Key Issues in Hymenoptera Venom Allergy: An Update.

In this review, the Hymenoptera Allergy Committee of the SEAIC analyzes the most recent scientific literature addressing problems related to the diagnosis of hymenoptera allergy and to management of venom immunotherapy. Molecular diagnosis and molecular risk profiles are the key areas addressed. The appearance of new species of hymenoptera that are potentially allergenic in Spain and the associated diagnostic and therapeutic problems are also described. Finally, we analyze the issue of mast cell activation syndrome closely related to hymenoptera allergy, which has become a new diagnostic challenge for allergists given its high prevalence in patients with venom anaphylaxis.

Insect Venom Immunotherapy: Analysis of the Safety and Tolerance of 3 Buildup Protocols Frequently Used in Spain.

INTRODUCTION: Hymenoptera venom immunotherapy (VIT) is an effective treatment but not one devoid of risk, as both local and systemic adverse reactions may occur, especially in the initial phases. We compared the tolerance to 3 VIT buildup protocols and analyzed risk factors associated with adverse reactions during this phase. MATERIALS AND METHODS: We enrolled 165 patients divided into 3 groups based on the buildup protocol used (3, 4, and 9 weeks). The severity of systemic reactions was evaluated according to the World Allergy Organization model. Results were analyzed using exploratory descriptive statistics, and variables were compared using analysis of variance. RESULTS: Adverse reactions were recorded in 53 patients (32%) (43 local and 10 systemic). Local reactions were immediate in 27 patients (63%) and delayed in 16 (37%). The severity of the local reaction was slight/moderate in 15 patients and severe in 13. Systemic reactions were grade 1-2. No significant association was found between the treatment modality and the onset of local or systemic adverse reactions or the type of local reaction. We only found a statistically significant association between severity of the local reaction and female gender. As for the risk factors associated with systemic reactions during the buildup phase, we found no significant differences in values depending on the protocol used or the insect responsible. CONCLUSIONS: The buildup protocols compared proved to be safe and did not differ significantly from one another. In the population studied, patients undergoing the 9-week schedule presented no systemic reactions. Therefore, this protocol can be considered the safest approach.

Olive, grass or both? Molecular diagnosis for the allergen immunotherapy selection in polysensitized pollinic patients.

BACKGROUND: Grass and olive are the most frequently pollens that induce seasonal allergic rhinitis in Spain. Cross-reactivity due to panallergens shared by them and overlapping pollination complicates the recognition of allergy-causing agents, making it difficult to identify the most appropriate allergen immunotherapy (AIT) to use. The aim of this study was to determine the sensitization pattern to major grass and olive pollen allergens using component-resolved diagnostics in patients with seasonal allergic rhinitis (SAR) and positive skin prick test to grass and olive pollens and evaluate how knowledge of the sensitization patterns might influence AIT prescription. METHODS: After informed written consent, a total of 1263 patients were recruited. A serum determination of specific IgE levels to Ole e 1 and Phl p 1 + 5 was performed to all patients. A comparison was made before and after obtaining the specific IgE results, and differences in diagnosis were stated. RESULTS: At the 0.35 kU/l cut-off point, 71.2% of patients were positive to Ole e 1 and Phl p 1 + 5, 14% were positive only to Phl p 1 + 5 and 12% were positive only to Ole e 1. Based on available clinical data and skin prick test results, 922 (73%) patients would have been indicated for a mixture of grass and olive pollens for AIT. In 56.8% of patients, there was non-coincidence in the composition of AIT that would be selected before and after investigators received the in vitro data. CONCLUSION: The diagnostic accuracy of the recombinant allergen-specific IgE test could help to improve the selection of specific-allergen immunotherapy in polysensitized patients.

Ibuprofen-induced aseptic meningoencephalitis confirmed by drug challenge.

Drug-induced aseptic meningitis (DIAM) is a diagnostic challenge. The major causative agents are nonsteroidal anti-inflammatory drugs (particularly ibuprofen), antibiotics, intravenous immunoglobulin, and OKT3 monoclonal antibodies. DIAM is more frequently observed in patients with autoimmune diseases. A 36-year-old woman was attended in our department 3 months after being diagnosed with aseptic meningoencephalitis. She had had 2 episodes in 9 months. Neurological symptoms were associated with ibuprofen. A challenge with acetylsalicylic acid was negative, whereas a drug challenge with ibuprofen was positive. Thirty minutes after ingesting 50 mg of ibuprofen, she experienced general malaise and progressively developed chills, fever (39.5 degrees C), headache, and nuchal rigidity. Lumbar puncture showed normal glucose and high protein levels. Neutrophilic pleocytosis was observed at the first admission; lymphocytosis was predominant in the second and third episodes. DIAM is a rare and severe hypersensitivity reaction. Drug challenge enabled us to make an accurate diagnosis.

