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.

Hymenoptera Venom Allergy: Management of Children and Adults in Clinical Practice.

Hymenoptera venom allergy is an epidemiologically underestimated condition and a major cause of morbidity worldwide. Preventing future allergic reactions in patients who experience a systemic reaction is based on the correct management of the emergency followed by an accurate diagnosis, prescription of adrenaline autoinjectors, and, where indicated, specific venom immunotherapy. Some epidemiological studies highlight our poor knowledge of this disease and the frequent inadequacy of its management. Moreover, they emphasize the importance of such a life-saving treatment as specific immunotherapy. The availability of high-quality hymenoptera venom extracts for diagnostic and therapeutic use has dramatically improved the prognosis and quality of life of allergic patients. Subcutaneous venom immunotherapy is currently the most effective form of allergen-based immunotherapy, with a carry-over effect lasting up to several years after its interruption. This report on the management of hymenoptera venom-allergic children and adults was prepared by a panel of Italian experts. The main objective of this consensus document is to review the scientific evidence related to diagnosis, therapy, and management of patients allergic to hymenoptera venom. Thus, we can improve our knowledge of the disease and promote good clinical practices. The present document provides practical suggestions for correct diagnosis, prescription of emergency therapy and immunotherapy, and strategies for patient care.

Hymenoptera venom allergy: management of children and adults in clinical practice

Hymenoptera venom allergy is an epidemiologically underestimated condition and a major cause of morbidity worldwide. Preventing future allergic reactions in patients who experience a systemic reaction is based on the correct management of the emergency followed by an accurate diagnosis, prescription of adrenaline autoinjectors, and, where indicated, specific venom immunotherapy. Some epidemiological studies highlight our poor knowledge of this disease and the frequent inadequacy of its management. Moreover, they emphasize the importance of such a life-saving treatment as specific immunotherapy. The availability of high-quality hymenoptera venom extracts for diagnostic and therapeutic use has dramatically improved the prognosis and quality of life of allergic patients. Subcutaneous venom immunotherapy is currently the most effective form of allergen-based immunotherapy, with a carry-over effect lasting up to several years after its interruption. This report on the management of hymenoptera venom-allergic children and adults was prepared by a panel of Italian experts. The main objective of this consensus document is to review the scientific evidence related to diagnosis, therapy, and management of patients allergic to hymenoptera venom. Thus, we can improve our knowledge of the disease and promote good clinical practices. The present document provides practical suggestions for correct diagnosis, prescription of emergency therapy and immunotherapy, and strategies for patient care

La alergia al veneno de himenópteros es una condición subestimada epidemiológicamente que representa una causa importante de morbilidad en todo el mundo. La prevención de reacciones alérgicas futuras en pacientes que han desarrollado una reacción sistémica se basa en el manejo correcto de la emergencia, seguido de un diagnóstico correcto, la prescripción de autoinyectores de adrenalina y, en el caso de estar indicada, la prescripción de inmunoterapia específica con veneno (VIT). Varios estudios epidemiológicos destacan el escaso conocimiento de esta enfermedad y un frecuente tratamiento insuficiente. Además, enfatizan la importancia de la inmunoterapia específica, un tratamiento que puede salvar la vida del paciente. La disponibilidad de extractos de veneno de himenóptera de alta calidad para uso diagnóstico y terapéutico ha mejorado drásticamente el pronóstico y la calidad de vida de estos enfermos. La VIT subcutánea representa la forma más efectiva de inmunoterapia con alérgeno actualmente disponible, con una eficacia persistente que dura hasta varios años después de su interrupción. Este consenso sobre la evaluación clínica tanto de niños como de adultos alérgicos al veneno de himenópteros ha sido elaborado por un panel de expertos italianos. Su objetivo principal es revisar la evidencia científica disponible en el diagnóstico, la terapia y la evaluación clínica de los pacientes alérgicos al veneno de himenópteros con el propósito de mejorar el conocimiento sobre esta enfermedad y promover buenas prácticas clínicas. Se incluyen sugerencias prácticas para un diagnóstico correcto, la prescripción de terapia de emergencia e inmunoterapia, así como estrategias para el manejo de los pacientes

Occupational asthma induced by exposure to quinoa

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Approach to the diagnosis of drug hypersensitivity reactions: similarities and differences between Europe and North America.

