Venom Immunotherapy Does Not Affect Survival of Patients with Malignant Tumor in Poland.

Background: Allergen immunotherapy (AIT) is a well-established and efficient method of causative treatment for allergic rhinitis, asthma and insect venom allergy. Traditionally, a recent history of malignant neoplasm is regarded as a contraindication to AIT due to concerns that AIT might stimulate tumor growth. However, there are no data confirming that the silencing of the Th2 response affects prognosis in cancer. Objectives: The aim of this study was to investigate frequency of malignant tumors in patients undergoing AIT and the association between AIT and cancer-related mortality. Patients and Methods: A group of 2577 patients with insect venom allergy undergoing AIT in 10 Polish allergology centers was screened in the Polish National Cancer Registry. Data on cancer type, diagnosis time and patients' survival were collected and compared with the general population. Results: In the study group, 86 cases of malignancies were found in 85 patients (3.3% of the group). The most common were breast (19 cases), lung (9 cases), skin (8 cases), colon and prostate cancers (5 cases each). There were 21 cases diagnosed before AIT, 38 during and 27 after completing AIT. Laplace's crude incidence rate was 159.5/100,000/year (general population rate: 260/100,000/year). During follow-up, 13 deaths related to cancer were revealed (15% of patients with cancer). Laplace's cancer mortality rate was 37.3/100,000/year (general population rate: 136.8/100,000/year). Conclusions: Malignancy was found in patients undergoing immunotherapy less often than in the general population. Patients with cancer diagnosed during or after AIT did not show a lower survival rate, which suggests that AIT does not affect the prognosis.

Efficacy and Safety of Donidalorsen for Hereditary Angioedema.

BACKGROUND: Hereditary angioedema is a rare disorder characterized by episodic, potentially life-threatening swelling caused by kallikrein-kinin dysregulation. Long-term prophylaxis can stabilize this system. Donidalorsen, an antisense oligonucleotide, specifically reduces prekallikrein expression. METHODS: In this phase 3, double-blind, randomized trial, we assigned patients with hereditary angioedema to receive donidalorsen (80 mg subcutaneously) or placebo once every 4 or 8 weeks. The primary end point was the time-normalized number of investigator-confirmed hereditary angioedema attacks per 4 weeks (attack rate) from week 1 to week 25. RESULTS: A total of 90 patients received donidalorsen every 4 weeks (45 patients), donidalorsen every 8 weeks (23 patients), or placebo (22 patients). The least-squares mean time-normalized attack rate was 0.44 (95% CI, 0.27 to 0.73) in the 4-week group, 1.02 (95% CI, 0.65 to 1.59) in the 8-week group, and 2.26 (95% CI, 1.66 to 3.09) in the placebo group. The mean attack rate from week 1 to week 25 was 81% lower (95% CI, 65 to 89) in the 4-week group than in the placebo group (P<0.001) and 55% lower (95% CI, 22 to 74) in the 8-week group than in the placebo group (P = 0.004); the median reduction in the attack rate from baseline was 90% in the 4-week group, 83% in the 8-week group, and 16% in the placebo group. The mean attack rate during weeks 5 to 25 was 87% lower (95% CI, 72 to 94) in the 4-week group than in the placebo group (P<0.001) and 60% lower (95% CI, 25 to 79) in the 8-week group than in the placebo group. Donidalorsen administered every 4 weeks resulted in an improvement in the least-squares mean total score for the change at week 25 on the Angioedema Quality-of-Life Questionnaire (scores range from 0 to 100, with a score of 100 indicating the worst possible quality of life) that was 18.6 points (95% CI, 9.5 to 27.7) better than that with placebo (P<0.001). The most common adverse events were erythema at the injection site, headache, and nasopharyngitis; 98% of adverse events were mild or moderate in severity. CONCLUSIONS: Donidalorsen treatment reduced the hereditary angioedema attack rate, a finding that supports potential prophylactic use for hereditary angioedema. (Funded by Ionis Pharmaceuticals; OASIS-HAE ClinicalTrials.gov number, NCT05139810.).

