Hypersensitivity reactions amongst Hungarian Patients with Hereditary Angioedema due to C1-Inhibitor Deficiency.

Background: In hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE), bradykinin-mediated submucosal and/or subcutaneous angioedema dominates the clinical picture. The deficiency of C1-inhibitor can lead to the over-activation of the complement system. Complement plays an important role in all types of hypersensitivity reactions. On the other hand, during the degranulation of mast cells, heparin is also released amongst other substances. Heparin can activate the plasma kinin-kallikrein system, leading to bradykinin generation. These observations suggest a possible connection between C1-INH-HAE and mast cell-mediated hypersensitivity reactions. Objective: To assess the occurrence of hypersensitivity reactions in the Hungarian C1-INH-HAE population. Methods: Patients filled out a questionnaire of 112 questions, either online or on paper. The questions were about hypersensitivity and C1-INH-HAE symptoms, the relation between these 2, general health, and demographic data. The study protocol was approved by the institutional review board of Semmelweis University, Budapest, and informed consent was obtained from the participants. Results: One hundred and six patients (64 female, 42 male, median age 46 years) responded, with 63.2% having hypersensitivity. Hypersensitivity was provoked by pollen in 25.5% of patients, by contact sensitivity in 22.6%, by food in 21.7%, by insect sting in 19.8%, by pet in 15.1%, by drug in 14.2%, by dust mite in 5.7%, and by mold in 1.9%. In 11 patients, hypersensitivity symptoms appeared after the diagnosis of C1-INH-HAE. Six hypersensitive patients experienced improvement in their symptoms; 42 remained the same, but none experienced worsening after the diagnosis of C1-INH-HAE. In 7.8% of the hypersensitive patients, a C1-INH-HAE attack worsened the hypersensitivity symptoms, while 15.7% of the hypersensitive patients experienced a C1-INH-HAE attack provoked by contact with the provoking factor. Conclusion: While 63.2% of our C1-INH-HAE patients have reported hypersensitivity symptoms, Eurostat's latest data puts the prevalence of self-reported allergies in Hungary at 19.3%. Since in our experience most Hungarian patients report hypersensitivity reactions as allergies, this may support a possible connection between the 2 diseases, but further molecular studies are needed.

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.

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.

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.

[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.

The natural history of hereditary angioedema and the impact of treatment with human C1-inhibitor concentrate during pregnancy: a long-term survey.

OBJECTIVE: The course of hereditary angioedema (HAE) and the efficacy and safety of human C1-INH concentrate were appraised during pregnancy and the postpartum period, in patients with HAE. STUDY DESIGN: Retrospective analysis of clinical data on 118 pregnancies (82 full-term and 36 abortions) in 41 female patients, extracted from the National HAE Registry, medical charts and patient diaries. RESULTS: HAE attack frequency increases in 48% of pregnancies, whereas 33% of pregnancies were associated with mitigation of clinical signs and 19% of the pregnancies had no influence on the course of HAE, as compared to disease severity seen during the 2-year period preceding the pregnancy. During 46 full-term pregnancies, 26 patients reported attacks; 52% of these occurred in the third trimester. Abdominal attacks are the most common presentation of HAE during pregnancy. Attack number was significantly higher in patients who had sustained their initial attack before 8 years of age. Attack number increased during the third trimester if the fetus was afflicted by HAE. During the postpartum period, attacks occurred in 6/82 pregnancies. Patients received 91 vials of C1-INH concentrate altogether for the relief of acute attacks and for short- or long-term prophylaxis during pregnancy. This therapy was effective in all instances; no adverse effects were observed. CONCLUSIONS: Pregnancy can either aggravate or mitigate edematous attacks, or alternatively, it may have no influence on the severity of the disease. According to our experience, C1-INH concentrate is an effective and safe therapeutic option during pregnancy.

Baseline level of functional C1-inhibitor correlates with disease severity scores in hereditary angioedema.