Drug hypersensitivity reactions (DHRs) affect an unknown proportion of the general population, and are an important public health problem due to their potential to cause life-threatening anaphylaxis and rare severe cutaneous allergic reactions. DHR evaluations are frequently needed in both ambulatory and hospital settings and have a complex diagnosis that requires a detailed clinical history and other tests that may include in vitro tests and in vivo procedures such as skin tests and drug provocation tests. Although over the years both European and U.S. experts have published statements on general procedures for evaluating DHRs, a substantial discordance in their daily management exists. In this review, we highlight both the differences and the similarities between the European and U.S. PERSPECTIVES: While a general consensus exists on the importance of skin tests for evaluating DHRs, concordance between Americans and Europeans exists solely regarding their use in immediate reactions and the fact that a confirmation of a presumptive diagnosis by drug provocation tests is often the only reliable way to establish a diagnosis. Finally, great heterogeneity exists in the application of in vitro tests, which require further study to be well validated.

Clinical approach on challenge and desensitization procedures with aspirin in patients with ischemic heart disease and nonsteroidal anti-inflammatory drug hypersensitivity.

BACKGROUND: Hypersensitivity to acetylsalicylic acid (ASA) constitutes a serious problem for subjects with coronary artery disease. In such subjects, physicians have to choose the more appropriate procedure between challenge and desensitization. As the literature on this issue is sparse, this study aimed to establish in these subjects clinical criteria for eligibility for an ASA challenge and/or desensitization. METHODS: Collection and analysis of data on ASA challenges and desensitizations from 10 allergy centers, as well as consensus among the related physicians and an expert panel. RESULTS: Altogether, 310 subjects were assessed; 217 had histories of urticaria/angioedema, 50 of anaphylaxis, 26 of nonimmediate cutaneous eruptions, and 17 of bronchospasm related to ASA/nonsteroidal anti-inflammatory drugs (NSAID) intake. Specifically, 119 subjects had index reactions to ASA doses lower than 300 mg. Of the 310 subjects, 138 had an acute coronary syndrome (ACS), 101 of whom underwent desensitizations, whereas 172 suffered from a chronic ischemic heart disease (CIHD), 126 of whom underwent challenges. Overall, 163 subjects underwent challenges and 147 subjects underwent desensitizations; 86 of the latter had index reactions to ASA doses of 300 mg or less. Ten subjects reacted to challenges, seven at doses up to 500 mg, three at a cumulative dose of 110 mg. The desensitization failure rate was 1.4%. CONCLUSIONS: In patients with stable CIHD and histories of nonsevere hypersensitivity reactions to ASA/NSAIDs, an ASA challenge is advisable. Patients with an ACS and histories of hypersensitivity reactions to ASA, especially following doses lower than 100 mg, should directly undergo desensitization.

Drug allergy passport and other documentation for patients with drug hypersensitivity - An ENDA/EAACI Drug Allergy Interest Group Position Paper.

The strongest and best-documented risk factor for drug hypersensitivity (DH) is the history of a previous reaction. Accidental exposures to drugs may lead to severe or even fatal reactions in sensitized patients. Preventable prescription errors are common. They are often due to inadequate medical history or poor risk assessment of recurrence of drug reaction. Proper documentation is essential information for the doctor to make sound therapeutic decision. The European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology have formed a task force and developed a drug allergy passport as well as general guidelines of drug allergy documentation. A drug allergy passport, a drug allergy alert card, a certificate, and a discharge letter after medical evaluation are adequate means to document DH in a patient. They are to be handed to the patient who is advised to carry the documentation at all times especially when away from home. A drug allergy passport should at least contain information on the culprit drug(s) including international nonproprietary name, clinical manifestations including severity, diagnostic measures, potential cross-reactivity, alternative drugs to prescribe, and where more detailed information can be obtained from the issuer. It should be given to patients only after full allergy workup. In the future, electronic prescription systems with alert functions will become more common and should include the same information as in paper-based documentation.

Self-medication of anaphylactic reactions due to Hymenoptera stings-an EAACI Task Force Consensus Statement.

