Influencing factors on the safety and effectiveness of venom immunotherapy.

BACKGROUND AND OBJECTIVE: The safety profile of venom immunotherapy (VIT) is a relevant issue and considerable differences in safety and efficacy of VIT have been reported. The primary aim of this study was to evaluate the safety of ACE inhibitors and beta-blockers during VIT, which has already been published. For a second analysis, data concerning premedication and venom preparations in relation to systemic adverse events (AE) during the up-dosing phase and the first year of the maintenance phase were evaluated as well as the outcome of field stings and sting challenges. METHODS: The study was conducted as an open, prospective, observational, multicenter study. In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during the up-dosing and 19.7% of patients during the maintenance phase. Taking antihistamines had no effect on the frequency of systemic AE (p=0.11) but large local reactions (LLR) were less frequently seen (OR: 0.74; 95% CI: 0.58-0.96; p=0.02). Aqueous preparations were preferentially used for up-dosing (73.0%) and depot preparations for the maintenance phase (64.5%). The type of venom preparation neither had an influence on the frequency of systemic AE nor on the effectiveness of VIT (p=0.26 and p=0.80, respectively), while LLR were less frequently seen when depot preparations were used (p<0.001). CONCLUSION: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLR but not systemic AE. All venom preparations used were equally effective and did not differ in the frequency of systemic AE.

Limited Long-Term Impact of Insect Venom Immunotherapy on the Micro-RNA Landscape in Whole Blood.

OBJECTIVE: To perform a genome-wide characterization of changes in microRNA (miRNA) expression during the course of venom immunotherapy (VIT). METHODS: miRNA was isolated from the whole-blood of 13 allergic patients and 14 controls, who experienced no allergic reaction upon stings by honeybees and wasps. We analyzed 2549 miRNAs from the whole blood of these patients prior to VIT and 12 months after the start of VIT. The results for differential expression obtained on a microarray platform were confirmed by quantitative real-time PCR. Out of the 13 patients, 8 had a negative allergic reaction with VIT, thus indicating that this approach was successful. RESULTS: By comparing time points before and 12 months after ultrarush VIT, correlation analysis and principal component analysis both indicated a limited effect of VIT on the overall miRNA expression pattern. Volcano plot analysis based on raw P values revealed few deregulated miRNAs, most of which were increasingly expressed after VIT as compared with before VIT. Based on the 50 most altered miRNAs, no clear clustering was observed before or after VIT. CONCLUSIONS: Our results indicate an overall reduced effect of VIT on the miRNA expression pattern in whole blood.

Can obstructive intralymphatic granulomas be the cause of cheilitis granulomatosa?

Cheilitis granulomatosa (ChG), also known as Miescher's cheilitis, is an uncommon, immunologically mediated nonnecrotizing granulomatous inflammatory disease characterized by recurrent, painless swelling of the lips. The aim of the study was a pathomorphological and immunohistochemical assessment of cases clinically classified as ChG to investigate potential pathological mechanisms of ChG symptoms and to verify the hypothesis of intravascular granulomas as a cause of lymphatic vessel obstruction and localized edema in ChG. We report 6 patients with ChG who clinically presented localized edema of the lips. Lip biopsy with pathomorphological and immunohistochemical examination was performed in all cases. We found discrete, non-necrotizing granulomas which were adjacent to numerous blood and lymphatic vessels. The lumen of lymphatic channels was dilated and was either empty or contained lymph and few macrophages or was completely occluded by nearby granulomas. All patients demonstrated a characteristic pattern of lymphangiectasia and perivascular lymphatic aggregates with evidence of non-necrotizing granulomas. None manifested intralymphatic granulomas. These results do not support the view that lymphatic vessel obstruction is caused by intravascular histiocytic granulomas described as the main part in the etiology of lymphatic edema in ChG. However, perivascular granulomas and dilation of lymphatic vessels confirm presence of inflammatory lymphostasis in all studied cases of ChG.

Safety of Ultrarush Venom Immunotherapy: Comparison Between Children and Adults.