Oral Sebetralstat for On-Demand Treatment of Hereditary Angioedema Attacks.

BACKGROUND: Approved on-demand treatments for hereditary angioedema attacks need to be administered parenterally, a route of administration that is associated with delays in treatment or withholding of therapy. METHODS: In this phase 3, double-blind, three-way crossover trial, we randomly assigned participants at least 12 years of age with type 1 or type 2 hereditary angioedema to take up to two oral doses of sebetralstat (300 mg or 600 mg) or placebo for an angioedema attack. The primary end point, assessed in a time-to-event analysis, was the beginning of symptom relief, defined as a rating of "a little better" on the Patient Global Impression of Change scale (ratings range from "much worse" to "much better") at two or more consecutive time points within 12 hours after the first administration of the trial agent. Key secondary end points, assessed in a time-to-event analysis, were a reduction in attack severity (an improved rating on the Patient Global Impression of Severity [PGI-S] scale, with ratings ranging from "none" to "very severe") at two or more consecutive time points within 12 hours and complete attack resolution (a rating of "none" on the PGI-S scale) within 24 hours. RESULTS: A total of 136 participants were assigned to one of six trial sequences, with 110 treating 264 attacks. The time to the beginning of symptom relief with the 300-mg dose and the 600-mg dose was faster than with placebo (P<0.001 and P = 0.001 for the two comparisons, respectively), with median times of 1.61 hours (interquartile range, 0.78 to 7.04), 1.79 hours (1.02 to 3.79), and 6.72 hours (1.34 to >12), respectively. The time to reduction in the attack severity with the 300-mg dose and the 600-mg dose was faster than with placebo (P = 0.004 and P = 0.003), with median times of 9.27 hours (interquartile range, 1.53 to >12), 7.75 hours (2.19 to >12), and more than 12 hours (6.23 to >12). The time to complete resolution was faster with the 300-mg and 600-mg doses than with placebo (P = 0.002 and P<0.001). The percentage of attacks with complete resolution within 24 hours was 42.5% with the 300-mg dose, 49.5% with the 600-mg dose, and 27.4% with placebo. Sebetralstat and placebo had similar safety profiles; no serious adverse events related to the trial agents were reported. CONCLUSIONS: Oral sebetralstat provided faster times to the beginning of symptom relief, reduction in attack severity, and complete attack resolution than placebo. (Funded by KalVista Pharmaceuticals; KONFIDENT ClinicalTrials.gov number, NCT05259917; EudraCT number, 2021-001226-21.).

Assessment of HAE prophylaxis transition from androgen therapy to berotralstat: A subset analysis of the APeX-S trial.

Background: Given the recent approval of oral berotralstat in several countries for hereditary angioedema (HAE) prophylaxis, transition from long-term androgens to berotralstat may occur in clinical practice. The open-label, Phase II APeX-S trial provided an opportunity to assess the safety and effectiveness of berotralstat in patients previously treated with differing durations of androgens and shorter transition periods. Therefore, we examined the safety, effectiveness, and impact on quality of life of berotralstat after prior androgen use in patients from the APeX-S trial. Alanine aminotransferase (ALT) elevations were also examined because of the association with androgen exposure and hepatic function impairment. Methods: We conducted an analysis of a subset of 39 patients from the APeX-S trial aged ≥12 years with HAE due to C1 inhibitor deficiency (HAE-C1-INH) with prior androgen use who discontinued androgen therapy within <60 days of receiving berotralstat. Patients received daily berotralstat (150 mg) and were divided into subgroups for this analysis based on time between androgen discontinuation and berotralstat commencement (<14 days versus 14 to <60 days). Results: Berotralstat was generally well tolerated, with nasopharyngitis (21%), upper respiratory tract infection (15%), nausea (15%), diarrhea (15%), and abdominal pain (10%) being the most common adverse events occurring in ≥10% of the total subset. Only 7/145 (5%) of all APeX-S study patients with a prior history of androgen therapy experienced ALT elevations, 6 of which were grade 3 or 4 toxicities. All 7 patients recovered without sequelae and belonged to the subgroup of patients who transitioned <14 days after discontinuing androgens (n = 18). A reduction in monthly attack rate versus Month 1 was observed over 12 months for all patients who transitioned from prior androgen therapy to berotralstat prophylaxis in under 60 days, irrespective of duration of prior androgen therapy or timing of transition (N = 39). Similarly, meaningful patient-reported improvements from both Angioedema Quality of Life Questionnaire and Treatment Satisfaction Questionnaire for Medication scores were achieved, with a sustained benefit shown over the berotralstat treatment period. Conclusions: Berotralstat treatment led to sustained HAE symptom control irrespective of duration of prior androgen therapy or timing of transition. Most patients safely transitioned from long-term androgens to berotralstat. Although occurring in a small group of patients, liver-related adverse events following berotralstat treatment may be associated with a shorter androgen washout period, but further research is required to confirm this. Clinical trial registration: NCT03472040. Retrospectively registered March 21, 2018.