An anaphylactic reaction due to a Hymenoptera sting is a clinical emergency, and patients, their caregivers as well as all healthcare professionals should be familiar with its recognition and acute management. This consensus report has been prepared by a European expert panel of the EAACI Interest Group of Insect Venom Hypersensitivity. It is targeted at allergists, clinical immunologists, internal medicine specialists, pediatricians, general practitioners, emergency department doctors, and any other healthcare professional involved. The aim was to report the scientific evidence on self-medication of anaphylactic reactions due to Hymenoptera stings, to inform healthcare staff about appropriate patient self-management of sting reactions, to propose indications for the prescription of an adrenaline auto-injector (AAI), and to discuss other forms of medication. First-line treatment for Hymenoptera sting anaphylaxis is intramuscular adrenaline. Prescription of AAIs is mandatory in the case of venom-allergic patients who suffer from mast cell diseases or with an elevated baseline serum tryptase level and in untreated patients with a history of a systemic reaction involving at least two different organ systems. AAI prescription should also be considered in other specific situations before, during, and after stopping venom immunotherapy.

In vitro tests for drug hypersensitivity reactions: an ENDA/EAACI Drug Allergy Interest Group position paper.

Drug hypersensitivity reactions (DHRs) are a matter of great concern, both for outpatient and in hospital care. The evaluation of these patients is complex, because in vivo tests have a suboptimal sensitivity and can be time-consuming, expensive and potentially risky, especially drug provocation tests. There are several currently available in vitro methods that can be classified into two main groups: those that help to characterize the active phase of the reaction and those that help to identify the culprit drug. The utility of these in vitro methods depends on the mechanisms involved, meaning that they cannot be used for the evaluation of all types of DHRs. Moreover, their effectiveness has not been defined by a consensus agreement between experts in the field. Thus, the European Network on Drug Allergy and Drug Allergy Interest Group of the European Academy of Allergy and Clinical Immunology has organized a task force to provide data and recommendations regarding the available in vitro methods for DHR diagnosis. We have found that although there are many in vitro tests, few of them can be given a recommendation of grade B or above mainly because there is a lack of well-controlled studies, most information comes from small studies with few subjects and results are not always confirmed in later studies. Therefore, it is necessary to validate the currently available in vitro tests in a large series of well-characterized patients with DHR and to develop new tests for diagnosis.

Prevalence, pathogenesis, and treatment options for mastocytosis-related osteoporosis.

Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability. The mechanism of bone loss is the result of different pathways, not yet fully discovered. The main actor is the osteoclast with a relative or absolute predominance of bone resorption. Among the stimuli that drive osteoclast activity, the most important one seems to be the RANK-RANKL signaling, but also histamine and other cytokines play a significant role in the process. The central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy.

Drug hypersensitivity in clonal mast cell disorders: ENDA/EAACI position paper.

Mastocytosis is a clonal disorder characterized by the proliferation and accumulation of mast cells (MC) in different tissues, with a preferential localization in skin and bone marrow (BM). The excess of MC in mastocytosis as well as the increased releasability of MC may lead to a higher frequency and severity of immediate hypersensitivity reactions. Mastocytosis in adults is associated with a history of anaphylaxis in 22-49%. Fatal anaphylaxis has been described particularly following hymenoptera stings, but also occasionally after the intake of drugs such as nonsteroidal anti-inflammatory drugs, opioids and drugs in the perioperative setting. However, data on the frequency of drug hypersensitivity in mastocytosis and vice versa are scarce and evidence for an association appears to be limited. Nevertheless, clonal MC disorders should be ruled out in cases of severe anaphylaxis: basal serum tryptase determination, physical examination for cutaneous mastocytosis lesions, and clinical characteristics of anaphylactic reaction might be useful for differential diagnosis. In this position paper, the ENDA group performed a literature search on immediate drug hypersensitivity reactions in clonal MC disorders using MEDLINE, EMBASE, and Cochrane Library, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation.

Mastocytosis and allergic diseases.

