The Role of Bradykinin Receptors in Hereditary Angioedema Due to C1-Inhibitor Deficiency.

BACKGROUND: Hereditary angioedema (HAE) is a rare, genetic disease caused by the decreased level or function of the C1 inhibitor. The primary mediator of symptoms in HAE is bradykinin acting through its two receptors, namely receptors 1 (BR1) and 2 (BR2). Although BR2 is well characterized, the role of BR1 remains unclear. OBJECTIVE: To study the role of bradykinin receptors 1 (BR1) in the etiopathogenesis of HAE. METHODS: A total of 70 individuals, 40 patients with HAE, and 30 healthy subjects were recruited to the study. HAE was diagnosed in accordance with the international guideline. The level of bradykinin receptors was determined in populations of CD3+, CD4+, CD8+, and CD14++CD16-, CD14++CD16+ monocytes. In addition, the level of disease activity-specific markers was measured. RESULTS: There were statistically significant differences in the subpopulation of lymphocytes and monocytes between patients with HAE compared to healthy subjects. The level of BR1 and BR2 on PBMCs was comparable in healthy subjects and HAE patients during remission with significant overexpression of both receptors, triggered by HAE attack. Moreover, a significant increase in TNF-alpha and IL-1 plasma levels was observed among HAE patients. CONCLUSIONS: BR1 expression may play an important role in the pathomechanism of HAE.

Abdominal and pelvic imaging in the diagnosis of acute abdominal attacks in patients with hereditary angioedema due to C1-inhibitor deficiency.

Introduction: Hereditary angioedema (HAE) is a rare inherited autosomal dominant disease caused by deficiency or dysfunction of C1 inhibitor (C1INH). Clinical symptoms include recurrent subcutaneous and submucosal angioedema of the internal organs. Abdominal attacks affect more than 90% of patients, are often misdiagnosed and result in unnecessary surgical procedures. Aim: To analyse the utility of imaging studies (USG, CT) in patients with C1INH-HAE during an abdominal attack and remission. Material and methods: We enrolled 40 patients with type I and II HAE (30 women, 10 men; mean age 39 years). The diagnosis of C1INH-HAE was based on patient and family history, significantly reduced values of C1INH serum level and activity. Abdominal and pelvic ultrasound were performed in patients within the first 6 h of the abdominal attack and repeated during remission. Moreover, 23 cases underwent abdominal or pelvic computed tomography during acute abdominal symptoms. The most common ultrasound and CT findings showed the transient presence of a significant amount of fluid in the free abdominal cavity and intestinal oedema during the symptom progression and spontaneously disappearing during the seizure in 90% and 50% of patients, respectively. CT revealed also an enlargement of the mesenteric lymph nodes as well as a fat stranding along the bowel wall thickening. Conclusions: Ultrasound or CT imaging facilitates the diagnosis of the patient suspected of having an abdominal attack due to C1INH-HAE. They allow to identify transitional presence of an abundant fluid in the free abdominal cavity and intestinal swelling which spontaneously disappear with a symptoms attack.

The Role of Bradykinin Receptors in the Etiopathogenesis of Chronic Spontaneous Urticaria.

Background and Objectives: Chronic spontaneous urticaria (CSU) is a distressing skin condition, which manifests as red, swollen, itchy, and sometimes painful hives or wheals appearing on skin. Recently, CSU has been associated with bradykinin release, which was previously discovered to be the main trigger of hereditary angioedema attacks. To study the role of bradykinin receptors 1 (BR1) and 2 (BR2) in the etiopathogenesis of CSU. Materials and Methods: A total of 60 individuals, 30 patients with CSU and 30 healthy subjects, were recruited to the study. CSU was diagnosed in accordance with the standardized protocol of dermatological assessment of skin symptoms. The level of bradykinin receptors was determined in populations of CD3+, CD4+, and CD8+ lymphocytes as well as in CD14++CD16-, CD14++CD16+ and CD14+CD16+ monocytes. In addition, urticaria activity score summed over 7 days (UAS-7) was assessed and correlated with BR1 and BR2 expression. Results: A statistically significant higher concentration of BR1 expression in lymphocytes was found in patients with CSU, compared to the control group (p < 0.001). Moreover, a statistically significant positive correlation was observed between UAS-7 and BR1/BR2 expression in CD14++CD16- cells (p = 0.03, R = 0.4). Conclusions: Bradykinin receptors are elevated in selected populations of lymphocytes in symptomatic CSU patients compared to healthy controls, indicating their role in the etiopathogenesis of the disease.