An investigational oral plasma kallikrein inhibitor for on-demand treatment of hereditary angioedema: a two-part, randomised, double-blind, placebo-controlled, crossover phase 2 trial.

BACKGROUND: Guidelines recommend effective on-demand therapy for all individuals with hereditary angioedema. We aimed to assess the novel oral plasma kallikrein inhibitor, sebetralstat, which is in development, for on-demand treatment of hereditary angioedema attacks. METHODS: In this two-part phase 2 trial, individuals with type 1 or 2 hereditary angioedema aged 18 years or older were recruited from 25 sites, consisting of specialty outpatient centres, across nine countries in Europe and the USA. Individuals were eligible if they had experienced at least three hereditary angioedema attacks in the past 93 days, were not on prophylactic therapy, and had access to and the ability to self-administer conventional attack treatment. In part 1 of the trial, participants were given a single 600 mg open-label oral dose of sebetralstat to assess safety, pharmacokinetics, and pharmacodynamics of the dose. Part 2 was a randomised, double-blind, placebo-controlled, two-sequence, two-period (2 × 2) crossover trial; participants were randomly assigned (1:1) to either sequence 1, in which they were given a single dose of 600 mg of sebetralstat to treat the first eligible attack and a second dose of placebo to treat the second eligible attack, or sequence 2, in which they were given placebo to treat the first eligible attack and then 600 mg of sebetralstat to treat the second eligible attack. Participants and investigators were masked to treatment assignment. The primary endpoint was time to use of conventional attack treatment within 12 h of study drug administration, which was assessed in all participants who were randomly assigned to treatment and who received study drug for two attacks during part 2 of the study. Safety was assessed in all participants who received at least one dose of study drug, starting in part 1. This study is registered with ClinicalTrials.gov, NCT04208412, and is completed. FINDINGS: Between July 2, 2019, and Dec 8, 2020, 84 individuals were screened and 68 were enrolled in part 1 and received sebetralstat (mean age 38·3 years [SD 13·2], 37 [54%] were female, 31 [46%] were male, 68 [100%] were White). 42 (62%) of 68 participants completed pharmacokinetic assessments. Sebetralstat was rapidly absorbed, with a geometric mean plasma concentration of 501 ng/mL at 15 min. In a subset of participants (n=6), plasma samples obtained from 15 min to 4 h after study drug administration had near-complete protection from ex vivo stimulated generation of plasma kallikrein and cleavage of high-molecular-weight kininogen. In part 2, all 68 participants were randomly assigned to sequence 1 (n=34) or sequence 2 (n=34). 53 (78%) of 68 participants treated two attacks (25 [74%] in the sequence 1 group and 28 [82%] in the sequence 2 group). Time to use of conventional treatment within 12 h of study drug administration was significantly longer with sebetralstat versus placebo (at quartile 1: >12 h [95% CI 9·6 to >12] vs 8·0 h [3·8 to >12]; p=0·0010). There were no serious adverse events or adverse event-related discontinuations. INTERPRETATION: Oral administration of sebetralstat was well tolerated and led to rapid suppression of plasma kallikrein activity, resulting in increased time to use of conventional attack treatment and faster symptom relief versus placebo. Based on these results, a phase 3 trial to evaluate the efficacy and safety of two dose levels of sebetralstat in adolescent and adult participants with hereditary angioedema has been initiated (NCT05259917). FUNDING: KalVista Pharmaceuticals.

