Practice parameters for diagnosing and managing iodinated contrast media hypersensitivity.

Immediate and nonimmediate hypersensitivity reactions to iodinated contrast media (ICM) have been reported to occur in a frequency of about 0.5%-3% of patients receiving nonionic ICM. The diagnosis and management of these patients vary among guidelines published by various national and international scientific societies, with recommendations ranging from avoidance or premedication to drug provocation test. This position paper aims to give recommendations for the management of patients with ICM hypersensitivity reactions and analyze controversies in this area. Skin tests are recommended as the initial step for diagnosing patients with immediate and nonimmediate hypersensitivity reactions; besides, they may also help guide on tolerability of alternatives. Re-exposition or drug provocation test should only be done with skin test-negative ICMs. The decision for performing either re-exposition or drug provocation test needs to be taken based on a risk-benefit analysis. The role of in vitro tests for diagnosis and pretreatment for preventing reactions remains controversial.

ß-blockers and ACE inhibitors are not a risk factor for severe systemic sting reactions and adverse events during venom immunotherapy.

BACKGROUND: There is controversy whether taking ß-blockers or ACE inhibitors (ACEI) is a risk factor for more severe systemic insect sting reactions (SSR) and whether it increases the number or severity of adverse events (AE) during venom immunotherapy (VIT). METHODS: In this open, prospective, observational, multicenter trial, we recruited patients with a history of a SSR and indication for VIT. The primary objective of this study was to evaluate whether patients taking ß-blockers or ACEI show more systemic AE during VIT compared to patients without such treatment. RESULTS: In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. Of all patients included, 388 (27.2%) took antihypertensive (AHT) drugs (10.4% took ß-blockers, 11.9% ACEI, 5.0% ß-blockers and ACEI). Only 5.6% of patients under AHT treatment experienced systemic AE during VIT as compared with 7.4% of patients without these drugs (OR: 0.74, 95% CI: 0.43-1.22, p = 0.25). The severity of the initial sting reaction was not affected by the intake of ß-blockers or ACEI (OR: 1.14, 95% CI: 0.89-1.46, p = 0.29). In total, 210 (17.7%) patients were re-stung during VIT and 191 (91.0%) tolerated the sting without systemic symptoms. Of the 19 patients with VIT treatment failure, 4 took ß-blockers, none an ACEI. CONCLUSIONS: This trial provides robust evidence that taking ß-blockers or ACEI does neither increase the frequency of systemic AE during VIT nor aggravate SSR. Moreover, results suggest that these drugs do not impair effectiveness of VIT. (Funded by Medical University of Graz, Austria; Clinicaltrials.gov number, NCT04269629).

Risk factors and indicators of severe systemic insect sting reactions.

Hymenoptera venom allergy ranks among the top three causes of anaphylaxis worldwide, and approximately one-quarter of sting-induced reactions are classified as severe. Fatal sting reactions are exceedingly rare, but certain factors may entail a considerably higher risk. Delayed administration of epinephrine and upright posture are situational risk factors which may determine an unfavorable outcome of the acute anaphylactic episode and should be addressed during individual patient education. Systemic mastocytosis and senior age are major, unmodifiable long-term risk factors and thus reinforce the indication for venom immunotherapy. Vespid venom allergy and male sex likewise augment the risk of severe or even fatal reactions. Further studies are required to assess the impact of specific cardiovascular comorbidities. Available data regarding potential effects of beta-blockers and/or ACE inhibitors in coexisting venom allergy are inconclusive and do not justify recommendations to discontinue guideline-directed antihypertensive treatment. The absence of urticaria/angioedema during sting-induced anaphylaxis is indicative of a severe reaction, serum tryptase elevation, and mast cell clonality. Determination of basal serum tryptase levels is an established diagnostic tool for risk assessment in Hymenoptera venom-allergic patients. Measurement of platelet-activating factor acetylhydrolase activity represents a complementary approach but is not available for routine diagnostic use.

Differential diagnosis of late-type reactions to injected local anaesthetics: Inflammation at the injection site is the only indicator of allergic hypersensitivity.