A novel deep intronic SERPING1 variant as a cause of hereditary angioedema due to C1-inhibitor deficiency.

BACKGROUND: In about 5% of patients with hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) no mutation in the SERPING1 gene is detected. METHODS: C1-INH-HAE cases with no mutation in the coding region of SERPING1 after conventional genotyping were examined for defects in the intronic or untranslated regions of the gene. Using a next-generation sequencing (NGS) platform targeting the entire SERPING1, 14 unrelated C1-INH-HAE patients with no detectable mutations in the coding region of the gene were sequenced. Detected variants with a global minor allele frequency lower than the frequency of C1-INH-HAE (0.002%), were submitted to in silico analysis using ten different bioinformatics tools. Pedigree analysis and examination of their pathogenic effect on the RNA level were performed for filtered in variants. RESULTS: In two unrelated patients, the novel mutation c.-22-155G > T was detected in intron 1 of the SERPING1 gene by the use NGS and confirmed by Sanger sequencing. All bioinformatics tools predicted that the variant causes a deleterious effect on the gene and pedigree analysis showed its co-segregation with the disease. Degradation of the mutated allele was demonstrated by the loss of heterozygosity on the cDNA level. According to the American College of Medical Genetics and Genomics 2015 guidelines the c.-22-155G > T was curated as pathogenic. CONCLUSIONS: For the first time, a deep intronic mutation that was detected by NGS in the SERPING1 gene, was proven pathogenic for C1-INH-HAE. Therefore, advanced DNA sequencing methods should be performed in cases of C1-INH-HAE where standard approaches fail to uncover the genetic alteration.

Genetic variants of SERPING1 gene in Polish patients with hereditary angioedema due to C1 inhibitor deficiency.

Hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE) type I and II is a rare and life-threatening disease caused by SERPING1 gene mutations. Previous genetic studies indicated a wide spectrum of disease-associated variants in the SERPING1 gene and often lack of correlation with patient's phenotypes. The aim of this study was to evaluate the presence, type, and localization of mutations in the SERPING1 gene in 41 Polish patients with C1-INH-HAE and their relation with case/family history, type of C1-INH-HAE, fC1-INH, age of onset, and disease severity. Sanger sequencing and MLPA method were used for detection of disease-associated variants. In 34 (82.9%) patients, mutations located in various regions of SERPING1 gene were revealed. The detected alterations in patients with C1-INH-HAE type I differed and were positioned in various exons/introns of the SERPING1 gene. The most frequent disease-associated variants appeared in exon 3 (especially in type I) and in exon 8 (type I and II). Out of 20 different disease-causing variants, 9 were not previously described. We did not find any relation between the type and location of the mutations and no type of features included in phenotype evaluation of the patients, such as case and family history, type of C1-INH-HAE, age of onset, biochemical parameters, or severity of disease.

Assessment of inhibitory antibodies in patients with hereditary angioedema treated with plasma-derived C1 inhibitor.