Mastocytosis is a clonal disorder characterized by proliferation and accumulation of mast cells in various tissues, mainly skin and bone marrow. It can cause a wide variety of clinical manifestations-other than urticaria pigmentosa-that can lead to inappropriate release of mediators by mast cells. The most severe manifestation is anaphylaxis. The triggers of anaphylaxis in adults with mastocytosis are numerous, but Hymenoptera stings seem to be the most frequent, followed by foods and drugs. Therefore, to prevent severe reactions, it is very important to recognize and avoid potential triggers; in addition, venom-allergic patients must receive lifelong immunotherapy, which has proven very effective. Given that published data on drug anaphylaxis in patients with mast cell disorders are scarce, it is not currently possible to provide clear recommendations. The risk of systemic reactions during general anesthesia can be reduced by assessing risk on an individual basis (previous reaction to a drug or reaction during surgery) and by avoiding specific trigger factors (patient temperature changes, infusion of cold solution, tissue trauma, friction, and other mechanical factors).

Mastocytosis and allergic diseases

Mastocytosis is a clonal disorder characterized by proliferation and accumulation of mast cells in various tissues, mainly skin and bone marrow. It can cause a wide variety of clinical manifestations-other than urticaria pigmentosa-that can lead to inappropriate release of mediators by mast cells. The most severe manifestation is anaphylaxis. The triggers of anaphylaxis in adults with mastocytosis are numerous, but Hymenoptera stings seem to be the most frequent, followed by foods and drugs. Therefore, to prevent severe reactions, it is very important to recognize and avoid potential triggers; in addition, venom-allergic patients must receive lifelong immunotherapy, which has proven very effective. Given that published data on drug anaphylaxis in patients with mast cell disorders are scarce, it is not currently possible to provide clear recommendations. The risk of systemic reactions during general anesthesia can be reduced by assessing risk on an individual basis (previous reaction to a drug or reaction during surgery) and by avoiding specific trigger factors (patient temperature changes, infusion of cold solution, tissue trauma, friction, and other mechanical factors) (AU)

La mastocitosis es una enfermedad clonal caracterizada por la proliferacion y acumulo de mastocitos (MC) en diferentes tejidos, sobre todo en la piel y en la medula osea (MO), que da lugar a una amplia variedad de manifestaciones clinicas, entre ellas la urticaria pigmentosa, siempre debidas a la inapropiada liberacion de mediadores de MC, siendo la mas grave de ellas la anafilaxia. Los desencadenantes de la anafilaxia en adultos con mastocitosis son numerosos, pero la picadura de himenopteros parece ser la mas frecuente, seguida de algunos alimentos y medicamentos. En la prevencion de las reacciones graves es muy importante reconocer y evitar el posible agente desencadenante, siendo tambien importante que los pacientes con alergia a venenos sigan un tratamiento largo con inmunoterapia que se ha demostrado efectivo en dichos pacientes. Los datos publicados sobre anafilaxia por medicamentos en pacientes con mastocitosis son escasos y no es posible dar unas claras recomendaciones sobre este tema. El riesgo de reacciones sistemicas durante la anestesia general puede reducirse haciendo un seguimiento de los riesgos personales de cada paciente (con reacciones previas a medicamentos o durante una cirugia), y evitando los factores desencadenantes (cambios de temperatura, infusion con soluciones frias, friccion y otros agentes mecánicos (AU)

The role of basophil activation test in special populations with mastocytosis and reactions to hymenoptera sting.

BACKGROUND: Systemic mastocytosis (SM) may be associated with hymenoptera allergy. In such cases, immunotherapy is a life-saving treatment, but a circumstantiated diagnosis is needed for its prescription. Patients with SM and previous reactions to stings, but with negative tests represent a diagnostic dilemma. The basophil activation test (BAT) may be helpful in refining the diagnosis. OBJECTIVE: We assessed the usefulness of BAT in subpopulations of mastocytosis patients, including those with negative tests for insect allergy. METHODS: Within a population of patients with mastocytosis and previous stings, we studied by BAT and augmented intradermal test (IDT) (10 µg/ml) two groups: (1) with reactions to stings and negative tests; (2) without reactions and negative tests. Basophil activation test was performed with different venoms, assessing at flow cytometry basophils' activation. RESULTS: Sixty-three patients had mastocytosis and 52 had reactions to previous hymenoptera stings. Of them, seven proved negative to diagnostic tests. In six of seven of those patients, BAT was negative with all venoms, and in one, basophils resulted activated also with the negative control. In six patients without previous reactions and negative tests, BAT was totally negative in five of six patients and weakly positive to Hornet in one. Finally, the IDT at 10 µg/ml venom produced nonspecific positive results in most cases. CONCLUSION: In patients with mastocytosis, the negative results of standard tests are reliable, because BAT and IDT at higher concentration do not add useful information.