BACKGROUND: The ultrarush protocol is an attractive approach in the buildup phase of venom immunotherapy (VIT-UR). However, the degree of risk of VIT-UR in children remains unknown. The objective of this study was to compare the safety of VIT-UR in children and adults. METHODS: We performed a study based on prospectively gathered medical records of children and adults with hymenoptera venom allergy treated with VIT-UR in 3 allergy centers in Poland. RESULTS: The study population comprised 134 children (mean [SD] age, 12.6 [3.7] years; males, 70.1%) and 207 adults (mean age, 42.4 [14.0] years; males, 47.8%). The number of children in the subgroups of bee venom (BV) allergy and wasp venom (WV) allergy were comparable, although sensitization to WV was more predominant in the adult group (70.1%). Skin reactivity to both venoms was more common in children than in adults (P < .001); however, children had higher concentrations of total IgE and specific IgE to BV (both P < .001). Systemic allergic reactions (VIT-SARs) occurred in 6.2% of the patients (3.7% in children and 7.7% in adults; nonsignificant). In adults, SARs occurred more frequently in patients treated with BV than WV extracts (21.4% vs 2.6%; P < .001). The same pattern was observed in children (7.2% vs 0%; P = .058). However, VIT-SARs to BV were less frequent in children than in adults (P = .034). Similarly, no significant relationship was noted between children and adults receiving WV VIT (2.6% vs 0%; nonsignificant). The severity of VIT-SAR did not differ between children and adults. CONCLUSIONS: VIT-UR is safer in children. Age below 18 is not a risk factor for VIT-SARs.

Melkersson-Rosenthal syndrome: lymphoscintigraphy-documented impairment and restoration of facial lymphatic drainage in the course of disease.

Melkersson-Rosenthal syndrome (MRS) is an idiopathic, rare disorder manifested by facial swelling, congenital plicated tongue and recurrent peripheral facial nerve palsy. Labial involvement alone is referred to as cheilitis granulomatosa. Differential diagnosis of MRS includes allergic angioedema, bacterial, viral or filarial infections as well as autoimmunological inflammation in the course of systemic lupus erythematosus, dermatomyositis, and others. We present 4 patients who experienced periodically painless edema of the face and/or lips. Lesions were diagnosed as recurrent Quincke's edema and were treated with antihistamine agents and glucocorticoids without improvement. In all four cases of MRS, we were able to document impaired lymphatic drainage from the swollen area using lymphoscintigraphy. We also documented in follow-up lymphoscintigraphy a restoration of lymphatic flow in three of the four patients with MRS and these results corresponded with clinical improvement. We have demonstrated that lymphatic pathology plays an important role in pathophysiology of chronic facial swelling in patients with Melkersson-Rosenthal syndrome.

Skin prick test response to enzyme enolase of the baker's yeast (Saccharomyces cerevisiae) in diagnosis of respiratory allergy.

BACKGROUND: The aim of the study is to prove that Saccharomyces cerevisiae enolase, the major allergen of the baker's yeast, induces allergic immediate response in patients with inhalant allergy sensitized to Candida albicans extract. MATERIAL AND METHODS: The study was performed in three groups of patients: I. 20 atopic patients with respiratory allergy sensitized to Candida albicans and inhalant allergens (mite, feather, pollens) II. 30 patients with respiratory allergy, positive skin tests to inhalant allergens but negative skin tests to Candida albicans and other fungi; III. 20 nonatopic, healthy individuals. Skin prick test of purified enolase from Saccharomyces cerevisiae (bakers yeast) at concentration 1 and 10 mg/ml was performed in all groups. The results were documented planimetrically. RESULTS: 95% of patients sensitized to Candida albicans extract showed positive skin reactions to Saccharomyces cerevisiae enolase, 10% of patients of group II and none of the patients of the control group had positive skin responses to enolase. The mean wheal size (mm2) in skin prick test to Candida albicans, Saccharomyces cerevisiae enolase at concentration 10 mg/ml was x = 15.17 +/- 11.08, 15.76 +/- 19.67 and at concentration 1 mg/ml 10.02 +/- 10.49, respectively. CONCLUSIONS: 1. Saccharomyces cerevisiae enolase induces an immediate allergic reaction in skin in subjects with respiratory allergy and positive skin prick test results to Candida albicans and other fungi. 2. Enolase can be an important allergenic component of the Candida albicans extract.