BACKGROUND: Limited data are available regarding C1 inhibitor (C1-INH) administration and anti-C1-INH antibodies. OBJECTIVE: To assess the incidence of antibody formation during treatment with pasteurized, nanofiltered plasma-derived C1-INH (pnfC1-INH) in patients with hereditary angioedema with C1-INH deficiency (C1-INH-HAE) and the comparative efficacy of pnfC1-INH in patients with and without antibodies. METHODS: In this multicenter, open-label study, patients with C1-INH-HAE (≥12 years of age) were given 20 IU/kg of pnfC1-INH per HAE attack that required treatment and followed up for 9 months. Blood samples were taken at baseline (day of first attack) and months 3, 6, and 9 and analyzed for inhibitory anti-C1-INH antibody (iC1-INH-Ab) and noninhibitory anti-C1-INH antibodies (niC1-INH-Abs). RESULTS: The study included 46 patients (69.6% female; mean age, 38.9 years; all white) who received 221 on-site pnfC1-INH infusions; most patients received 6 or fewer infusions. No patient tested positive (titer ≥1:50) for iC1-INH-Ab at any time during the study. Thirteen patients (28.2%) had detectable niC1-INH-Abs in 1 or more samples. Nine patients (19.6%) had detectable niC1-INH-Abs at baseline; 3 of these had no detectable antibodies after baseline. Of 10 patients (21.7%) with 1 or more detectable result for niC1-INH-Abs after baseline, 6 had detectable niC1-INH-Abs at baseline. Mean times to symptom relief onset and complete symptom resolution per patient were similar for those with or without anti-niC1-INH-Abs. CONCLUSION: Administration of pnfC1-INH was not associated with iC1-INH-Ab formation in this population. Noninhibitory antibodies were detected in some patients but fluctuated during the study independently of pnfC1-INH administration and appeared to have no effect on pnfC1-INH efficacy. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01467947.

[Acquired angioedema ­ clinical characteristic of the patients diagnosed in 2012-2016 with acquired C1 inhibitor deficiency].

Acquired angioedema is a rare disease caused by a deficiency of C1 esterase inhibitor with recurrent swelling symptoms. It may occur in the course of lymphoproliferative disorders or autoimmune diseases. Symptoms resemble hereditary angioedema, and the only differentiating features is negative family history, late onset of symptoms and accompanying lymphoproliferative disorder. The aim of the study was to analyze the cases of acquired angioedema. The retrospective analysis of 341 patients from the registry of patients with C1 inhibitor deficiency. Results: We identified 4 patients among 119 with HAE (3.57%) diagnosed in this same period of time 2012-2016 who fulfilled the criteria of acquired edema. In two cases the primary reason of angioedema was lymphoproliferive disease, in two monoclonal gammapathy of unknown reason. We analyzed also the results of laboratory tests C4, C1 inhibitor, C1q. In all cases the face was dominated localization. After the treatment of primary lymphoproliferive disease, in two cases, we observed total remission of angioedema. Only one patient with gammapathy require treatment with C1 inhibitor during the attacks. In these case we observed both plasma deriver, and recombinant C1 inhibitor were effective.

Molecular methods of diagnosing allergic sensitization in patients with atopic dermatitis and infected by with Staphylococcus aureus.

The severity of allergic symptoms in patients with atopic dermatitis (AD) intensifies when the number of colonies patient's of Staphylococcus aureus on patents' skin increases. The basic feature determining the quality of any diagnostic test for S. aureus is its credibility. Performing a test always carries the risk of obtaining false positive and/or false negative results. Furthermore, producing material for microbiological analysis of internal body cavities is sometimes difficult. Therefore, in our study, we compared the results of three tests to determine if their results were mutually compatible and if they confirmed whether S. aureus was present in patients with AD and what was its role in the development of the disease in those patients. Infection with S. aureus was tested in patients with AD and healthy volunteers using the API Staph system. The specific IgE antibodies for staphylococcal enterotoxin A (SEA) and B (SEB) were measured using the UniCAP system. The secretion of IFN-γ, IL-2, IL-13 by peripheral blood mononuclear cells (PBMCs) after stimulation with SEA and SEB were studied with Elispot assay. We found that only certain patients with AD and S. aureus produced antibodies against SEA and SEB in the acute phase of AD. The secretion of IFN-γ was low in patients with exacerbated AD and S. aureus. Testing for the presence of S. aureus in the mucous membrane of the nasal vestibule and skin lesions is not sufficient for complex diagnosis of the role of S. aureus in the pathomechanism of AD. Measuring the presence of antibodies against bacterial components in patients' serum and the reactivity of patients' immune cells against these bacterial components is required in order to accurately diagnose this role of S. aureus in a patient.

[Gluten--mechanisms of intolerance, symptoms and treatment possibilities of IgE-related allergy for gluten in the light of actual clinical and immunological studies]. / Gluten--mechanizmy nietolerancji, objawy i mozIiwosci lecznicze IgE-zaleezinej alergii na gluten w swietle aktualnych badan klinicznoimmunologicznych.