BACKGROUND: Anaphylaxis-like reactions developing within a few minutes are the most frequent complications of subcutaneous or submucosal injections of local anaesthetics (LAs), and topically applied LAs are potential contact allergens. In addition, injected LAs have been reported to induce delayed reactions, including local inflammation at the injection site, and various general symptoms. OBJECTIVES: To assess the frequency and symptoms of late-type hypersensitivity occurring several hours after LA injections. METHODS: We retrospectively evaluated clinical data and test results from all patients referred to our allergy clinic in a period of 20 years for diagnostic work-up of LA-associated late-type reactions. RESULTS: Of 202 patients reporting symptoms with onset at least 1 hour after LA injection, 40 had cutaneous inflammation confined to the injection site, and 162 reported various systemic symptoms. LA hypersensitivity could be excluded in all patients with systemic complaints by means of skin testing and subsequent subcutaneous provocation. In 8 of the 40 patients (20%) with local inflammatory reactions, late-type allergic LA hypersensitivity was confirmed. CONCLUSIONS: Late-type LA allergy commonly causes inflammatory skin reactions confined to the injection site. Conversely, LAs are highly unlikely to trigger delayed systemic symptoms such as urticarial or exanthematous skin eruptions.

Potent NLRP3 Inflammasome Activation by the HIV Reverse Transcriptase Inhibitor Abacavir.

There is experimental and clinical evidence that some exanthematous allergic drug hypersensitivity reactions are mediated by drug-specific T cells. We hypothesized that the capacity of certain drugs to directly stimulate the innate immune system may contribute to generate drug-specific T cells. Here we analyzed whether abacavir, an HIV-1 reverse transcriptase inhibitor often inducing severe delayed-type drug hypersensitivity, can trigger innate immune activation that may contribute to its allergic potential. We show that abacavir fails to generate direct innate immune activation in human monocytes but potently triggers IL-1ß release upon pro-inflammatory priming with phorbol ester or Toll-like receptor stimulation. IL-1ß processing and secretion were sensitive to Caspase-1 inhibition, NLRP3 knockdown, and K+ efflux inhibition and were not observed with other non-allergenic nucleoside reverse transcriptase inhibitors, identifying abacavir as a specific inflammasome activator. It further correlated with dose-dependent mitochondrial reactive oxygen species production and cytotoxicity, indicating that inflammasome activation resulted from mitochondrial damage. However, both NLRP3 depletion and inhibition of K+ efflux mitigated abacavir-induced mitochondrial reactive oxygen species production and cytotoxicity, suggesting that these processes were secondary to NLRP3 activation. Instead, depletion of cardiolipin synthase 1 abolished abacavir-induced IL-1ß secretion, suggesting that mitochondrial cardiolipin release may trigger abacavir-induced inflammasome activation. Our data identify abacavir as a novel inflammasome-stimulating drug allergen. They implicate a potential contribution of innate immune activation to medication-induced delayed-type hypersensitivity, which may stimulate new concepts for treatment and prevention of drug allergies.

Sensitization to Hymenoptera venom marker allergens: Prevalence, predisposing factors, and clinical implications.

BACKGROUND: The prevalence and predisposing factors of asymptomatic sensitization to Hymenoptera venom marker allergens are largely unknown. OBJECTIVE: To evaluate sensitization profiles in a group of 490 dermatologic patients without a history of sting-induced anaphylaxis. METHODS: Clinical data were collected using a structured questionnaire; sera were tested for total IgE and specific IgE to venom preparations, recombinant venom marker allergens, inhalative allergens, and cross-reactive carbohydrate determinants. RESULTS: The lifetime prevalence of Hymenoptera stings was 85.3%. IgE rates exceeding cut-off values of 0.35 kUA /L were 17.3% for rVes v 1, 18.0% for rVes v 5, and 3.5% for rApi m 1. Median specific/total IgE ratios for the above mentioned marker allergens were 0.05%, 0.02%, and 0.00%, respectively. Marker allergen-directed sensitization was detectable in 85.5% of 138 Vespula venom-reactive sera. Of 68 bee venom-reactive participants, 23.5% were sensitized to rApi m 1 and 64.7% to any one or several of five commercially available bee venom allergens. Although double reactivity to bee and Vespula venom was clearly associated with sensitization to cross-reactive carbohydrate determinants (P < 0.001), sensitization to marker allergens of both species was detectable in most double-reactive sera (56.5%). Vespula venom marker allergen-directed sensitization was associated with recent stings (P = 0.010), large local reactions (P = 0.009), total IgE elevation (P < 0.001), and sensitization to cross-reactive carbohydrate determinants (P = 0.008). CONCLUSIONS AND CLINICAL RELEVANCE: The high sensitization rates observed in individuals without a history of sting-induced anaphylaxis as well as total IgE levels and cross-reactive carbohydrate determinant-directed reactivity as potential confounders need to be considered in any interpretation of positive test results for Hymenoptera venom marker allergens.