The diagnosis of hereditary angioedema (HAE) is based on complement tests. We studied for the first time the possible association between complement parameters measured at the time of diagnosis and disease severity in 115 patients with HAE. Serum levels of functional C1-inhibitor (C1-INH(f)), antigenic C1-inhibitor (C1-INH(a)), C4 and hemolytic activity of the classical pathway (CH50) were determined at the time of diagnosis. We found a significant correlation between severity scores and baseline C1-INH(f) levels, as determined by ELISA assay (p=0.0003). On the other hand, there was no correlation between severity scores and other complement parameters (C1-INH(a), C4, and CH50). We consider the correlation between severity scores and baseline C1-INH(f) levels an important pathophysiological observation. Our findings underlie the potential significance of monitoring functional C1-INH levels in relation to clinical disease course.

The effect of long-term danazol prophylaxis on liver function in hereditary angioedema-a longitudinal study.

BACKGROUND: Danazol is a drug most widely used for the prophylaxis of hereditary angioedema resulting from the deficiency of the C1-inhibitor. Potential hepatotoxic or liver tumor-inducing side effects of long-term danazol prophylaxis have been investigated during the follow-up of hereditary angioedema patients. METHODS: Characteristic parameters of liver function (including bilirubin, GOT, GPT, gammaGT, total protein, ALP, LDH), as well as findings of viral serology screens and abdominal ultrasonography-determined during years 0 and 5 of follow-up of patient groups taking/not taking danazol-have been reviewed and analyzed comparatively. RESULTS: From a population of 126 hereditary angioedema patients, 46 subjects taking danazol and another 46 not taking danazol fulfilled the inclusion criteria. Longitudinal follow-up did not reveal any clinically relevant difference between the liver function parameters determined in years 0 and 5 in the two groups. Abdominal ultrasound did not detect neoplastic or other potentially treatment-related alterations of the liver parenchyma. There were no discontinuations of treatment during the study. CONCLUSIONS: Our results clearly suggest that, administered at the lowest effective dose, danazol does not induce liver injury in hereditary angioedema patients.

Hereditary angioedema: a decade of human C1-inhibitor concentrate therapy.

BACKGROUND: C1-inhibitor (C1-INH) is a serine protease inhibitor regulating the complement, kinin-kallikrein, coagulation, and fibrinolytic systems. Hereditary angioedema (HAE) is caused by an inherited deficiency of C1-INH characterized by sudden, recurrent edematous swellings of the subcutaneous or submucosal tissues. The optional therapy for the acute management of HAE is administration of human C1-INH (hC1-INH) concentrate. However, hC1-INH is not available in many countries, in which case fresh frozen plasma is an alternative. OBJECTIVE: To summarize our experience with hC1-INH concentrate in patients with HAE. METHODS: Clinical and laboratory information on the effectiveness and safety of hC1-INH administered to relieve 468 acute edematous attacks in 61 patients with HAE was analyzed. RESULTS: Severe abdominal or subcutaneous attacks and laryngeal edema were consistently relieved by the administration of 500 U hC1-INH concentrate. Symptoms improved within 15 to 60 minutes of administration. Progression of the attacks was never observed, and there were no recurrent attacks within 72 hours. hC1-INH concentrate requirements did not change after repeated use. hC1-INH concentrate proved effective in the management of 94 attacks in 22 children and 6 attacks in 4 pregnant women. Adverse reactions, viral infections, and antibody formation against the purified protein did not occur. CONCLUSION: The administration of hC1-INH concentrate in HAE is highly effective and safe for the treatment of acute attacks and short-term prophylaxis and in pediatric patients and pregnant women. CLINICAL IMPLICATIONS: Human C1-INH concentrate is effective and safe for the treatment of acute HAE attacks as well as for short-term prophylaxis.

Management of hereditary angioedema in pediatric patients.

Hereditary angioneurotic edema is a rare disorder caused by the congenital deficiency of C1 inhibitor. Recurring angioedematous paroxysms that most commonly involve the subcutis (eg, extremities, face, trunk, and genitals) or the submucosa (eg, intestines and larynx) are the hallmarks of hereditary angioneurotic edema. Edema formation is related to reduction or dysfunction of C1 inhibitor, and conventional therapy with antihistamines and corticosteroids is ineffective. Manifestations occur during the initial 2 decades of life, but even today there is a long delay between the onset of initial symptoms and the diagnosis of hereditary angioneurotic edema. Although a variety of reviews have been published during the last 3 decades on the general management of hereditary angioneurotic edema, little has been published regarding management of pediatric hereditary angioneurotic edema. Thus, we review our experience and published data to provide an approach to hereditary angioneurotic edema in childhood.