Gluten is the product of a chemical bond of wheat prolamin proteins (glia- dins and glutenins) in an aqueous me- dium. IgE mediated gluten allergy can be induced either by gluten as an in- gredient in foods or wheat prolamines present in the air. The aim of the study was clinical analysis of 13 patients, who demonstrated elevated levels of gluten specific IgE and identification of the most allergenic protein fractions from several samples of wheat using serum of examined subjects. Clinical analysis showed the occupational allergy to gluten in the form of rhinitis, asthma and airborne dermatistis in 9 subjects, whose symptoms disappeared during isolation from occupational exposure despite the use of a normal diet. In case of 4 patients with severe forms of chronic urticaria and atopic dermatitis, who are also allergic to grass pollen at the same time, the introduction of a gluten-free diet resulted in improvement of health conditions. The study of wheat protein fractions revealed a significant polymorphism dependent on the wheat sample. In the protein fractions, low and high molecular glutenin fractions, and alpha, beta, gamma, and omega-gliadins were separated. It has been shown that the strongest immunogenic effect causes omega-5 gliadin fraction. The removal of this fraction resulted in reduction of skin reactivity evaluated by skin prick test in the studied patients.

[Squamous epithelium in the nasal cytology]. / Nablonek plaski w obrazie cytologicznym blony sluzowej nosa.

Nasal mucosa cytology is an additional examination useful to differentiate chronic rhinitis in allergological and laryngological diagnostics, including chronic sinusitis. The aim of the study was to estimate the cytological picture in a group of patients with the highest percentage of squamous epithelia, suggesting the atrophic rhinitis. The analysis was carried out on the basis of cytological results performed in 3055 patients diagnosed because of chronic rhinitis. Among these patients, in 31 individuals the higher percentage (30% - 76%) of squamous cells was found. In six patients, the clear predominance of squamous cells over ciliated and goblet cells (3:1) was reported. Only in three patients the increased percentage in eosinophils was stressed (3%, 5% and 9% respectively). No basic and metaplastic cells were observed in the studied cytograms. The squamous cells occurred probably as a result of normal mucosa damages during the different inflammatory changes, both allergic and non-allergic, the impact of toxic agents, irritants (including nasal drops). The higher percentage of squamous cells in the nasal cytogram could have explained the low effectiveness of local inflammatory treatment in these patients.

Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.

BACKGROUND: Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. METHODS: In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. RESULTS: A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. CONCLUSIONS: In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

C1-INH concentrate for treatment of acute hereditary angioedema: a pediatric cohort from the I.M.P.A.C.T. studies.

BACKGROUND: We analyzed the clinical response of pediatric and adolescent hereditary angioedema (HAE) patients to pdC1-INH in the International Multicenter Prospective Angioedema C1-INH Trials (I.M.P.A.C.T.) 1 and 2. METHODS: Patients included in this post hoc analysis of prospectively collected data were between 10 and 18 yr old with type I or II HAE and a documented history of abdominal or facial attacks. Patients received a single injection of pdC1-INH concentrate (Berinert(®) , CSL Behring, Marburg, Germany) 20 U/kg. Efficacy end-points were time from the administration of study drug to onset of symptom relief and time to complete relief of all symptoms. RESULTS: Seven pediatric patients were included in I.M.P.A.C.T.1 with only 1 attack analyzed per patient. Median time to onset of relief was 0.42 h and to complete resolution was 8.08 h. No patient experienced a worsening of symptoms during the 0-4-h assessment period. Nine patients who experienced a total of 115 attacks were included in the analysis of I.M.P.A.C.T.2. Abdominal attacks were rated as 'severe' more frequently than were other types of attacks. The number of attacks per patient ranged from 2 to 42, and study participation ranged from 1 to 38 months. Median times to onset of symptom relief and to complete symptom resolution were 0.49 h and 14.1 h, respectively. Of 4 treatment-emergent adverse events in both studies, only 2 were considered related to treatment. CONCLUSIONS: Study results showed that outcomes with pdC1-INH treatment of HAE in pediatric patients are comparable with outcomes in adults.