Bet v 1- and Bet v 2-Associated Plant Food Sensitization in Uganda and Germany: Differences and Similarities.

BACKGROUND: Birch pollen allergy and concomitant plant food sensitization are well documented in Europe. However, there are currently no data available on pollen-associated plant food sensitization or even pollen allergy in tropical Africa. Our study aimed to investigate Bet v 1- and Bet v 2-associated plant food sensitization in atopic patients from Uganda and compare it with sensitization rates in German patients. METHODS: Sera from 83 Ugandan and 97 German atopic patients were analysed using UniCAP100™ for allergen-specific IgE against the birch tree pollen allergens Bet v 1 and Bet v 2 as well as the plant foods hazelnut, apple, kiwi, pea, peach, cherry, litchi, peanut, and soy. RESULTS: As expected, sensitization to Bet v 1 and cross-reactive plant food allergens was more common in German atopic patients. In contrast, the prevalence of sensitization against Bet v 2 was remarkably similar in Ugandan and German patients. Interestingly, in Ugandan patients we found IgE-mediated sensitization against plant foods such as hazelnut, pea, peach, cherry, and litchi that are neither cultivated nor consumed in Uganda. CONCLUSIONS: For Ugandan atopic patients, sensitization against the Bet v 2 allergen (a plant profilin) may explain cross-reactivity to several plant foods which are not consumed in Uganda. Additionally, it is probable that sensitization of Ugandan atopics to alder pollen (Alnus acuminata, plant family Betulaceae) caused serological cross-reactivity with Betula verrucosa-related allergens.

Hymenoptera venom immunotherapy while maintaining cardiovascular medication: safe and effective.

BACKGROUND: The hypothetical risks of cardiovascular medication during Hymenoptera venom immunotherapy (VIT) are still a matter of controversy. OBJECTIVE: To assess the potential influence of ß-blockers (BBs) and/or angiotensin-converting enzyme inhibitors (ACEIs) on the long-term safety and outcome of VIT. METHODS: Data on the course of VIT maintenance phase, Hymenoptera re-stings, and concurrent medication were retrospectively derived from standardized questionnaires in a cohort of patients with significant cardiovascular comorbidity. RESULTS: Of 225 patients, 125 (55.6%) were taking cardiovascular medication at the time of data collection: 71 (31.6%) took an ACEI, and 40 (17.8%) took a BB. A total of 3,397 months of maintenance VIT during intake of an ACEI and 1,418 months during BB therapy were evaluated. Cumulative VIT-related reaction rates, including subjective symptoms, were 9.1% per treatment cycle and 0.31% per injection, with objective reaction rates of 1.7% and 0.06%, respectively. The incidence of adverse events was significantly higher in patients with a previous history of systemic reactions at VIT buildup (P = .004). Surprisingly, reaction rates were lower in patients taking any kind of cardiovascular medication (P = .04) or an ACEI (P = .03). The overall reexposure rate to Hymenoptera stings was 42.7%, and the field sting-induced objective reaction rate was 7.3%. There was no evidence of an increase of field sting-related relapse or hospitalization rates by concurrent cardiovascular medication. CONCLUSION: Cardiovascular medication does not impair the safety and/or the efficacy of Hymenoptera VIT.

