Venom Immunotherapy in High-Risk Patients: The Advantage of the Rush Build-Up Protocol.

BACKGROUND: Venom immunotherapy (VIT) is considered to be the gold standard treatment for patients with hymenoptera venom allergy. This treatment induces systemic reactions (SR) in a significant number of patients. OBJECTIVE: To evaluate the outcome of VIT in patients with known risk factors for VIT-induced SR and to compare rush VIT (RVIT) and conventional VIT (CVIT). METHODS: All of the patients who received VIT and had at least one of the following risk factors were included: current cardiovascular disease, uncontrolled asthma, high basal serum tryptase, current treatment with ß-blockers or angiotensin-converting enzyme inhibitors, and age >70 or <5 years. RESULTS: Sixty-four patients were included, and most of them (52; 81.5%) were allergic exclusively to bee venom. Thirty-five (54.7%) patients underwent RVIT and 29 CVIT. The incidence of patients who developed SR during the build-up phase was similar for RVIT and CVIT (25.7 and 27.5%, respectively; p = 1). However, the incidence of SR per injection was significantly higher in CVIT than in RVIT (5.6 and 2.75%, respectively; p = 0.01). Most reactions (79.1%) were mild, limited to the skin. Most of the patients (92.1%) reached the full maintenance dose of 100 µg. This dose was reached by a significantly larger number of patients receiving RVIT compared to CVIT (100 and 82.7%, respectively; p = 0.01). None of the patients experienced exacerbation of their concurrent chronic disease during VIT. CONCLUSION: VIT can be performed safely and efficiently in patients with risk factors for immunotherapy. In these patients RVIT appears to be safer and more efficient than CVIT.

The Importance of Amoxicillin and Amoxicillin-Clavulanate Determinants in the Diagnosis of Immediate Allergic Reactions to ß-Lactams.

BACKGROUND: Immediate allergic reactions to ß-lactam antibiotics are considered to be one of the most important drug hypersensitivities. A positive skin test (ST) with a combination of major and minor penicillin determinants is usually sufficient to recommend avoidance of the culprit drug, whereas a negative ST is usually followed by an oral challenge test (OCT). Recently, concern has been raised regarding the role of amoxicillin (AMX) ST in the diagnosis of AMX allergy. OBJECTIVE: The aim of this study was to examine the additive value of AMX determinants in STs of patients with immediate hypersensitivity reactions to AMX or AMX-clavulanate (AMX-C). METHODS: Patients with a history of immediate AMX or AMX-C allergy underwent an ST using a combination of penicilloyl-polylysine (PPL) and minor determinants as well as AMX. An ST with AMX-C was added when appropriate. RESULTS: Thirty-one patients were evaluated. Eight patients, all of them with a history of AMX allergy, had positive reactions only to the AMX component. Two patients with AMX-C allergy had a positive ST reaction only to the AMX-C component. Moreover, only 14 patients (13 with AMX and 1 with AMX-C allergy) had a positive reaction to PPL, whereas most patients (54.8%) had positive reactions to other determinants. One patient, who was positive for AMX, developed several urticarial lesions after the test. CONCLUSIONS: Skin testing with AMX and AMX-C is mandatory in patients with immediate allergy to these drugs. Failure to perform it may result in a false-negative ST jeopardizing these patients with anaphylactic reactions during a hazardous OCT.

Rank-based genome-wide analysis reveals the association of ryanodine receptor-2 gene variants with childhood asthma among human populations.

BACKGROUND: The standard approach to determine unique or shared genetic factors across populations is to identify risk alleles in one population and investigate replication in others. However, since populations differ in DNA sequence information, allele frequencies, effect sizes, and linkage disequilibrium patterns, SNP association using a uniform stringent threshold on p values may not be reproducible across populations. Here, we developed rank-based methods to investigate shared or population-specific loci and pathways for childhood asthma across individuals of diverse ancestry. We performed genome-wide association studies on 859,790 SNPs genotyped in 527 affected offspring trios of European, African, and Hispanic ancestry using publically available asthma database in the Genotypes and Phenotypes database. RESULTS: Rank-based analyses showed that there are shared genetic factors for asthma across populations, more at the gene and pathway levels than at the SNP level. Although the top 1,000 SNPs were not shared, 11 genes (RYR2, PDE4D, CSMD1, CDH13, ROBO2, RBFOX1, PTPRD, NPAS3, PDE1C, SEMA5A, and CTNNA2) mapped by these SNPs were shared across populations. Ryanodine receptor 2 (RYR2, a statin response-related gene) showed the strongest association in European (p value=2.55×10(-7)) and was replicated in African (2.57×10(-4)) and Hispanic (1.18 × 10(-3)) Americans. Imputation analyses based on the 1000 Genomes Project uncovered additional RYR2 variants associated with asthma. Network and functional ontology analyses revealed that RYR2 is an integral part of dermatological or allergic disorder biological networks, specifically in the functional classes involving inflammatory, eosinophilic, and respiratory diseases. CONCLUSION: Our rank-based genome-wide analysis revealed for the first time an association of RYR2 variants with asthma and replicated previously discovered PDE4D asthma gene across human populations. The replication of top-ranked asthma genes across populations suggests that such loci are less likely to be false positives and could indicate true associations. Variants that are associated with asthma across populations could be used to identify individuals who are at high risk for asthma regardless of genetic ancestry.