Epidemiologic observations on Hymenoptera allergy in Spain: the Alergológica-2005 study.

BACKGROUND: To date there has been an absence of nation-wide epidemiologic studies on insect allergy in Spain. OBJECTIVES: To measure the frequency and to determine the characteristics of Hymenoptera hypersensitivity in a Spanish population at a particular point in time and compare with the data obtained in a similar study carried out in 1992. MATERIAL AND METHODS: An observational, prospective and cross-sectional study (Alergológica-2005) was carried out all over Spain. RESULTS: The number of patients included in the study was 4991, of whom 77 (1.54%) were diagnosed with insect sting allergy. This represented an increase of 0.7% compared to Alergológica-1992. The honey bee was responsible for 45.5% of reactions, Vespula spp for 27.3% and Polistes spp for 23.4%. 64.9% of reactions were systemic. The group with Hymenoptera allergy had a predominance of males (69.1% vs. 42.7% in the general sample, P < .0001), older patients (median age 37,4 vs. 32,1, P < .013), and homes in rural zones (33% vs. 18.3%, P < .004). The median of days necessary to reach a diagnosis was lower (P < .0001). This population needed assistance in emergency units and hospitalisation more frequently. They had a low score on the mental component of the quality of life questionnaire. CONCLUSIONS: There was an increase in cases diagnosed with insect allergy with regard to Alergológica-1992. The typical patient profile is of a man, living in a small village, working outdoors with significant exposure to insect stings and in contact with farm animals, without atopic diseases. Bees and wasps are equally responsible of the stings. The need of emergency assistance in those patients is higher and the waiting time to be attended by an allergist is shorter.

Significance of infrequent and unspecific pathologies recorded in the Spanish Survey Alergológica-2005.

BACKGROUND: There are infrequent or unspecific diseases that occupy an important part of time in the job of the allergists. OBJECTIVE: We sought to evaluate the frequency and to determine the characteristics of uncommon or unspecific diseases seen by allergists in Spain, and to compare these data with findings obtained in a similar study undertaken in 1992. MATERIAL AND METHODS: An observational, prospective and cross-sectional study named "Alergológica 2005" was carried out in Spain. A part of this study analyzed the demographic, healthcare and clinical aspects of infrequent or unspecific diseases categorized as "Other allergic diseases" (OAD) or "Other non-allergic diseases" (ONAD). RESULTS: The survey comprised 4991 patients. In OAD, 45 patients were included. In ONAD, 290 patients were included. Significant diagnoses were gastroallergic anisakiasis (10 patients), idiopathic anaphylaxis (7 patients), and hypersensitivity pneumonitis (2 patients). In the ONAD group, non allergic respiratory diseases were the most frequent diagnosis. Mean time spent to reach a diagnosis was 14.2 days. However, the median of this time was only 1 day. Main diagnostic methods employed were a clinical history/physical examination in 86% of patients and skin tests in 73.7%. CONCLUSION: Several unspecific diseases affected more than 60% of patients in the two groups together. Findings show the current knowledge of allergic disorders due to Anisakis simplex. Diagnoses of hypersensitivity pneumonitis seem to be as frequent as previously published. Idiopathic anaphylaxis seems to be less frequent. The wide-range of times needed to reach a diagnosis was in agreement with the mixture of diseases included in both groups.

Efficacy and quality of life with once-daily sublingual immunotherapy with grasses plus olive pollen extract without updosing.

OBJECTIVE: The purpose of this randomized, double-blind, placebo-controlled study was to evaluate the clinical efficacy and tolerance of once-daily sublingual immunotherapy without updosing. Reduction in symptoms and medication use was the primary endpoint. METHODS: One hundred five patients with rhinitis and/or asthma due to grass and olive sensitization were randomized to be treated with placebo or active sublingual immunotherapy with the SLITone grass mix plus olive pollen extract for 6 months before the 2005 pollen season. Patients recorded symptoms and medication intake for 8 weeks during the pollen seasons in 2004 (n=37) and 2005 (n=85). RESULTS: Allergic symptoms were significantly decreased in the active immunotherapy group (P = .004) but not in the placebo group. There were no differences in scores between groups during the 2005 pollen season. Subjective assessments on a visual analog scale and a quality-of-life questionnaire indicated an improvement in actively treated patients with significant differences in both symptoms and medication use (P = .006). The rate of systemic adverse reactions was comparable in the 2 groups. No anaphylactic or severe adverse reactions were reported. Local adverse reactions, which were more common in the active immunotherapy group, were mostly immediate, were limited to the lips and mouth, and did not require treatment. CONCLUSION: Once-daily sublingual immunotherapy without updosing was well tolerated. The actively treated patients showed a significant reduction in symptom and medication scores and an improvement in their quality of life although there were no significant differences between the groups probably due to the low allergen season in which the study was evaluated.