Risk stratification of systemic allergic reactions during Hymenoptera venom immunotherapy buildup phase.

BACKGROUND: Comparability of previous studies assessing the incidence of systemic reactions during Hymenoptera venom immunotherapy (VIT) is impaired by methodical differences concerning the definition and classification of VIT-induced anaphylaxis. Our study aims to systematically evaluate the time course and clinical symptoms of VIT-related systemic reactions. PATIENTS AND METHODS: 12-year data on 818 buildup cycles including 8,504 single injections were retrieved from detailed inpatient treatment protocols. The severity of VIT-related anaphylaxis was graded according to a system proposed by the World Allergy Organization in 2010. RESULTS: Objective allergic reactions occurred in 28 (3.4 %) buildup cycles; treatment with antihistamines and/or corticosteroids was invariably effective. 23 exclusively cutaneous reactions occurred after a median time interval of 60 minutes (5-480 min.) following the last injection. 0.6 % of the buildup cycles were complicated by moderate to severe anaphylaxis, which occurred more rapidly than mere urticaria and predominantly during honeybee VIT. Patients with moderate to severe anaphylaxis more frequently reported severe index sting reactions and had higher baseline serum tryptase concentrations. CONCLUSIONS: Objective allergic reactions during VIT are rare, and severe anaphylaxis is extremely rare. The use of a consistent classification system for VIT-induced systemic reactions is required to identify risk factors not only for their general incidence, but also for the exceptionally severe anaphylactic reactions.

Angiolymphoid hyperplasia with eosinophilia and Kimura's disease - a clinical and histopathological comparison.

Angiolymphoid hyperplasia with eosinophilia (ALHE) is a benign vascular neoplasm mainly affecting middle-aged women. Lesions typically affect the head and neck region. ALHE is considered a distinct disease entity different from Kimura's disease, a benign reactive lymphoid proliferation that is predominantly seen in young Asian men although it can affect all ethnic groups. In contrast to ALHE, Kimura's disease is typically associated with peripheral blood eosinophilia, increased serum IgE and lymphadenopathy. Several case reports suggest an overlap between ALHE and Kimura's disease. We review the current literature and discuss whether AHLE and Kimura's disease might represent two extreme variants of the same disease entity.

Drug-induced exanthems: correlation of allergy testing with histologic diagnosis.

BACKGROUND: Skin biopsies are commonly performed to confirm drug-induced exanthem (DIE). However, the relevance of histologic examination in discriminating between DIE and non-DIE (NDIE) is controversial. OBJECTIVE: A retrospective analysis was performed to evaluate the reliability of histologic diagnosis of DIE. METHODS: In all, 91 patients with a skin biopsy specimen of an acute exanthem temporally related to a single identifiable drug underwent complete allergy testing. Their biopsy specimens were retrospectively re-evaluated by 2 dermatopathologists blinded to the original reports to test for discrimination between DIE versus NDIE. RESULTS: In 35 patients, non-IgE-mediated drug allergy was confirmed by allergy testing, whereas in 56 patients drug hypersensitivity could be excluded. Sensitivity of pathology reports for diagnosis of DIE reached 62.9% with a positive predictive value of 40.7%. Specificity was 41.1% with a negative predictive value of 69.7%. No significant difference in tissue eosinophilia was detected between DIE and NDIE. LIMITATIONS: This was a retrospective study. CONCLUSIONS: Dermatopathologic evaluation of skin biopsy specimens is of limited use in differentiating between DIE and NDIE. All efforts should be made to subject these patients to thorough allergy testing for definitely confirming or ruling out drug hypersensitivity.

Treatment of disseminated granuloma annulare with oral vitamin E: 'primum nil nocere'.