Food-specific IgG4 lack diagnostic value in adult patients with chronic urticaria and other suspected allergy skin symptoms.

BACKGROUND: Specific IgG4 dosing against food is proposed to the public by a lot of commercial laboratories as a reliable method to diagnose food intolerance. Actually, few data on IgG4 responses to foods in adults are available in the literature. In this study we evaluated the clinical utility of specific IgG4 dosing against food in adult patients with suspected food allergy/intolerance. METHODS: A case series of 73 adult patients with suspected food allergy and clinical manifestations of chronic urticaria or other allergy-supposed skin symptoms were tested for specific IgG4 against foods. An open food challenge was carried out for all IgG4-positive food. All positive open tests were controlled by double-blind placebo-controlled food challenge. RESULTS: Forty-five patients (62%) were IgG4 positive for a number of foods, mainly egg, milk, casein and wheat. None of the patients with IgG4-positive testing showed adverse reactions, neither immediate nor delayed, to the corresponding food. CONCLUSIONS: In adult patients, testing for specific IgG4 lacks clinical utility for the diagnosis of food allergy or intolerance. Dosing of IgG4 should not be part of the diagnosis and therapy of adult patients with allergy-like skin diseases.

Cross reactivity between European hornet and yellow jacket venoms.

BACKGROUND: Cross-reactions between venoms may be responsible for multiple diagnostic positivities in hymenoptera allergy. There is limited data on the cross-reactivity between Vespula spp and Vespa crabro, which is an important cause of severe reactions in some parts of Europe. We studied by CAP-inhibition assays and immunoblotting the cross-reactivity between the two venoms. METHODS: Sera from patients with non discriminative skin/CAP positivity to both Vespula and Vespa crabro were collected for the analyses. Inhibition assays were carried out with a CAP method, incubating the sera separately with both venoms and subsequently measuring the specific IgE to venoms themselves. Immunoblotting was performed on sera with ambiguous results at the CAP-inhibition. RESULTS: Seventeen patients had a severe reaction after Vespa crabro sting and proved skin and CAP positive also to vespula. In 11/17 patients, Vespula venom completely inhibited IgE binding to VC venom, whereas VC venom inhibited binding to Vespula venom only partially (<75%). In 6 subjects the CAP-inhibition provided inconclusive results and their sera were analysed by immunoblotting. The SDS-PAGE identified hyaluronidase, phospholipase A1 and antigen 5 as the main proteins of the venoms. In 5 sera the levels of IgE against antigen 5 of Vespa crabro were higher than IgE against Vespula germanica, thus indicating a true sensitisation to crabro. CONCLUSION: In the case of multiple positivities to Vespa crabro and Vespula spp the CAP inhibition is helpful in detecting the cross-reactivities.

Long-term tolerability of etoricoxib in different types of NSAID-intolerant subjects.

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAIDs) are a frequent cause of hypersensitivity reactions, therefore, in clinical practice, it's important to find safe and effective substances. OBJECTIVE: To evaluate the tolerability of etoricoxib and its subsequent actual use and safety at home. METHODS: Etoricoxib tolerance was assessed by single-blind-placebo-controlled oral challenges and its subsequent use was checked by a standardized telephone call. The test was performed in 139 subjects (83 single NSAID reactors and 56 multiple NSAID reactors). RESULTS: The drug was not tolerated in 4 cases (2.8%) causing wheals on the face area in 3 single reactors and a severe generalised reaction occurring three hours after the intake of a therapeutic dose in a multiple reactor. The phone calls showed that 64 (52.8%) patients did not take etoricoxib, mostly due to the fear of adverse effects; in 5 cases (4.2%), the practitioner prescribed a different NSAIDs. Only 52 (43%) subjects took etoricoxib after oral challenges; all tolerated the drug but 2 single reactors, who reported a very mild labial oedema. CONCLUSION: Our study confirmed the good long-term tolerability of etoricoxib in patients with a history of hypersensitivity to other NSAIDs without differences between single and multiple reactors. Nonetheless, in NSAID-intolerant subjects this drug should be first challenged in specialised centres due to the risk ofsevere reactions.