Monoclonal antibody desensitization in a patient with a generalized urticarial reaction following denosumab administration.

Denosumab is a human monoclonal antibody indicated for the treatment of osteoporosis in postmenopausal women with a high risk of fractures. To our knowledge, no cases of desensitization to this drug have been described in the literature. We report the first case of generalized urticarial reaction and facial angioedema after therapy with denosumab. A subcutaneous desensitization protocol was successfully completed in this patient. Rapid desensitization is a promising method for the delivery of denosumab after a hypersensitivity reaction, and should be considered in osteoporosis treatment when no acceptable therapeutic alternatives are available.

Bread eating induced oral angioedema due to alpha-amylase allergy.

Inhalation of dust from different enzymes can be the cause of occupational asthma in exposed workers. Enzymes from different sources are being increasingly used in food. Few cases of food allergy to alpha-amylase induced by eating bread have been reported. Those cases were reported in bakery-related patients and in a pharmaceutical-industry worker. A 25-year-old farmer suffered sneezing, rhinorrhea, oropharyngeal itching, hoarseness, cough, and non-wheezy dyspnea after eating white bread. Skin prick tests (SPT) with common aeroallergens and food allergens revealed only sensitization to Olea europaea pollen. SPT response was positive to Aspergillus oryzae alpha-amylase. Specific IgE against alpha-amylase was positive. A double-blind placebo-controlled challenge with 5 mg of uncooked -amylase induced sneezing, cough, oral angioedema within 10 minutes. The provocation test with 50 g of white bread gave similar findings. This case indicates that alpha-amylase contained in bread may provoke IgE-mediated food allergy. It is worth noting that in this case, the only source of alpha-amylases sensitization was bread.

Two cases of specific adverse reactions to systemic corticosteroids.

Although true allergic reactions due to systemic corticosteroid therapy are not frequent, they should be kept in mind since allergic reactions to this kind of therapy are possible. We report two cases of specific adverse reactions resulting from systemic corticosteroid therapy which were diagnosed by provocation tests. The corticosteroids involved in each case were paramethasone and betamethasone, and methyl-prednisolone in both of them. Additives and other corticosteroids were studied by skin tests and challenges, with negative results. The structures of paramethasone and betamethasone are similar, with a 16 carbon methyl group in both, and with a fluoride in the alpha position of the 6 carbon in paramethasone, and a fluoride in the beta position of the 9 carbon and a 6 carbon methyl group in betamethasone. Methyl-prednisolone differs from that of other corticosteroids in its 6 carbon methyl group. We report two cases of specific adverse reactions caused by corticosteroids. Positive challenge tests showed a possible immunologic hypersensitivity mechanism in both cases. The patients' reactions demonstrated cross-reactivity between methyl-prednisolone and the corticosteroids having a 16 carbon methyl group, and fluoride or methyl radicals on the 6 carbon.

Atopy and bronchial hyperresponsiveness in pure extrinsic childhood asthma.

Nonspecific bronchial hyperresponsiveness and atopy are considered risk factors in the development of asthma. Bronchial responsiveness to allergens could be the most important factor in extrinsic asthma. The trial was designed to investigate the role of specific and nonspecific bronchial responsiveness and atopy in a pure model of extrinsic asthma in children. One hundred and thirty-seven patients with pollen allergy were evaluated. Twenty children with allergy to grass pollen (Lolium perenne) alone, with symptoms only in the grass pollen season, were selected. Their score of symptoms, airway responsiveness to methacholine in and out of season, airway responsiveness to Lolium perenne out of season, and total and specific IgE were assessed. Twelve were male and eight female. Mild asthma was observed in 14, and moderate asthma in six. Age of onset of symptoms ranged from three to 13 years of age. Significant seasonal increase in airway responsiveness to methacholine was found (p = 0.002). Specific bronchial challenge test was positive in all patients. Lolium pernne PD20 ranged from 2.3 to 155.5 inhalation units. An inverse association between age of onset of symptoms and severity of asthma was shown (p = 0.001). Increase in nonspecific bronchial responsiveness was related to the appearance of symptoms during the spring, but it showed no relationship to the severity of symptoms. Severity of asthma during the spring correlated with the intensity of allergen airway responsiveness (p = 0.02). Levels of total and specific IgE were not related to the degree of specific or nonspecific airway responsiveness. Severity of extrinsic childhood asthma is determined by bronchial response to allergens. Bronchial hyperresponsiveness to methacholine during the spring can be the consequence of environmental exposure to allergens. The intensity of airway responsiveness to methacholine has no predictive value in the severity of pure extrinsic childhood asthma.

Delayed hypersensitivity to enoxaparin.

