Clinical Relevance of Specific IgE in Penicillin Allergy Investigation.

INTRODUCTION: Patients with immediate type allergic reactions to penicillins are at risk of anaphylaxis on reexposure. Diagnostic gold standard is drug provocation test (DPT) if allergy is not diagnosed by other means, such as skin testing or in vitro testing with measurement of specific IgE. Specific IgE testing carries low risk for the patient and blood sampling can be performed in primary care, but it is reported to have low sensitivity. The aim of this study was to evaluate if clinical characteristics of patients with suspected allergic reactions to penicillin and elevated specific IgE to penicillins, differed from patients without specific IgE, to identify predictors for elevated specific IgE to penicillins. METHODS: Levels of specific IgE to five penicillins (penicillin G, penicillin V, amoxicillin, ampicillin, and penicillin minor determinants) were available for 9,100 patients. Using multiple logistic regression, clinical data from 430 patients in this group who had elevated specific IgE to one or more penicillins were compared to data from 4,094 patients without specific IgE to penicillins, who had undergone DPT with a penicillin. RESULTS: In total 5.2% of patients had elevated specific IgE to one or more penicillins. Significantly more patients with elevated specific IgE had a history of immediate type reactions (<2 h) (OR = 4.34, p < 0.001); circulatory symptoms (OR = 1.63, p = 0.03) or angioedema (OR = 1.46, p = 0.005). Also, significantly more patients with elevated specific IgE had been treated with adrenaline (OR = 2.21, p = 0.005), steroids (OR = 1.76, p < 0.001), or antihistamines (OR = 1.83, p < 0.001). CONCLUSION: A history of an immediate type reaction requiring treatment, combined with elevated specific IgE to one or more penicillins is suggestive of an IgE mediated penicillin allergy and further allergy investigations may not be needed. Specific IgE to penicillins may be used early in allergy investigation of patients with severe immediate type reactions to penicillins.

Delabeling of Penicillin Allergy: Room for Improvement.

BACKGROUND: Penicillin allergy labels have been shown to be associated with suboptimal treatment, negative health outcomes, and increased antibiotic resistance. Many inpatients claim to have penicillin allergy, but studies show that allergy can be disproved and the label removed in up to 90% of cases. OBJECTIVES: The purpose of the study was to investigate the proportion of patients with a penicillin allergy label in a Danish hospital and to classify patients according to the risk of having penicillin allergy in "no risk," low, and high risk. METHODS: For 22 days, inpatients with penicillin allergy labels were interviewed, had their dispensed penicillin prescriptions examined, and were subsequently categorized into risk groups based on the risk evaluation criteria in national guidelines. RESULTS: In total, 260 patients had a penicillin allergy label (10% of the inpatients). Out of 151 included patients, 25 were "no risk" patients (17%), who could potentially have their penicillin allergy label removed without testing. 42 were low-risk patients (28%). 10 "no risk" patients and 20 low-risk patients had been prescribed and dispensed one or more penicillins despite an allergy label. CONCLUSION: Ten percent of inpatients have a penicillin allergy label in a Danish hospital. 17% of these could potentially have their penicillin allergy label removed without allergy testing.

Safe De-Labeling of Patients at Low Risk of Penicillin Allergy in Denmark.

INTRODUCTION: Penicillin allergy is suspected in 10% of hospital inpatients but can be disproved in 90% of cases. Direct oral provocation without preceding tests among low-risk patients has proven to be safe in studies of both children and adults and is gaining use across the world. The aims of this study were to investigate the rate of severe allergic reactions to direct oral drug provocation, without preceding tests, in penicillin allergy patients stratified to be at low risk, as well as to examine if these patients have barriers to penicillin allergy de-labeling and future use of penicillins. METHODS: Adult patients referred to a university hospital allergy clinic with a suspected penicillin allergy were prospectively risk evaluated. Patients stratified to be at low risk were offered a direct oral provocation with a single-dose amoxicillin followed by 4 days of continued treatment. The same risk stratification criteria were applied to a larger retrospective cohort. RESULTS: In the prospective study population, 202 patients had a direct oral drug provocation and 20 (10%) were positive. There were no cases of anaphylaxis or severe delayed hypersensitivity. Fifteen reactions were benign rashes with onset >1 day after initial dosing, and 13 of these were maculopapular rashes. The same low-risk criteria were applied retrospectively to patients in a drug provocation database, and 1,759 patients fulfilled the criteria; of these, 10% had positive provocations, and there were no cases of anaphylaxis or severe delayed hypersensitivity. De-labeled patients in the prospective study reported not to fear future penicillin intake, after prolonged provocation. CONCLUSION: The risk stratification criteria for identifying low-risk patients for the oral drug provocation test without prior skin testing were safe in terms of avoiding anaphylaxis or severe delayed hypersensitivity. Benign delayed skin reactions still occurred, and access to allergy advice and follow-up is necessary.

