an overview on the complement parameters having an importance in the diagnosis or in predicting the severity of HAE.