[Oxidation phenotype as a risk factor for development of allergic diseases]. / Fenotyp oksydacji jako czynnik zwiekszajacy ryzyko wystapienia chorób alergicznych.

The relationship between genetically determined polymorphic metabolism and susceptibility to allergic diseases has aroused much interest. The aim of our study was to evaluate whether patients with allergic diseases, like atopic asthma and allergic rhinitis differ from healthy persons in their ability to oxidize sparteine as a model drug. The study was completed by 200 persons, 40 patients with allergic diseases--20 with atopic asthma and 20 with allergic rhinitis and 160 healthy volunteers as a control group. The results of our study revealed a predominance of very extensive metabolizers of sparteine among patients with allergic diseases in comparison with healthy volunteers. The difference in the oxidation metabolic ratio (MR) frequency distribution between patients with allergic diseases and healthy persons was statistically significant. Relative risk (odds ratio) of development of atopic asthma was 3.29 times higher, and that of allergic rhinitis 2.94 times higher for persons with very extensive oxidation phenotype. Our results represent some evidence for a possible relationship between extensive, rapid oxidation phenotype and the higher susceptibility to development of atopic asthma and allergic rhinitis.

[The results of research on the prevalence of allergy to Hymenoptera venom in Southwestern Poland]. / Wyniki badan nad wystepowaniem alergii na jad owadów blonkoskrzydlych na terenie Dolnego Slaska.

A questionnaire designed to estimate the prevalence of allergic reactions to Hymenoptera venom was posted to 1000 inhabitants of south west Poland. 881 persons responded to the questionnaire. 255 (28.9%) reported allergic reactions to stinging insects venom 141 persons (16%) report large local reactions (LL) and 114 (12.9%) systemic reactions (SYS) after stinging. At the second stage of the study 95 persons, out of the 255, were examined by a physician and tested with the intracutaneous skin test. Anamnesis carried out by the physician initially confirmed venom allergy in 87% of the LL group and 77.5% of the SYS group. Skin test results verified the above assessments confirming venom allergy in 38% persons initially reporting LL reactions and in 55% of those initially reporting SYS reaction.

[Toxic reaction induced by Hymenoptera stings]. / Reakcja toksyczna po uzadleniu przez owady blonkoskrzydle.

Clinical symptoms of toxic reactions occurred in two patients following multiple stinging by bees and wasps respectively. The first cause is that of 76-year old woman attacked by a swarm of bees (about 200 stings), the other case presents a 69-year old man who was stung by several dozen of wasps. In the first case the toxic reaction was manifested by shock, acute renal failure, tissue damage of the skin, muscles and liver and haemolysis which resulted in the patients death. These symptoms occur as a results of the cytotoxic effects of bee venom components such as melittin, phospholipase and kinins. In the course of the disease, noteworthy are: the initial phase mimicking an anaphylactic shock, haemolysis and rhabdomyolysis which lead to acute renal failure with tubular necrosis. In the second case skin symptoms prevailed. Additionally, laboratory tests showed increased CPK as a results of myolysis caused by components of insect venom. The progress of toxic reactions following multiple stinging especially by bees, calls for hospital observation of stung patients with careful monitoring of renal function.

[Evaluation of diagnostic value of skin test, venom specific antibodies against EgE and basophil histamine release test in hymenoptera allergy]. / Ocena przydatnosci diagnostycznej testów skórnych, stezen jadoswoistych przeciwcial IgE i testu wyzwalania histaminy z granulocytów zasadochlonnych w alergii na owady blonkoskrzydle.

The study compares results of skin test and assessments of venom specific IgE levels (FAST) in patients with Hymenoptera sting allergic reactions. Results of the two diagnostic methods show considerable correlation. Positive correlation occurred in 90% of the patients (92.4% bee venom sensitive allergic patients and 80% wasp venom sensitive patients). Negative correlation occurred in 2% of the patients. In the remaining 8% of the group the results did not correlate. Basophil histamine release test was performed in 13 patients with allergic reactions after stinging. 77% of the basophil histamine release test results showed positive correlation with the other two tests. No correlation was found between the size skin test, the class of the FAST test, and the result of basophil histamine release test. No relationship was found either, between results of the described test and the severity of sting reaction classified to Mueller scale.