Helicobacter pylori infection as a triggering factor of attacks in patients with hereditary angioedema.

BACKGROUND: Helicobacter pylori infection is considered among the causative factors of urticaria and angioedema. Having conducted a study on 65 patients, Hungarian authors reported in 2001 that successful eradication of H. pylori is followed by a significant reduction in the number of attacks in patients with hereditary angioedema (HAE). The present study aimed to reinvestigate the relationship between H. pylori infection and the attack rate in the framework of an international collaborative study. MATERIALS AND METHODS: Within the framework of the PREHAEAT project launched by the European Union, further 152 patients were studied in seven collaborating centers, and participants of the earlier study were followed up in order to detect any relationship between H. pylori infection and the occurrence of attacks in patients suffered from HAE. RESULTS: The proportion of patients experiencing frequent (> or = 5 per year) abdominal attacks was higher (p = .002) among the H. pylori-infected participants of the international study who underwent eradication as compared to the rest of patients. Successful eradication of H. pylori significantly (p = .0006) reduced the number of attacks in these patients as well. Nine subjects of the previous Hungarian study who underwent eradication therapy for dyspepsia were followed up for an additional 4 years. In these patients, attack frequency remained consistently low. CONCLUSIONS: As shown by experience from the Hungarian and the international trial, the number of frequent, edematous abdominal attacks may decrease substantially following the eradication of H. pylori from HAE patients infected with this pathogen. Therefore, screening of patients with HAE for H. pylori infection seems warranted. Eradication of H. pylori may lead to a marked reduction in disease severity.

Relationship between copy number of genes (C4A, C4B) encoding the fourth component of complement and the clinical course of hereditary angioedema (HAE).

In order to study if in patients with hereditary angioedema (HAE), copy number of the two genes (C4A and C4A) encoded in the central region of main histocompatibility complex (MHC) influences the diagnostically important C4 serum concentration as well as the clinical course of the disease, we determined copy number of the complement C4A and C4B genes in DNA samples of 95 HAE patients and 246 healthy controls. Distribution of both the C4A and C4B copy numbers significantly (p=0.0183 and 0.0318, respectively) differed between the two groups, the most marked difference we observed was the lower frequency of the high (3 or 4) C4A copy numbers in the patients. As it expected, the dosage of both C4A and C4B genes positively correlated to the longitudinally measured serum C4 concentrations. Moreover, we found an unexpected clinical correlation with the dosage of the C4B gene. The course of the disease was milder in the 9/95 patients carrying 3 or 4 copies of C4B gene, compared to the rest of patients, i.e. diagnosis was established at significantly (p=0.0052) older age (36.0 (31.0-39.5)) years versus 20.5 (7.5-31.5 years), bi-yearly attack rate was significantly (p=0.0145) lower (1.0 (0.0-11.0)) versus 11.0 (3.5-21.5), and the over-all activity of the classical pathway and the enzyme-inhibitor activity of the C1-inhibitor (C1-INH) was closer to the normal values. These observations indicate that high copy number of the C4B gene can be a protective factor against disease severity in HAE and therefore its determination is warranted.

C1-inhibitor (C1-INH) autoantibodies in hereditary angioedema. Strong correlation with the severity of disease in C1-INH concentrate naïve patients.