Immunotherapy with commercial venoms is efficacious for anaphylactic reactions to Vespa orientalis stings.

BACKGROUND: Vespa orientalis (VO) stings occasionally induce anaphylaxis. In the absence of commercial VO venom, allergists use commercial venoms for immunotherapy, despite having no indication regarding efficacy. We attempted to examine the effectiveness of immunotherapy with commercial venoms in patients with VO allergy and to identify the venom accountable for this effect. METHODS: Patients who unequivocally identified VO as the culprit insect were administered venom immunotherapy with the commercial venoms available in Israel to which they had positive skin tests. Patients were also skin tested with VO venom sac extracts and, after reaching the maintenance dose, were sting challenged by a live insect. The allergenic components in the venom were determined by immunoblotting. RESULTS: Twelve patients were recruited and, based on their skin test results, all were treated with yellow jacket (YJ) venom, either alone or combined with other venoms. All 8 patients who were sting challenged by VO demonstrated positive skin test responses to VO venom. Six of the stung patients tolerated the sting challenge uneventfully. Two patients developed minimal transient symptoms that resolved spontaneously. SDS-PAGE with patient sera suggested cross-reactivity between VO and YJ venoms at molecular weights of 39-42 kDa. Using phospholipases, antigen 5 and hyaluronidase derived from several Vespa, Dolichovespula and Vespula species, hyaluronidase is possibly accountable for inducing the allergic reaction. CONCLUSION: In the absence of commercial VO venom the practice of treating patients allergic to this insect with available commercial venoms seems to be efficacious and YJ venom is probably responsible for this effect.

Chronic urticaria and autoimmunity: associations found in a large population study.

BACKGROUND: Chronic urticaria (CU) is a common disease in which most cases were considered to be idiopathic. Recent evidence indicates that at least a subset of cases of chronic idiopathic urticaria are autoimmune in origin. OBJECTIVE: We aimed to characterize the association between CU, autoimmune diseases, and autoimmune/inflammatory serologic markers in a large unselected population. METHODS: Data on 12,778 patients given a diagnosis of CU by either allergy or dermatology specialists during 17 years in a large health maintenance organization in Israel were collected. For each patient, we collected information on diagnosis of major, well-defined autoimmune diseases and autoimmunity- and inflammatory-related serologic markers. Similar data were collected for a control group comprised of 10,714 patients who visited dermatologists, family physicians, or allergy specialists and had no indication of CU. RESULTS: Having CU was associated with an increased odds ratio for hypothyroidism, hyperthyroidism, and antithyroid antibodies. Female patients with CU had a significantly higher incidence of rheumatoid arthritis, Sjögren syndrome, celiac disease, type I diabetes mellitus, and systemic lupus erythematosus, mostly diagnosed during the 10 years after the diagnosis of CU. High mean platelet volume, positive rheumatoid factor, and antinuclear antibodies were all significantly more prevalent in patients with CU. CONCLUSIONS: A strong association was found between CU and major autoimmune diseases. A common pathogenic mechanism is implied by the high prevalence of autoantibodies and the existence of a chronic inflammatory process expressed by the high mean platelet volume. These findings have implications for the diagnosis, management, and prognosis of patients with CU.

Drug allergy in hospitalized patients: the contribution of allergy consultation and a structured questionnaire.

BACKGROUND: Hospitalized patients with an alleged history of drug allergy pose medical and economic concerns when selecting medications for treatment, possibly leading to deviations from standards of care and the use of expensive agents. Accurate history taking and clear documentation of drug allergy are essential for preventing subsequent administration of the offending drug and overdiagnosis of drug allergy. We aimed to evaluate drug allergy-related history taking by internists compared to allergists and to prospectively assess the effect of a simple, structured questionnaire on the accuracy of drug allergy diagnosis. METHODS: Consenting patients with an alleged drug allergy who were able to give a coherent history were recruited from two internal medicine wards. In both wards, the internists' drug allergy diagnosis was initially compared to that of the allergists. In the second part, in the intervention ward, after the same procedure, the internists completed the structured questionnaire. Their diagnostic conclusions with and without the questionnaire were compared. RESULTS: 202 patients labeled with a medication allergy were enrolled. In the control and intervention wards, 54 and 58% of the patients, respectively, labeled by the internists as allergic, were found not to be allergic by the allergist. In the intervention ward, after using the questionnaire, the percentage of patients tagged by the internists as allergic dropped initially by 31% and finally by 59%. CONCLUSIONS: Discrepancies between drug allergy diagnosis of internists and allergists are common. Allergist consultation or use of a simple structured questionnaire may be beneficial for accurate diagnosis of drug allergies.

Management of patients with known drug hypersensitivity in an emergency department in Israel.