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.

Long-term safety and effectiveness of berotralstat for hereditary angioedema: The open-label APeX-S study.

BACKGROUND: Berotralstat (BCX7353) is an oral, once-daily inhibitor of plasma kallikrein recently approved for prevention of angioedema attacks in adults and adolescents with hereditary angioedema (HAE). The objective of this report is to summarize results from an interim analysis of an ongoing long-term safety study of berotralstat in patients with HAE. METHODS: APeX-S is an ongoing, phase 2, open-label study conducted in 22 countries (ClinicalTrials.gov, NCT03472040). Eligible patients with a clinical diagnosis of HAE due to C1 inhibitor deficiency (HAE-C1-INH) were centrally allocated to receive berotralstat 150 or 110 mg once daily. The primary objective was to determine long-term safety and the secondary objective was to evaluate effectiveness. RESULTS: Enrolled patients (N = 227) received berotralstat 150 mg (n = 127) or 110 mg (n = 100) once daily. The median (range) duration of exposure was 342 (11-540) and 307 (14-429) days for the 150-mg and 110-mg groups, respectively. Treatment-emergent adverse events (TEAEs) occurred in 91% (n = 206) of patients. The most common TEAEs across treatment groups were upper respiratory tract infection (n = 91, 40%), abdominal pain (n = 57, 25%), headache (n = 40, 18%), and diarrhea (n = 31, 14%) and were mostly mild to moderate. Fifty percent (n = 113) of patients had at least one drug-related adverse event (AE; 150 mg, n = 57 [45%]; 110 mg, n = 56 [56%]), and discontinuations due to AEs occurred in 19 (8%) patients (150 mg, n = 13 [10%]; 110 mg, n = 6 [6%]). Three (1.3%) patients experienced a drug-related serious TEAE. Among patients who received berotralstat through 48 weeks (150 mg, n = 73; 110 mg, n = 30), median HAE attack rates were low in month 1 (150 mg, 1.0 attacks/month; 110 mg, 0.5 attacks/month) and remained low through 12 months (0 attacks/month in both dose groups). Mean HAE attack rates followed a similar trend, and no evidence for patient tolerance to berotralstat emerged. In both dose groups, angioedema quality of life scores showed clinically meaningful changes from baseline. CONCLUSIONS: In this analysis, both berotralstat doses, 150  and 110 mg once daily, were generally well tolerated. Effectiveness results support the durability and robustness of berotralstat as prophylactic therapy in patients with HAE. TRIAL REGISTRATION: The study is registered with ClinicalTrials.gov (NCT03472040).

Venom allergy treatment practices in Poland in comparison to guidelines: next edition of the national audit.

INTRODUCTION: Venom immunotherapy treatment (VIT) is the only causal treatment of hymenoptera venom anaphylaxis, which aims to provide long-lasting immunoprotection against severe reactions to subsequent stings. AIM: To reassess the compliance of VIT procedures in the Polish allergy centres with the European guidelines. MATERIAL AND METHODS: A structured questionnaire survey conducted in all 33 VIT-centres. The response rate was 94%. RESULTS: The ultrarush initial protocol was the most common protocol (71%, n = 22), usually lasting for 3.5 h (50%, n = 7). The most frequent (36%, n = 11) time interval from the initial to the first maintenance dose (MD) was 14 days, ranging from 7 to 35 days. All centres used an MD of 100 µg. The most frequent time interval between subsequent MDs was 4 weeks (58%, n = 18). Five years' of VIT was declared by 71% (n = 22). Before the termination of treatment, more than half of the centres (58%, n = 18) performed sIgE and almost half (42%, n = 13) performed skin tests. To confirm VIT efficacy, few centres (26%, n = 8) conducted the sting challenge. About half of centres provided the patients with an adrenalin auto-injector both at the time of initial diagnostics and at the end of treatment. More than half (55%, n = 17) used antihistamines in all patients. Almost half (45%, n = 14) declared to stop treatment with ß-blockers and almost one fourth (23%, n = 7) discontinued angiotensin-converting-enzyme inhibitors. CONCLUSIONS: In the most important procedures, there is a very high compliance with the guidelines. In the areas where the guidelines are not precise, we observed a large spread of results.