The presence of autoantibodies to C1-inhibitor (C1-INH-Abs) is a hallmark of acquired C1-inhibitor deficiency. However, only scarce data are available on their prevalence in hereditary angioedema (HAE). In a prospective study performed between 2001 and 2004 in 95 patients with Type I or II HAE, serum samples were taken one to three times a year and clinical status of the patients was registered. Serum samples were tested for total activity of the classical pathway, C1q, C3, C4 and C1-inhibitor (C1-INH) concentration and activity levels, as well as the presence of IgG, IgA and IgM type anti-C1-inhibitor antibodies (C1-INH-Ab). Fifty-four healthy age and gender matched persons served as control. Significant differences between the patients and controls in the occurrence of elevated (2S.D. higher than mean of control) C1-INH-Abs titers was found only in the case of IgM type C1-INH-Abs. Elevated (>4.22AU/ml) IgM C1-INH-Abs levels were found in 31 and 4% of the patients and controls, respectively (p<0.001). Surprisingly, high titer IgM C1-INH-Abs were present with equal frequency in the 41 HAE patients ever treated with C1-INH concentrate and in the 54 C1-INH treatment naïve patients. In the latter group, strong positive correlation between the levels of the IgM C1-INH-Abs and the most severe disease (score 1) (p=0.0021) and the yearly attack rate (p=0.0173) were obtained. In addition, the levels of the IgM C1-INH-Abs exhibited strong negative correlation to the C1-inhibitor concentration and functional activity, total classical complement pathway activity, and a positive correlation to total IgM concentration. Taken together, these data indicate that IgM type C1-INH-Abs are present with highly elevated frequency in HAE patients irrespectively of the previous treatment with C1-INH concentrate. Most probable production of these autoantibodies is the consequence of the activation of complement and other plasma enzyme systems during HAE attacks. Determination of IgM C1-INH-Abs can be used as an activity marker in HAE.

[Effectiveness of mometasone furoate nasal spray in seasonal allergic rhinitis. First experiences in practice after the introduction of the drug in Hungary]. / Mometazon furoat orrspray hatékonyságának vizsgálata. A gyógyszer hazai bevezetését követó elsó pollenszezon gyakorlati tapasztalatai.

INTRODUCTION: The authors appraised the clinical efficacy of mometasone furoate in patients with seasonal allergic rhinitis and rhinoconjunctivitis. PATIENTS AND METHODS: An open, two-week trial was conducted in 89 patients between 1 July and 15 September 2001. A baseline oto-rhinolaryngological examination was performed. Nasal obstruction, rhinorrhea, sneezing, and itching as well as ocular, throat and ear clinical signs and general symptoms including cough and dyspnea were characterized using a symptom score. Mometasone furoate was administered intranasally in 100 micrograms doses into both nostrils. Depending on the severity of symptoms, antiallergic eye drops and systemic antihistamines were also allowed. After two weeks of treatment, a follow-up physical examination was performed and the symptom score was re-evaluated. Potential adverse events that had occurred during the treatment period were recorded. RESULTS: Mometasone furoate nasal spray alleviated all four nasal symptoms promptly and effectively. In particular, treatment resulted in a 93 percent decrease of overall symptom score. None of the participants discontinued treatment due to the occurrence of adverse effects. CONCLUSION: These results demonstrate that mometasone furoate nasal spray is a safe and effective intranasal corticosteroid for the therapy of SAR/SARC seasonal allergic rhinitis and rhinoconjunctivitis.

Clinical management of hereditary angio-oedema in children.

Hereditary angio-oedema (HAE) results from the deficiency of C1-esterase inhibitor (C1-INH). The clinical picture of this autosomal dominant disorder is characterized by recurrent attacks of subcutaneous oedema and/or potentially life-threatening swelling of the submucosa. This review discusses the authors' decade-long experience obtained in the treatment and follow-up of pediatric patients with HAE. Twenty-six children with HAE were reviewed. Pedigree analysis was performed in all cases to identify afflicted relatives. C1-INH concentrate was reserved for the emergency treatment of acute oedematous attacks, whereas tranexamic acid and danazol were administered for short- or long-term prophylaxis. Follow-up care included laboratory tests and abdominal ultrasound, which was repeated at regular intervals. Twenty-one children had Type I HAE and five suffered from Type II HAE. Clinical manifestations of the disease first occured in children when 2.5-12 years of age. Oedema formation primarily afflicted subcutaneous tissues. Mechanical trauma was identified as a precipitating factor in 20 patients. Pedigree analysis revealed 24 patients with relatives who suffered from HAE. Long-term prophylaxis with tranexamic acid or danazol was initiated in 11 patients; two children required short-term prophylaxis. No drug-related adverse effects were observed, except for one case of delayed menarche. Therapy improved serum complement parameters significantly and substantially reduced the frequency and severity of clinical episodes. Adequate prophylaxis and follow-up care can spare pediatric patients from oedematous attacks caused by HAE. Undesirable adverse effects can be avoided and the patient's quality of life enhanced considerably by administering the lowest effective drug dose.