[Administration of conestat alfa, human C1 esterase inhibitor and icatibant in the treatment of acute angioedema attacks in adults with hereditary angioedema due to C1 esterase inhibitor deficiency. Treatment comparison based on systematic review results]. / Konestat alfa, ludzki inhibitor C1 esterazy oraz ikatybant w leczeniu ostrych ataków obrzeku u osób doroslych z dziedzicznym obrzekiem naczynioruchowym spowodowanym niedoborem inhibitora C1 esterazy. Porównanie opcji terapeutycznych na podstawie przegladu systematycznego.

INTRODUCTION: Hereditary angioedema (HAE) is a genetic disease caused by C1-esterase inhibitor deficiency, characterized by recurrent attacks of intense, massive, localized subcutaneous oedema that can involve all parts of the body. The aim of this study is a comparison of the clinical effectiveness of conestat alfa, human C1 esterase inhibitor (C1INH), and icatibant in the treatment of acute angioedema attacks in adults with HAE. MATERIALS AND METHODS: A systematic review of literature published up to May 2012 was performed to assess the efficacy and safety of conestat alfa, C1INH, and icatibant in the treatment of acute angioedema attacks in adults with HAE. Databases were searched at MEDLINE (PubMed), EMBASE, and Cochrane. The general search structure was designed as a combination of keywords or synonyms: (hereditary angioedema) AND (conestat alfa OR human C1 esterase inhibitor concentrate OR synonyms OR icatibant). Only randomized clinical studies were selected. RESULTS: Systematic review yielded no clinical trials directly comparing the therapeutic options mentioned. Two randomized clinical trials were found which compared each of the following: conestat alfa, C1INH, and icatibant with placebo. Based on the gathered evidence it was demonstrated that taking any of the medicinal substances mentioned in the treatment of acute angioedema attack results in shorter time to beginning of relief of symptoms, time to minimal symptoms, the probability of the treatment response after 4 hours is increased, and the safety profile is comparable to placebo. CONCLUSIONS: Due to significant heterogeneity of identified trials, the scientific evidence available was insufficient to point out the most effective therapeutic option in the treatment of acute oedemas in HAE.

Patient-dependent differentiation of gluten protein IgE-binding epitopes in wheat allergy.

Gliadins and glutenins--the main components of wheat gluten--are highly complex and polymorphic proteins of wheat kernels. They are also allergenic proteins causing a range of food allergies. We hypothesized that the diversity of chemical structures and properties may relate to the diversification of immunoreactive properties of various subunits and fractions of gluten proteins. In the present study we used IgE sera, obtained from patients manifesting different symptoms of wheat allergies, for immunobloting analysis, to prove the specificity of immunological reaction between IgE antibodies and individual gliadins and glutenins, separated by SDS-PAGE. The results suggest that patients have different characteristics of IgE binding to the separated protein subunits and fractions. Sera of two patients showed strong binding of omega-gliadins, while alpha-gliadins and LMW glutenin subunits of MW = 43 and 45 kDa were highly allergenic for two other subjects in the test group of patients.

[Oral allergy syndrome in patients with pollen allergy]. / Zespól alergii jamy ustnej u pacjentów z alergia pylkowa.

The symptoms of pollen allergy in the European population occur in a period of increased pollen precipitation, and take the form of allergic rhinitis and conjunctivitis, bronchial asthma, contact urticaria, and food allergy. Diagnosis in addition to medical history, takes into account the positive results of skin tests and elevated allergen-specific IgE antibodies (specific IgE) in serum. These studies are considered to be objective diagnostic tests confirming the diagnosis of pollen allergy. Not in every case there is a correspondence of symptoms and results of diagnostic tests, which puts into question the accuracy of the diagnosis of pollen allergy. The aim of this study was to test the characteristics of patients with oral allergy syndrome on the background of all patients with pollen allergy and evaluation of the diagnostic value of history, skin tests and specific IgE levels in the diagnosis of patients with pollen allergy and oral allergy syndrome. A retrospective analysis of the cases of 85 patients with a diagnosis of pollen allergy and the 30 patients with OAS was performed. In our study the most common sensitizing allergen in patients with OAS was birch pollen, while patients showing no symptoms of OAS were equally sensitive to timothy and birch pollen. The main food responsible for the presence of the OAS in the mechanism of cross-allergy to pollen was an apple. Among patients with OAS we did not show significantly higher incidence of polyvalent allergies. It was shown, however, that there is a tendency that the maximum concentration of allergen-specific IgE causing clinically significant symptoms, ie in line with the pollen season, is higher in the OAS patients than in the absence of OAS. Further research is needed using new diagnostic methods, which would predict future symptoms after eating certain foods in particularly endangered patients with pollen allergy.