BACKGROUND: Disseminated granuloma annulare (DGA) is a benign and usually asymptomatic skin disease. However, many patients feel aesthetically disfigured and ask for treatment. Until today, no standard therapy is recommended. OBJECTIVE: To evaluate the safety and efficacy of oral vitamin E treatment compared to the natural course of DGA. METHODS: This single-centre observational cohort study included 38 consecutive patients with histologically confirmed DGA. 21 patients underwent treatment with oral vitamin E, whereas 17 patients preferred a wait-and-see approach. RESULTS: Complete healing (40%) and improvement (30%) were frequently seen under oral vitamin E therapy. However, DGA also spontaneously disappeared in 31% and improved in 25% of untreated control patients. Vitamin E therapy was very well tolerated. CONCLUSIONS: Oral vitamin E treatment is a safe and probably effective therapy for DGA. As the natural course of DGA leads to complete healing or significant improvement in many cases, 'primum nil nocere' should be the maxim.

Pitfall scarring alopecia: favus closely mimicking lichen planus.

We describe a woman presenting primarily with slowly progressing scarring alopecia. Course, symptoms, and clinical picture were highly suggestive for lichen planus. But mycological investigations revealed that cicatricial alopecia was caused by a specific infection with Trichophyton schoenleinii running a chronic course with minimal skin inflammation.

Do-it-yourself cement work: the main cause of severe irritant contact dermatitis requiring hospitalization.

BACKGROUND: There are myriads of potentially irritant agents causing acute irritant contact dermatitis. In the large majority of cases, dermatitis is mild to moderate, and patients do not need hospitalization. However, some agents or special circumstances may cause severe dermatitis requiring more intensive therapy. OBJECTIVES: The aim of this study was to evaluate causative agents of severe acute irritant contact dermatitis requiring hospitalization. METHODS: In this single-centre observational cohort study, we included 54 consecutive patients presenting with signs and symptoms of acute irritant contact dermatitis for which hospitalization was necessary. The severity of dermatitis was graded (grade I-IV) according to intensity, and details related to the skin irritation (irritant agent, area of exposure, time interval to onset of symptoms, and duration of hospitalization) were determined. RESULTS: All cases with severe ulcerative dermatitis (grade IV) were caused by wet cement, owing to prolonged skin contact. These cement burns are clearly associated with amateur work, younger age, male preponderance, and leg localization. CONCLUSIONS: The study data provide clear-cut evidence that wet cement is a severely irritant substance that regularly causes the most severe form of acute irritant contact dermatitis. The main causative prerequisite for these cement burns is do-it-yourself work with poor protective measures.

Over- and underestimated parameters in severe Hymenoptera venom-induced anaphylaxis: cardiovascular medication and absence of urticaria/angioedema.

BACKGROUND: Severe anaphylaxis in Hymenoptera venom allergy has been associated with a number of risk factors including elevation of baseline serum tryptase (BST), older age, concomitant diseases, and concurrent medication. OBJECTIVE: The aim of this study was to evaluate indicators and risk factors for severe anaphylaxis due to Hymenoptera field stings with an emphasis on details related to the sting reaction and concurrent medication. METHODS: In this single-center observational cohort study, we included 657 consecutive patients fulfilling the criteria for venom immunotherapy. Severity of sting-induced anaphylaxis was analyzed in relation to patient-specific risk factors (age and sex, preexisting cardiopulmonary conditions, cardiovascular medication) and details related to the sting reaction (culprit insect, localization of the sting, time interval to onset of symptoms, and presence or absence of cutaneous involvement). BST was determined in a subgroup of patients with moderate to severe anaphylaxis. RESULTS: Four significant indicators and risk factors of severe anaphylaxis were identified (P < .001): (1) elevation of BST, (2) absence of urticaria or angioedema during anaphylaxis, (3) time interval of less than 5 minutes from sting to onset of symptoms, and (4) senior age. The absence of urticaria/angioedema is significantly related to BST elevation (P = .02). No relationship could be established between the severity of anaphylaxis and comorbidities or concurrent cardiovascular medication. CONCLUSIONS: Absence of urticaria/angioedema is an indicator of severe anaphylaxis and possibly mastocytosis, requiring determination of BST. Study data do not provide evidence for an aggravation of sting-induced anaphylaxis by concurrent beta-blockade or angiotensin-converting enzyme inhibition.