Hymenoptera sting in the head and neck region is not a risk factor for grade IV systemic reactions in patients with venom allergy.

INTRODUCTION Hymenoptera insect stings (ISs) in the head and neck (H&N) region are commonly considered to be a risk factor for grade IV systemic reactions (SRs) in patients with Hymenoptera venom allergy (HVA). However, clinical data addressing this issue are scarce. OBJECTIVES The aim of our study was to verify whether ISs in the H&N region were related to a higher risk of grade IV SRs in patients with HVA. PATIENTS AND METHODS This retrospective cross­sectional study included 195 patients aged 2 to 74 years and treated with venom immunotherapy due to at least a grade II SR to ISs. The study sample comprised 109 adults (56%; mean [SD] age, 41.08 [14.62] years; male, 50.5%) and 86 children (mean [SD] age, 9.53 [4.37] years; male, 72.1%; P <0.001 for age and P = 0.002 for sex). The IS site was divided into 7 categories. RESULTS The H&N region was the most common site for the IS (one­third of the study group). In the entire study population, the risk of grade IV SRs was numerically, though insignificantly higher for ISs in the trunk (odds ratio [OR], 1.58; 95% CI, 0.42-5.92; P = 0.50) and legs (OR, 1.56; 95% CI, 0.49-5.10; P = 0.45), as compared with the H&N region. The H&N region showed a similar risk of grade IV SRs when compared with all the other IS sites combined into a single category (OR, 0.87; 95% CI, 0.43-1.75, P = 0.7). CONCLUSIONS ISs in the H&N region were not confirmed to be a risk factor for grade IV SRs in patients with HVA, regardless of age and sex.

Simplification of intradermal skin testing in Hymenoptera venom allergic children.

BACKGROUND: The direct comparison between children and adults with Hymenoptera venom anaphylaxis (HVA) has never been extensively reported. Severe HVA with IgE-documented mechanism is the recommendation for venom immunotherapy, regardless of age. OBJECTIVE: To determine the differences in the basic diagnostic profile between children and adults with severe HVA and its practical implications. METHODS: We reviewed the medical records of 91 children and 121 adults. RESULTS: Bee venom allergy was exposure dependent, regardless of age (P < .001). Atopy was more common in children (P = .01), whereas cardiovascular comorbidities were present almost exclusively in adults (P = .001). In the bee venom allergic group, specific IgE levels were significantly higher in children (29.5 kUA/L; interquartile range, 11.30-66.30 kUA/L) compared with adults (5.10 kUA/L; interquartile range, 2.03-8.30 kUA/L) (P < .001). Specific IgE levels for culprit insect venom were higher in bee venom allergic children compared with the wasp venom allergic children (P < .001). In adults, intradermal tests revealed higher sensitivity, accompanied by larger area of skin reactions, regardless of type of venom. At concentrations lower than 0.1 µg/mL, 16% of wasp venom allergic children and 39% of bee venom allergic children had positive intradermal test results. The median tryptase level was significantly higher in adults than in children for the entire study group (P = .002), as well as in bee (P = .002) and wasp venom allergic groups (P = .049). CONCLUSION: The basic diagnostic profile in severe HVA reactors is age dependent. Lower skin test reactivity to culprit venom in children may have practical application in starting the intradermal test procedure with higher venom concentrations.

[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.

[Honey bee venom allergy diagnostics].