Eosinophilic reaction in nasal cytology in patients sensitive to perennial and seasonal allergens.

Nasal exfoliative cytology is a complementary tool in diagnostics of allergic (AR) and non-allergic (NAR) rhinitis. The aim of the study was to determine the usefulness of the nasal cytology in patients sensitive to common inhalant allergens with positive SPT(+) and negative SPT(-) (Skin Prick Tests) depending on the symptoms of intermittent and persistent rhinitis. The study was performed in a group of 285 patients treated in the Department of Allergology University Hospital in Krakow, suspected on AR in 2008-2010. The patients were made a smear test of inferior nasal concha. The samples were stained using the eosin-hematoxylin method and examined under a light microscope (1000x). Patients were divided into two groups: SPT(+) (144 patients) and SPT(-) (141 patients). Depending on the percentage of obtained eosinophils each group was divided into three subgroups: 0-2%, 3-20%, >20%. In the most percentage of patients with 3-20% of eosinophils in nasal cytology were found, in both studied groups (SPT)(+) and (SPT)(-), while the highest percentage of eosinophils (> 20%) was observed in the bigger group of patients with SPT(+), than with SPT(-). The number of patients with eosinophils > 20% in the SPT(+) group was higher in patients with persistent symptoms (NS differences), while in the SPT(-) group, the number of patients with intermittent symptoms in the subgroup > 20% of eosinophils statistically prevailed (p<0.001). The mean percentage of eosinophils in both groups was comparable, while the statistically significant differences were found considering the distinguished subgroups. In intermittent SPT(+) group the most sensitizing allergens were pollen grains (birch or grass pollen), while the patients with persistent AR symptoms were mainly sensitive the house dust mites. The mean percentage of eosinophils in an exfoliative cytology correlated significantly with allergic rhinitis symptoms and SPT results, the most evident relationship was found between higher level of eosinophils and the patients with confirmed AR diagnosis on the basis of positive SPT, manifesting the intermittent symptoms.

Searching for Genetic Biomarkers for Hereditary Angioedema Due to C1-Inhibitor Deficiency (C1-INH-HAE).

Existing evidence indicates that modifier genes could change the phenotypic outcome of the causal SERPING1 variant and thus explain the expression variability of hereditary angioedema due to C1-inhibitor deficiency (C1-INH-HAE). To further examine this hypothesis, we investigated the presence or absence of 18 functional variants of genes encoding proteins involved in the metabolism and function of bradykinin, the main mediator of C1-INH-HAE attacks, in relation to three distinct phenotypic traits of patients with C1-INH-HAE, i.e., the age at disease onset, the need for long-term prophylaxis (LTP), and the severity of the disease. Genetic analyses were performed by a validated next-generation sequencing platform. In total, 233 patients with C1-INH-HAE from 144 unrelated families from five European countries were enrolled in the study. Already described correlations between five common functional variants [F12-rs1801020, KLKB1-rs3733402, CPN1-rs61751507, and two in SERPING1 (rs4926 and rs28362944)] and C1-INH-HAE severity were confirmed. Furthermore, significant correlations were found between either the age at disease onset, the LTP, or the severity score of the disease and a series of other functional variants (F13B-rs6003, PLAU-rs2227564, SERPINA1-rs28929474, SERPINA1-rs17580, KLK1-rs5515, SERPINE1-rs6092, and F2-rs1799963). Interestingly, correlations uncovered in the entire cohort of patients were different from those discovered in the cohort of patients carrying missense causal SERPING1 variants. Our findings indicate that variants other than the SERPING1 causal variants act as independent modifiers of C1-INH-HAE severity and could be tested as possible prognostic biomarkers.