BACKGROUND: Drug hypersensitivity (DH) is potentially life threatening. Its management in the emergency department (ED) is not always satisfactory. Previous studies have evaluated the management of allergic reactions in the ED, but none has specifically addressed patients with known DH. In this study we aimed to analyze the treatment offered to patients with DH presenting to the ED in a hospital in Israel for any reason. METHODS: Records of patients discharged from the ED on 19 randomly chosen dates between February 2004 and September 2005 were retrospectively reviewed. Data included demographics, diagnosis, previous drug allergies, training of the ED physician, time and day of the week, management, and discharge instructions. RESULTS: Of 3,996 admissions to the ED, 436 (11%) patients reported 531 hypersensitivities, 45 (10%) of which were treated incorrectly. Trainees in internal medicine made significantly fewer errors than did trainees in surgery (p < 0.0005). Most errors involved NSAID hypersensitivity. CONCLUSION: A known DH was overlooked in 45 patients admitted to the ED. The specialty of the treating physician was the only significant factor found to affect patient management. Physicians, especially surgeons, should receive guidance concerning the correct management of patients with DH. All physicians should be aware of the optimal management of these patients.

Three days rush venom immunotherapy in bee allergy: safe, inexpensive and instantaneously effective.

BACKGROUND: Rush venom immunotherapy (VIT) is highly effective in vespid venom allergy, but comparable data regarding bee venom (BV) allergy are sparse. We evaluated its safety, efficacy and cost in BV-allergic patients. METHODS: Conventional or rush VIT were offered to all patients with systemic reaction to insect sting. Rush VIT was also given to hyperreactive patients who failed to reach the maintenance dose with conventional VIT due to multiple systemic reactions. In BV-allergic patients, honeybee sting challenge was performed within 1 week after reaching the maintenance dose. RESULTS: 179 patients, some of them allergic to more than one venom, received 246 rush VIT courses. Bee VIT was administered to 132 patients (73.7%); 173 patients (96.6%) reached the maintenance dose. The incidence of systemic reactions was 29.6%. They were more common in VIT with BV than with vespid venoms (31.1 and 16.3%, respectively, p = 0.01). After excluding the hyperreactive subgroup (n = 20), this difference was not significant (23.7 and 16%, respectively, p = 0.19). Despite the high incidence of systemic reactions (15 of 20, 75%) among hyperreactive patients, 17 patients (85%) achieved the maintenance dose. Sting challenges resulted in systemic reaction in 4 of 8 (50%) hyperreactive patients and in 2 of 47 (4.3%) ordinary patients. The cost of rush VIT was 41% of that of conventional VIT. CONCLUSIONS: Rush VIT with BV is safe, instantaneously effective, less expensive and enables most patients with previous failures of conventional VIT to reach the maintenance dose.

Debilitating beliefs and emotional distress in patients given immunotherapy for insect sting allergy: a prospective study.

Patients who receive venom immunotherapy (VIT) for systemic reactions (SRs) to insect stings are advised that once they reach the maintenance dose they are almost 100% protected against future SRs. However, initial evidence indicates that some patients continue to perceive themselves as highly debilitated by the allergy and are preoccupied with the allergic event. These factors have significant impact on their emotional well-being and allergy-related quality of life (ARQOL). We aimed to explore prospectively whether patients would experience these adverse psychological outcomes after receiving VIT coupled with professional explanation and reassurance of protection. Thirty-four patients who received VIT for systemic insect allergy and were under close medical surveillance were included. Before and 1 year after initiation of treatment, patients completed a questionnaire that measured debilitating beliefs, preoccupation with the SR event, emotional distress ARQOL, and QOL in general. Physician-graded severity of the reaction was recorded as well. VIT had a beneficial effect on all allergy-related variables. Self-imposed debilitating beliefs, preoccupation with the anaphylactic event, and ARQOL significantly but modestly improved over time. No association was found between ARQOL and QOL in general. The later variable as well as emotional distress remained unchanged after the VIT. This study shows that patients with sting allergy guided by trained personnel and treated with VIT show a reduction in dysfunctional beliefs and an improvement in ARQOL. Disputing medically unfounded beliefs that persist in some patients might improve their ARQOL.

Variability of venom skin tests.

PURPOSE OF REVIEW: Venom skin tests constitute the cornerstone in establishing the diagnosis of venom allergy. In spite of their fundamental role, data regarding their reproducibility and variability are rather sparse. This paper is an overview of our current knowledge on the extent of variability in venom skin testing, the possible causes for this phenomenon and its clinical implications. It points out certain clinical situations in which this possible variability should be taken into account and anticipates potential venues of expanding our understanding of this debatable subject. RECENT FINDINGS: A single recent study addressed the reproducibility of skin tests and serum venom-specific immunoglobulin E levels. Using a simple positive-negative or vice versa criterion for all three venoms examined on two different sessions, this study showed an overall 66% reproducibility of the skin test reactions and 59% reproducibility of the venom-specific immunoglobulin E assay results. According to an accompanying editorial, however, the validity of these results needs to be confirmed. SUMMARY: Determination of the real magnitude of venom skin test variability is required. At present, in specific clinical situations, repeated skin tests and measurement of serum venom-specific immunoglobulin E should be considered before the initiation of venom immunotherapy.