A 65-year-old woman experienced immediate itchy erythematous patches at the subcutaneous injection sites of sodium enoxaparin. An erythematous and infiltrated 40 x 20 mm lesion on the abdominal wall could be observed at the site of enoxaparin injection when she was referred to our clinic 48 h after injection. Lesions subsided spontaneously within 1 week. She had been on this treatment 1 and 3 years before without any adverse reaction. To clarify the nature of the reaction, epicutaneous tests with sodium enoxaparin, calcium nadroparin and calcium heparin were performed, all with negative results. Skin prick test with sodium enoxaparin was also negative. Biopsy of the cutaneous lesion showed spongiotic dermatitis, strongly suggesting a delayed hypersensitivity mechanism. We report here on a new case of delayed hypersensitivity to enoxaparin. Being female, overweight and having prolonged application of the drug were suggested risk factors present in our patient. Biopsy was essential for diagnosis. Although type IV hypersensitivity reactions to enoxaparin are rare, we should start to suspect this condition in order not to underdiagnose it.

Importance of albumin in cross-reactivity among cat, dog and horse allergens.

Different allergenic proteins have been involved in cross-reactivity among animals. Albumins seem to be cross-sensitizing allergenic components. The aim of this study was to assess the importance of albumin as a cross-reactive allergen in patients sensitized to cat, dog and horse. One hundred and seventeen patients sensitized to cat were tested for IgE reactivity using skin prick tests and RAST assays with cat, dog and horse hair/dander extracts and their purified albumin extracts. RAST-inhibition studies were carried out to assess cross-reactivity among cat, dog and horse and among their purified albumins. It was found that 22% of patients exhibited specific IgE to cat albumin; 41% of patients sensitized to cat were also sensitized to dog and horse. Out of these patients, 21% had IgE to three albumins and 17% to two. Reciprocal inhibitions were observed among cat, dog and horse albumins and also among cat, dog and horse hair/dander extracts, using in the latter experiment sera from patients not sensitized to albumins. IgE binding to horse extract was inhibited 30% by its homologous albumin and IgE binding to cat and dog extracts in almost 15% by their respective albumins. It was concluded that albumins from these three animals share some epitopes that account for the cross-reactivity observed in around one-third of patients sensitized to cat, dog and horse. Nevertheless, more than 50% of specific IgE that cross-reacts among these three animals is directed to allergens other than albumin.

Evaluation of drug-related hypersensitivity reactions in children.

Patients with drug reactions are often referred to allergists for "allergy". Skin testing and clinical history seem to have a good negative predictive value, however, although drug challenge could be dangerous, it is the only way to confirm the diagnosis. We aimed to demonstrate that most children with a history of non-life-threatening drug reactions do not have a true drug allergy and examined the use of drug challenge in childhood. Patients with reactions were referred to our clinic by pediatricians. In 1 year, 354 reactions were studied in 239 children. Patients were classified according to their positive or negative history of drug allergy. Skin prick testing was done in all cases. Exclusion criteria for challenge included drug anaphylaxis, Stevens-Johnson syndrome, systemic reactions with severe concomitant illness, beta-inhibitor drug therapy or positive skin test to the implicated drug with a positive history. It was found that the beta-lactam antibiotics were involved in 50% of suspected reactions, aspirin in 10% and sulfonamides in 9%. Histories were considered positive only in 25%. Drug challenges confirmed only 4% of all reactions. It was concluded that drug challenge may be the gold standard for most childhood reactions that are considered to be allergic, non-life-threatening and drug-related. Only 4% of these suspected reactions were exclusively caused by drug allergy.

Occupational asthma due to carrot in a cook.

BACKGROUND: Few previous reports of carrot-induced asthma have been confirmed by objective tests. Hypersensitivity to carrot is frequently associated with allergy to Apiaceae spices and sensitization to birch and mugwort pollens. CLINICAL CASE: A 40-year-old cook woman was seen with sneezing, rhinorrhea, contact urticaria and wheezing within few minutes of handling or cutting raw carrots. She needed to leave out of the kitchen while the other cooks cut raw carrots. METHODS AND RESULTS: Skin tests were positive to carrot, celery, aniseed and fennel. Rubbing test with fresh carrot was positive. Specific IgE to carrot was 4.44 kU/L. Determinations of specific IgE to mugwort, grass and birch pollens were negative. Inhalative provocation test, performed as a handling test, was positive. The IgE-immunoblotting showed two bands in carrot extract: a band with apparent molecular weight of 30 kd and other band of 18 kd. This band of 18 kd was Dau c 1. The band of 30 kd could correspond a phenylcoumaran benzylic ether reductase. Dau c 1 did not appear to be the unique allergen in this case. Additional allergens may induce the sensitization. Primary sensitization due to airborne allergens of foods and the lack of pollen allergy in this patient are notorious events.