The most important contact sensitizers in Polish children and adolescents with atopy and chronic recurrent eczema as detected with the extended European Baseline Series.

The differential diagnostic work-up of children with chronic eczema should involve patch testing, also in cases with confirmed atopy. In our previous study, contact allergy was detected in every second child with chronic eczema. The aim of the present study was to identify the most important sensitizers in atopic children with eczema. During an allergy screening program, 103 consecutive children aged 7-8 and 93 adolescents aged 16-17 were enrolled. The inclusion criterion was chronic recurrent eczema as detected with the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and atopy, defined as positive skin prick test to one or more common airborne or food allergens. The children were patch-tested with the newly extended European Baseline Series (EBS, 28 test substances) supplemented with propolis, thimerosal, benzalkonium chloride, and 2-phenoxyethanol. In total, 67.0% children and 58.1% adolescents were found patch test positive. Among children, 35.9% reacted to nickel, 16.5% propolis, 11.7% thimerosal, 9.7% cobalt, each 6.8% fragrance mix (FM) I and chromium, and 5.8% to FM II. Among adolescents, 37.6% reacted to thimerosal, 19.4% to nickel, 6.5% to cobalt, and 5.4% to propolis. We demonstrate the advantage of using FM II - a new addition to the EBS that detects a relatively high proportion of contact hypersensitivity among children. An important sensitizer from outside EBS is propolis, which according to the frequency of sensitization occupies rank 2 in children and rank 4 in adolescents. These data show that propolis should be included into routine patch testing in children.

Hereditary angioedema: Validation of the end point time to onset of relief by correlation with symptom intensity.

Time to onset of symptom relief in hereditary angioedema (HAE) is a common primary end point in clinical studies but it has never been validated by correlation with the course of HAE symptoms. This study was designed as a retrospective validation of the primary end point for a placebo-controlled phase II/III study in patients with HAE. Ninety-eight abdominal attacks were treated with 10 or 20 U/kg of a highly purified C1 esterase inhibitor (C1-INH) concentrate or placebo. The primary end point was the time to onset of symptom relief, as determined by the patients. Patients assessed the intensity of the symptoms of pain, nausea, vomiting, cramps, and diarrhea over time. By Spearman rank correlation, the primary end point was compared with the time to first reduction of (1) any symptom intensity, (2) the sum of symptom intensity scores, and (3) the intensity of the last symptom present at baseline. The C1-INH, 20 U/kg, and placebo groups were compared by one-sided two-sample Wilcoxon tests. The time to first reduction in intensity of the last symptom present at baseline had the highest correlation with the primary end point (r = 0.77). The time to onset of symptom relief and the time to the first reduction in intensity of the last symptom were significantly shorter for the C1-INH, 20 U/kg, group compared with placebo (p = 0.009 and p = 0.0036, respectively). The association with the intensity of single symptoms confirmed that the time to onset of symptom relief is an appropriate end point for assessing the efficacy of C1-INH therapy.

[Immunotoxicology--new medical science]. / Immunotoksykologia--nowa nauka medyczna.

The constant increase in the incidence of allergic diseases, auto-immune diseases, infections and cancer is observed in our time from the beginning of the industrial revolution, i.e. in the second half of the nineteenth century. Epidemiological and clinical evidence suggests that environmental pollutants present in air, water, soil, foods may affect this phenomenon. Environmental pollutants, which are usually low molecular weight chemicals in high concentrations provoke irritant or toxic reactions and can be easily identified. In our time, these chemical contaminants are often present in low concentrations in the environment of space open and closed. Thus, they are poorly recognized by living organisms. However, several previous experimental and clinical studies suggest that they may affect the immune system and as weak immune stimulants may provoke hypersensitivity reactions (allergies or self-aggression) or weaken the natural antinflammatory and antineoplasmatic resistance. Immunotoxicology and alergolotoxicology have been proposed as a new medical science and research ideas that have lead to clarify the influence of the environmental chemical pollution on increased incidence of immunological diseases of our time.