Honey bee venom (Apis mellifera) is a mixture of many components, both amines, peptides enzymes and toxins. Most of the enzymes are allergens with different allergenic potential. It may affect not only to the symptoms, it may also contribute to the success of immunotherapy. In some cases the problem of a bee venom allergy diagnosis is difficult due to the imperfection of the classical diagnostic methods. In the present work reports in the literature regarding the bee venom allergy diagnosis on the basis of identification of the venom allergen sIgE to components are summarized. The use of recombinant allergens has allowed for the study of sIgE against the allergenic components, and thus determination of the individual profile of allergy. Extending the test panel of bee venom components to rApi m10 and rApi m3 compared to rApi m1 increases the diagnostic sensitivity by identifying new allergens that are not always present in the available preparations used in immunotherapy.

[Skin as a place of immunomodulation].

The skin is the largest organ of the human body which plays a key role not only in physiological processes such as thermoregulation and the maintenance of the correct water and electrolyte balance, but also forms an effective barrier against microorganisms, protecting the organism against harmful external factors. Moreover, the skin is an important organ involved in immune mechanisms. The skin is a place of drug application to treat various local and systemic diseases. Those drugs are proteins and peptides sensitive to digestion in gastrointestinal tract, or chemical molecules metabolized in the liver. Epicutaneous immunization (EC) is a new therapeutic method used to treat immunological disorders. The phenomenom of immunomodulation has already been exploited to treat allergic diseases and is called allergen specific immunotherapy. The authors describe the current state of knowledge of the immune regulatory mechanisms that allow to use the EC method to treat immunological diseases mediated by Th1, Tc1 or Th2 lymphocytes. The new aspect of this immunotherapy is immunopotentiation that involves components of the innate immune system, working via the TLRs. The first clinical trials give promising outcomes of the use of EC method in the treatment of multiple sclerosis and respiratory allergic diseases.

Recombinant human-C1 inhibitor is effective and safe for repeat hereditary angioedema attacks.

BACKGROUND: Hereditary angioedema (HAE) caused by a deficiency in functional C1 esterase inhibitor (C1INH) is characterized by recurrent episodes of cutaneous and/or mucosal/submucosal tissue swelling affecting multiple anatomic locations. Previous studies demonstrated efficacy of recombinant human C1INH (rhC1INH) for acute HAE attacks. OBJECTIVE: This study evaluated the efficacy and safety of rhC1INH (50 IU/kg) for the treatment of multiple HAE attacks in an open-label extension study. METHODS: Time to onset of symptom relief and time to minimal symptoms were assessed using a Treatment Effect Questionnaire (TEQ), a visual analog scale, and a 6-point ordinal scale Investigator Score. RESULTS: Forty-four patients received rhC1INH, and a single dose was administered for 215 of 224 (96%) attacks. Median time to beginning of symptom relief based on TEQ for the first 5 attacks was 75.0 (95% CI, 69-89) minutes, ranging from 62.5 (95% CI, 48-90) to 134.0 (95% CI, 32-119) minutes. Median time to minimal symptoms using TEQ for the first 3 attacks was 303.0 (95% CI, 211-367) minutes. rhC1INH was well tolerated. There were no discontinuations due to adverse events. No thrombotic or anaphylactic events were reported, and repeat rhC1INH treatments were not associated with neutralizing anti-C1INH antibodies. CONCLUSIONS: A single 50-IU/kg dose rhC1INH was effective for improving symptoms of an HAE attack with sustained efficacy for treatment of subsequent attacks. rhC1INH had a positive safety profile throughout the study. This study supports repeated use of rhC1INH over time in patients with HAE attacks.

[Pharmacogenomics of severe drug hypersensitivity reactions--from bench to bedside]. / Farmakogenomika ciezkich polekowych reakcji nadwrazliwosci--miedzy laboratorium a lózkiem chorego.

Recent remarkable findings of pharmacogenomics and basic scientific research provided insights in the pathogenesis of severe drug hypersensitivity reactions such as drug rush with eosinophilia and systemic symptoms (DRESS), abacavir hypersensitivity syndrome or blistering reactions (Stevens-Johnson syndrome, toxic epidermal necrolysis). There is increasing evidence for the strong associations of certain human leukocyte antigen (HLA) alleles with hypersensitivity to particular drugs. HLA genes may serve as genomic biomarkers of predisposition to severe adverse drug reactions and enable to prevent them. In this paper we review essentials and advances in this area.