[A comparative study on skin tests and allergen-specific IgE levels determined by enzyme allergo-sorbent testing (EAST)]. / Badania porównawcze zgodnosci testów skórnych ze stezeniem swoistych prezeciwcial IgE oznaczanych metoda enzyme allergo-sorbent testing (EAST).

Ninety seven randomly selected subjects with bronchial asthma and allergic rhinitis were classified for the comparative studies. The level of allergen specific IgE determined by Enzyme Allergo-Sorbent Testing (EAST) was compared with skin tests. The statistically significant correlation was found for 9 selected allergens. However, the Spearman's rank correlation coefficient values varied largely, depending on a given allergen. They ranged from 0.74 (Dermatophagoides pteronyssinus) to 0.33 (Birch pollen) what might be, in the authors' opinion, a result of Bencard allergens use for skin tests and Kallestad allergens for EAST.

[Skin tests, total IgE and venom specific IgE and IgG4 in serum of bee-keepers]. / Testy skórne i stezenia calkowitych i jadoswoistych IgE i IgG4 w surowicy pszczelarzy.

In 14 occupationally active bee-keepers, who tolerated stinging well, two diagnostic tests have been performed: 1. skin test at the venom concentration of 10(-3) g/l, 2. both total and venom specific IgE and IgG4 assessments. The study group consisted of 13 male and 1 female aged 34-56 (mean age 44.3). 7 out of 14 bee-keepers (50%) had positive skin tests; mean size being mean = 3.57 +/- 4.07 mm. None of the subjects showed increased total IgE levels, but 71.4% showed bee venom specific IgE (mean mean 1.64 +/- 1.34 FAST). Specific bee venom IgG4 occurred in 13 out 14 individuals (92.8%). Their average serum level was mean 21.74 +/- 17.16 IU/ml.

Specific allergen induced motility of peripheral blood mononuclear cells and polymorphonuclear leukocytes in insect sting allergy.

The motility of peripheral blood mononuclear cells (MNC) and polymorphonuclear (PMN) leukocytes from normal and bee venom allergic subjects was investigated by a modified Boyden micropore filter method. The study comprised MNC locomotion in bee venom and histamine gradients and PMN locomotion in bee venom and fMLP gradients. We demonstrated statistically significant increase in MNC and PMN motility towards bee venom in allergic patients group. This effect disappeared after the preincubation of MNC with anti-human IgE antibodies. We observed no such effect in PMN leukocytes. Increased MNC motility in histamine gradient was observed only in control subjects group. Similarly significant increase in PMN locomotion towards fMLP was found in both allergic and control subjects. The results here demonstrated suggest that a specific allergen might be a chemoattractant for peripheral blood MNC and PMN leukocytes from atopics and could be capable to induce non-infectious inflammatory reactions as a result of its interaction with these sensitive cells.

Acetylator phenotype in patients with allergic diseases and its clinical significance.

The genetic polymorphism of drug acetylation rate in man is an important determinant of the toxic and therapeutic response to certain drugs. This polymorphism can alter not only drug effects but may be a factor influencing the frequency of the occurrence of some disease states. The aim of our study was to establish whether there exists any correlation between the acetylator phenotype and the development of allergic diseases. In patients with allergic diseases and in healthy persons as a control group, the acetylation phenotype was determined by the sulfadimidinic method. In the group of patients with allergic diseases without infectional factor 76% slow and 24% rapid acetylators were found. This predominance of slow acetylators was statistically significant (by using chi 2 test) with comparison to the group of healthy persons, where 49% slow and 51% rapid acetylators were observed. Considerable predominance of slow acetylators in patients with allergic diseases suggest that phenotype of slow acetylation may be a factor playing some role in pathogenesis of allergic diseases and may be a factor predisposing to the development of these diseases.