Intradermal Testing Identifies 1 in 4 Patients with Nonimmediate Penicillin Allergy.

BACKGROUND: Intradermal testing with delayed reading (IDTdr), used routinely in many centers, may identify delayed reactions to penicillins. However, few studies have compared the results of IDTdr with drug provocation test (DPT). The aim of this study was to examine the proportion of provocation-positive patients testing positive on IDTdr. METHODS: Fifty-seven patients with a positive DPT occurring >2 h after intake of penicillin V, dicloxacillin, pivampicillin, or amoxicillin had an IDTdr with penicillin G, amoxicillin, ampicillin, and dicloxacillin. A control group included 18 patients with negative DPTs with the suspected penicillin. RESULTS: In total 25% (n = 14) of provocation-positive patients tested positive on IDTdr. Among patients with positive IDTdr, 9/14 (64%) versus 11/43 (26%) in the IDTdr negative group (p < 0.05) had required oral steroids to treat skin reactions following DPT. No other differences between IDTdr positive and negative groups were found. No controls had a positive IDTdr. CONCLUSION: Investigating with IDTdr would have identified 25% of patients with a DPT-verified allergy with delayed reactions. It is difficult to target subgroups who will test positive on IDTdr. There were more patients who tested positive on IDT who had received oral steroids after DPT, and this may be an indication that skin reaction severity plays a role in skin testing diagnostics. Further potential predictors for positivity of IDTdr, such as duration of skin symptoms, should be assessed in large studies in order to optimize the investigations of nonimmediate drug allergic reactions.

A EAACI drug allergy interest group survey on how European allergy specialists deal with ß-lactam allergy.

An accurate diagnosis of ß-lactam (BL) allergy can reduce patient morbidity and mortality. Our aim was to investigate the availability of BL reagents, their use and test procedures in different parts of Europe, as well as any differences in the diagnostic workups for evaluating subjects with BL hypersensitivity. A survey was emailed to all members of the EAACI Drug Allergy Interest Group (DAIG) between February and April 2016, and the questionnaire was meant to study the management of suspected BL hypersensitivity. The questionnaire was emailed to 82 DAIG centres and answered by 57. Amoxicillin alone or combined to clavulanic acid were the most commonly involved BL except in the Danish centre, where penicillin V was the most frequently suspected BL. All centres performed an allergy workup in subjects with histories of hypersensitivity to BL: 53 centres (93%) followed DAIG guidelines, two national guidelines and two local guidelines. However, there were deviations from DAIG recommendations concerning allergy tests, especially drug provocation tests. A significant heterogeneity exists in current practice not only among countries, but also among centres within the same country. This suggests the need to re-evaluate, update and standardize protocols on the management of patients with suspected BL allergy.

Insect Sting Reactions and Specific IgE to Venom and Major Allergens in a General Population.

BACKGROUND: Insect sting reactions are frequently reported, but population studies documenting the frequency and the relation to IgE-sensitization and serum tryptase are scarce. METHODS: Questionnaire data and results from measurements of specific IgE against venom, major allergens and cross-reacting carbohydrate determinants (CCDs) were collected from 2,090 adult participants in a cross-sectional survey. RESULTS: 13% of the population reported symptoms of sting reactions and about half were systemic in nature. In all, 15% were sensitized to venom but only 31% of these had reacted to stings and only 38% of those with reactions had IgE to venom. In addition, 12% with IgE to venom were double-sensitized (DS), i.e. to both bee and wasp venom. Among DS IgE to major venom allergens, rApi m 1, rVes v 1 and rVes v 5 were negative and of no help in 31%, but 59% could be identified as likely sensitized to bee or wasp. IgE to CCDs occurred in only 0.7%, but 80% of these were DS. Finally, 36% with IgE to CCDs had had symptoms, mostly local. Serum tryptase was not associated with a history of sting reactions. CONCLUSIONS: In a temperate climate, self-reported insect sting reactions and sensitization to venom are frequent, but in most cases, these are not seen in the same individual. In DS individuals, measurements of IgE to major allergens can be helpful in some but not all cases and additional analyses are needed. IgE to CCDs may have some clinical relevance.

SQ house dust mite sublingually administered immunotherapy tablet (ALK) improves allergic rhinitis in patients with house dust mite allergic asthma and rhinitis symptoms.