[Anaphylaxis as part of a clinical diagnosis of mastocytosi - case demonstration]. / Anafilaksja jako kliniczny element rozpoznania mastocytozy--demonstracja przypadku.

Mastocytosis is a heterogeneous group of diseases characterized by excessive proliferation and accumulation of mast cells--in one or more organs. The number of symptoms and clinical prognosis vary depending on the disease. One of the most severe potential outcome of mastocytosis is anaphylactic shock. Early diagnosis and identification of triggers enables education and avoidance them. We describe the case of a 31-year-old woman with systemic mastocytosis (SM) without skin symptoms with multiple anaphylactic reactions, including two severe. Systemic mastocytosis was confirmed in bone marrow and genetic studies. We identify allergic triggers: latex and cefuroxime and also other non-immunological triggers as non-steroidal anti-inflammatory drugs (NSAIDs). The patient never had any allergic reaction after Hymenoptera stings. Only one result of serum tryptase was elevated. There was a need to determine the safety of antibiotic use and anesthetic drugs before cesarean. The moment when the disease was diagnosed and triggers were identifie, helped avoid further severe reactions.

[A three year survey of the practical application of pollen monitoring in specific allergen immunotherapy]. / Zastosowanie monitoringu pylkowego podczas swoistej immunoterapii alergenowej--trzy lata obserwacji.

Specific allergen immunotherapy should be modified according to sensitivity of the patient and the time interval between injections and seasonal allergen exposition. The aim of the study was to check the effectiveness of the multinomial logistic regression models predicting the pollen concentration during the pollen season in the immunotherapy trial in patients treated with grass and birch allergens. The study was performed in Krakow in 2011-2013. Models were validated for 2012 and 2013. The effectiveness of the total correct predictions slightly differed depending on the time series, in case of birch pollen the similar percentage of correct predictions was found in both study year, while in case of grass pollen, the predictions were more correct in 2012. A group of patients treated with grass and birch allergens filled in the diary cards during the pollen season. After the 2011 season 14 diary cards were analysed, while 18 and 19, in 2012 and 2013, respectively. Because of manifested symptoms, the injection dose was reduced during the season in 12 patients in 2011, in 9 patients in 2012 and in 6 patients in 2013. No visits were delayed because of medical indications. In some cases patients got the injection in time of the high pollen occurrence (2 cases, in 2011 and 2012). In 2013 in 10/17 patients the high pollen exposure was avoided thanks the information from pollen monitoring, in opposite to 1 and 8 patients in 2011 and 2012, respectively. Patients used antihistaminic drugs on request. The regional pollen monitoring data and satisfied co-operation with patients makes the possibility of closer control of the injection doses administration during immunotherapy in the pollen season.

[Hymenoptera venom allergy. Analysis of double sensitization to wasp and bee venom in own material--diagnosis and classification for immunotherapy]. / Alergia na jad owadów blonkoskrzydlych. Analiza przypadków podwójnego uczulenia na jad osy i pszczoly w materiale wlasnym--diagnostyka i kwalifikacja do odczulania.

According to scientific societies guidelines the indication for venom immunotherapy is based on the clinical history of the patient. Diagnostic tests, like skin prick test or specific IgE serum estimation are conduct to prove IgE dependent mechanism of allergy and insect identification. Recent guidelines indicates for group of patients with severe systemic reactions as a candidates for diagnostic testing and in consequence for immunotherapy. In some countries diagnostic tests are also performed in patient who have a history of large local reactions, if they are considered as a candidates for immunotherapy. Double sensitization in cases of patients unable to identify the culprit insect is a diagnostic and therapeutic problem. In our group of patients (n = 113) we confirmed the double sensitization in 30% cases. The addition of a major allergen labeling reduced the number of people actually double-sensitized to 8.84%. It was observed that in patients who are not able to identify insect double sensitization phenomenon is particularly frequent as much as 45.5% and in the determination of the major allergens in 18.2%. Such patients needed detailed diagnosis and in many cases the use of two vaccines to conduct immunotherapy.

[Influence of venom immunotherapy on anxiety level of being re-stung]. / Wplyw immunoterapii swoistej z jadem owadów blonkoskrzydlych na poziom leku przed ponownym uzadleniem.

UNLABELLED: Hymenoptera venom allergy is related to higher risk of potential life -threatening anaphylactic reactions, which leads to anxiety and decreased quality of life. AIM: The aim of this paper was: 1) estimation of fear level of being re-stung among venom allergy adults treated with venom specific immunotherapy (VIT)--before and during treatment; 2) estimation of expectation of outcome of VIT as compared to level of anxiety of being re-strug, in the Visual Analogue Scale--VAS score; 3) identification of factors influencing changes in the fear level among patients during VIT. MATERIAL AND METHODS: The study group comprised 42 patients (18 women, 24 men) in the mean age 42.6 years, with bee or vespid allergy, who had been qualified to the VIT treatment with Alutard SQ. Visual Analogue Scale--VAS and the Expectation of Outcome Questionnaire were used. The demographic data were collected. RESULTS: The VAS score before VIT for insect venom allergic patients was 8.8 (SD = 0.9). It decreased after achieving maintenance dose to 3.1 (SD = 1.6) and was significantly lower in men (p < 0.05). Score achieved in the Expectation of Outcome Questionnaire was for each question 2.2 (SD = 1.5) and there was correlation with VAS score during VIT. CONCLUSIONS: The patients with insect venom allergy, who undergo a serious allergic reaction (SR) as a result of being stung and who are qualified to VIT, have a high level of anxiety of being re-stung. Achieving the maintenance dose of VIT, results in a significant decrease of anxiety level in women and men, significantly so in men. There is a significant correlation between VAS score and the Expectation of Outcome Questionnaire results during VIT. Both VAS for anxiety level and the Expectation of Outcome Questionnaire can be simple, easily available and useful instruments helping to estimate quality of life. VIT significantly decreases the patients level of anxiety of being restung and improves their quality of life.

[Response of peripheral blood mononuclear leukocyte to nickel stimulation in patients with systemic and contact allergy to nickel]. / Odpowiedz jednojadrzastych leukocytów krwi obwodowej na stymulacje siarczanem niklu u pacjentów z systemowa i kontaktowa alergia na nikiel.

UNLABELLED: Nickel is knows as the most common cause of allergic contact dermatitis, as well as diffuse eczema, allergic rhinitis and bronchial asthma. The mechanism of contact allergy to nickel is well known. In spite of numerous investigations, the mechanism of systemic allergy to nickel is still not clear. 22 patients with positive patch tests to nickel were analyzed. On basis of clinical symptoms the patients were divided into two groups: 1. with contact allergy dermatitis to nickel--8 patients 2. with systemic allergy to nickel (allergic rhinitis and/or diffuse eczema--14 patients. The control group included non-atopic patients with negative patch test to nickel--6 patients. 10 ml of blood were taken from each patient and peripheral mononuclear blood cells (PMBC) were isolated. In PBMC culture, NiSO4 and PHA were stimulated. The control group was non-stimulated cells. The supernatants were collected after 3 and 6 days of culture and the levels of cytokines IL-5, 4 and IFNgamma were measured (ELISA). The concentration of IFNgamma in supernatants from stimulated as well as non-stimulated cells from patients with contact allergy to nickel was higher in comparison to the control group. The concentration of IL-5 in this group was low. There was an increase in the production of IFNgamma and IL-5 after NiSO4 stimulation in patients with systemic allergy to nickel. The higher concentration of IFNgamma in the same groups of patients investigated was in supernatants from the third day of PBMC culture were compared to the sixth day. After 3 and 6 days of culture, the concentration of IL-4 (ELISA) was below detection level in all supernatants analyzed. SUMMARY: IFNgamma plays an essential role in the mechanism of developing of contact allergy to nickel; and IFNgamma as well as IL-5 play a role in the mechanism of developing systemic allergy to nickel. The third day of PBMC culture is more reliable for IFNgamma estimation.