BACKGROUND: House dust mite (HDM) allergy is associated with persistent allergic rhinitis (AR) and allergic asthma. OBJECTIVE: To investigate the efficacy and safety of a SQ HDM sublingually administered immunotherapy tablet (ALK, Hørsholm, Denmark) in adults and adolescents with HDM respiratory allergic disease and report the AR results. METHODS: Six hundred four subjects at least 14 years old with HDM AR and mild to moderate HDM allergic asthma were randomized 1:1:1:1 to double-blinded daily treatment with 1, 3, 6 SQ-HDM or placebo. End-of-treatment rhinoconjunctivitis symptoms and medication score were predefined extrapulmonary end points. A subgroup analysis was conducted post hoc in subjects with a total combined rhinitis score (TCRS) > 0 (ie, with AR symptoms and/or AR medication use during the 4-week baseline period). The subgroup was comprised of 498 subjects (82%). RESULTS: In the subgroup, the absolute difference in end-of-treatment TCRS between 6 SQ-HDM and placebo was -0.78 (95% confidence interval -1.47 to -0.07, relative difference 28.8%, P = .0357). Furthermore, a significant difference was found for the total score of the Rhinitis Quality of Life Questionnaire with Standardized Activities RQLQ(S) and for the individual domains: activities, sleep, non-nose and non-eye symptoms, and nasal symptoms. For the TCRS and Rhinitis Quality of Life Questionnaire score, a dose response was seen, with numerically lower, nonsignificant differences for 1 and 3 SQ-HDM. The predefined analysis for the entire trial population showed no statistically significant difference between the placebo and actively treated groups. No safety concerns were observed. CONCLUSION: Efficacy in mild to severe AR of 6 SQ-HDM compared with placebo was demonstrated by statistically significant improvements in TCRS and Rhinitis Quality of Life Questionnaire score in subjects with AR present at baseline. The treatment was well tolerated. TRIAL REGISTRATION: EudraCT, no 2006-001795-20; ClinicalTrials.gov, identifier NCT00389363.

Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Investigations meeting current standards are limited for the effect of house dust mite (HDM) allergy immunotherapy in asthmatic patients. OBJECTIVE: This trial investigated the efficacy and safety of a standardized quality (SQ; allergen standardization method proprietary to the trial sponsor) HDM SLIT-tablet (ALK, Hørsholm, Denmark) in adults and adolescents with HDM respiratory allergic disease. This publication reports the results of the endpoints related to asthma. METHODS: Six hundred four subjects 14 years or older with HDM allergic rhinitis and mild-to-moderate asthma were randomized 1:1:1:1 to double-blind daily treatment with one of 3 active doses (1, 3, or 6 SQ-HDM) or placebo. Their use of inhaled corticosteroid (ICS) was standardized and adjusted at baseline and the end of treatment to the lowest dose providing asthma control. The primary end point was a reduction in ICS dose from the individual subject's baseline dose after 1 year of treatment. RESULTS: The primary analysis revealed a mean difference between 6 SQ-HDM and placebo in the reduction in daily ICS dose of 81 µg (P = .004). Relative mean and median reductions were 42% and 50% for 6 SQ-HDM and 15% and 25% for placebo, respectively. No statistically significant differences were observed for the other assessed asthma parameters, reflecting the intended controlled status of the trial subjects. The most common adverse events were local reactions in the mouth. The rate and severity of adverse events were higher for 3 and 6 SQ-HDM than for 1 SQ-HDM and placebo. CONCLUSION: Efficacy in mild-to-moderate asthma of 6 SQ-HDM relative to placebo was demonstrated by a moderate statistically significant reduction in the ICS dose required to maintain asthma control. All active doses were well tolerated.

Asthma and respiratory symptoms among hairdressers in Denmark: results from a register based questionnaire study.

BACKGROUND: Hairdressers are at risk of developing occupational respiratory disorders due to persulfates and other hairdressing chemicals. METHODS: A register based questionnaire study comprising 7,840 graduates from hairdressing vocational schools was conducted. The postal questionnaire concerned self-reported asthma, airway symptoms, occupation, smoking, and atopic dermatitis. RESULTS: A response rate of 67.9% was obtained. The hairdressers reported asthma (11.2%), cough (25.3%), nasal congestion (24.0%), and rhinitis (18.2%). Less than 1/3 of all hairdressers with suspected occupational asthma reported their asthma as an occupational disease to the authorities. In total, 27.3% were daily smokers; the smoking pattern was similar between hairdressers with and without asthma. Local exhaust ventilation was only used consistently by 63.8% for permanent waving and hair coloring procedures. CONCLUSIONS: Asthma and especially respiratory symptoms were commonly reported by hairdressers, but rarely reported as an occupational disease. Local exhaust ventilation was inconsistently used. Our results underline the need for improved measures to ascertain and prevent occupational asthma in hairdressers.

The shape of and applied weight on skin prick lancets critically affect the wheal size in the skin prick test.

The global application of the skin prick test (SPT) is attributed to the low costs, easy execution, and in vivo approach. Still, the healthcare professionals' technique and the lancet shape may challenge the standardization of the method. Thus, we investigated the influence of the shape of the lancet and the applied weight on the wheal size of SPT. Two allergic and one non-allergic individual were tested with allergens (Dermatophagoides pteronyssinus and Phleum pratense) and histamine solution (positive control), respectively. Horizontally (HS) and diagonally (DS) shouldered lancets with the same tip length (1 mm) were tested under two different conditions: either 60 g or 120 g weight pressure. The wheal size induced by the 4 different combinations was measured. The higher-weight device (120 g) induced a significantly larger and less variable wheal response with the tested allergens and histamine. However, the shape of the lancet affected the wheal size more than the applied weight. The least variable response was measured to histamine for the horizontal-shouldered lancet combined with the higher weight, whereas the same lancet with the lower weight resulted in a significant number of false negative results.

Penicillin allergy delabeling has a significant impact on subsequent antibiotic use in primary care.

Efforts to delabel penicillin allergic patients are important as the majority of suspected penicillin allergy can be ruled out by relevant allergy testing. The aim is to change the antibiotic pattern in delabeled patients to minimize use of unnecessary broad-spectrum antibiotics, reducing the risk of antimicrobial resistance and making treatment more cost effective. However, published information on subsequent antibiotic use is scarce. To evaluate the effect of delabeling on subsequent antibiotic use in primary care, a cohort of 2911 patients tested for penicillin allergy was compared to a matched control group of 14,522 individuals from the background population. In total 86.4% of the tested patients were delabeled. For delabeled patients, penicillin use increased from 0.07 prescriptions per patient year before allergy investigation, to 0.53 prescriptions per patient year post investigation (p < 0.001). The use of fluoroquinolones and macrolides was reduced and reached a level comparable to the background population. This study shows that penicillin allergy delabeling has significant positive impact on subsequent antibiotic use in primary care, and that penicillin use increases to levels similar to the background population. Penicillin allergy delabeling should be prioritized as an important and efficient element in antimicrobial stewardship initiatives.

Treatment with epinephrine (adrenaline) in suspected anaphylaxis during anesthesia in Denmark.

BACKGROUND: Literature on the use of epinephrine in the treatment of anaphylaxis during anesthesia is very limited. The objective of this study was to investigate how often epinephrine is used in the treatment of suspected anaphylaxis during anesthesia in Denmark and whether timing of treatment is important. METHODS: A retrospective study of 270 patients investigated at the Danish Anaesthesia Allergy Centre after referral due to suspected anaphylaxis during anesthesia was performed. Reactions had been graded by severity: C1, mild reactions; C2, moderate reactions; C3, anaphylactic shock with circulatory instability; C4, cardiac arrest. Use of epinephrine, dosage, route of administration, and time between onset of circulatory instability and epinephrine administration were noted. RESULTS: A total of 122 (45.2%) of referred patients had C3 or C4 reactions; of those, 101 (82.8%) received epinephrine. Route of administration was intravenous in 95 (94%) patients. Median time from onset of reported hypotension to treatment with epinephrine was 10 min (range, 1-70 min). Defining epinephrine treatment less than or equal to 10 min after onset of hypotension as early, and more than 10 min as late, infusion was needed in 12 of 60 patients (20%) treated early versus 12 of 35 patients (34%) treated late (odds ratio, 2.09) (95% confidence interval, 0.81-5.35). CONCLUSION: Anaphylaxis may be difficult to diagnose during anesthesia, and treatment with epinephrine can be delayed as a consequence. Anaphylaxis should be considered and treated in patients with circulatory instability during anesthesia of no apparent cause who do not respond to the usual treatments.

Capsaicin-induced neurogenic inflammation in the skin in patients with symptoms induced by odorous chemicals.

BACKGROUND: Intradermal injection of capsaicin induces the axonal release of neuropeptides, vasodilatation and flare, e.g. neurogenic inflammation. The spatial profile of neurogenic inflammation in the skin has been studied in various experimental models. Polarization spectroscopy imaging introduced recently may be used for the quantitative assessment of the temporal profile of neurogenic inflammation expressed as erythema intensity. PURPOSE: In the present study, we aimed to compare capsaicin-induced erythema intensity with the flare area in patients with symptoms induced by odorous chemicals, thereby comparing the temporal and spatial profiles of neurogenic inflammation. METHODS: Sixteen patients fulfilling Cullen's criteria for multiple chemical sensitivity (MCS) and 15 eczema (EC) patients with airway symptoms elicited by odorous chemicals were compared with 29 age-matched, healthy controls. Participants were administered two intradermal injections of capsaicin 3.3 and 33µM. Erythema intensity was measured by polarization spectroscopy imaging and flare response was quantified by visual inspection. RESULTS: Erythema intensity and flare area did not differ between patients and controls, and they were not correlated. Erythema intensity and flare area showed a dose-dependent increase (P<0.05). Erythema intensity increased with age at 3.3µM but not at 33µM capsaicin, whereas the flare area increased with age at both concentrations (P<0.05). CONCLUSION: Capsaicin-induced erythema intensity and visual flare were normal in patients with MCS and EC patients with airway symptoms from odorous chemicals. Polarized light spectroscopy was a useful method for the measurement of the rapid temporal changes in erythema of experimental reactions.

Effect of general anesthesia and orthopedic surgery on serum tryptase.

BACKGROUND: Mast cell tryptase is used clinically in the evaluation of anaphylaxis during anesthesia, because symptoms and signs of anaphylaxis are often masked by the effect of anesthesia. No larger studies have examined whether surgery and anesthesia affect serum tryptase. The aim of this study was to investigate the effect of anesthesia and surgery on serum tryptase in the absence of anaphylaxis. METHODS: The study included 120 patients (median age, 54 yr; range, 19-94 yr) undergoing elective orthopedic surgery in general anesthesia. Exclusion criteria were allergic reactions during this or previous anesthesia, hematologic disease, or high-dose corticosteroid treatment. Blood samples for tryptase analysis (ImmunoCAP; Phadia, Uppsala, Sweden) were drawn shortly before anesthesia and after anesthesia and surgery. RESULTS: Median duration of anesthesia was 105 min (range, 44-263 min). Median interval between blood samples was 139 min (range, 39-370 min). Mean tryptase before surgery was 5.01 microg/l, with a mean decrease of 0.55 microg/l (P < 0.0001; 95% CI, 0.3-0.8) postoperatively. All patients received intravenous fluid (median value 750 ml; range, 200-2000 ml) perioperatively. There was no significant effect of gender, age, American Society of Anesthesiologist's physical status classification, or self-reported allergy on serum tryptase. CONCLUSIONS: Serum tryptase shows small intraindividual variation in the absence of anaphylaxis. A small decrease was observed postoperatively, likely due to dilution by intravenous fluid. On suspected anaphylaxis during anesthesia, tryptase values, even within the normal reference interval, should, when possible, be compared with the patient's own basal level taken more than 24 h after the reaction.

[Work-up of penicillin allergy].

Up to 10% of hospitalised patients are registered as penicillin allergic. However, 80-90% will tolerate penicillin after evaluation. New Danish guidelines suggest criteria for evaluation of patients based on risk stratification according to the severity of the index reaction. The allergy label can be removed immediately, if allergy can be ruled out using the criteria presented in this review, but all other patients should be referred for evaluation in a specialist allergy department. Specific IgE measurement should only be done in adult patients with an immediate reaction (onset less-than 2 h after intake of a tablet) or urticaria.

Intradermal Tests With Drugs: An Approach to Standardization.

Background: Intradermal tests (IDTs) are performed and interpreted differently in drug allergy centers making valid comparison of results difficult. Objective: To reduce method-related and intercenter variability of IDTs by the introduction of a standardized method. Materials and methods: In 11 centers of the European Network for Drug Allergy, IDTs were prospectively performed with saline and with amoxicillin (20 mg/ml) using (1) the local method and (2) the standardized European Network in Drug Allergy (ENDA) method (0.02 ml). The diameters of the initial injection wheal (Wi) for the different volumes and sites injected obtained from each center were analyzed. Results: The most reproducible method was to fill a syringe with test solution, then expel the excess fluid to obtain exactly 0.02 ml. The median Wi diameter with 0.02 ml injection using the standardized method was 5 mm [range 2-10 mm; interquartile range (IQR) 5-5 mm; n = 1,096] for saline and 5 mm (range 2-9 mm; IQR = 4.5-5 mm; n = 240) for amoxicillin. IDT injection sites did not affect the Wi diameter. Training improved precision and reduced the variability of Wi diameters. Conclusion: Using the standardized IDT method described in this multicenter study helped to reduce variability, enabling more reliable comparison of results between individuals and centers.