Atopy patch testing with aeroallergens in a large clinical population of dermatitis patients in Germany and Switzerland, 2000-2015: a retrospective multicentre study.

BACKGROUND: The diagnostic significance of the atopy patch test for the management of dermatitis possibly triggered by aeroallergens is still controversial. However, sufficiently large studies with routinely tested standardized aeroallergen patch test preparations in dermatitis patients are lacking. OBJECTIVE: To evaluate the reaction frequency and the reaction profiles of 10 until mid-2015 commercially available, standardized aeroallergen patch test preparations of the 'Stallerpatch' test series (Stallergenes, Antony Cedex, France) in a large multicentre patient cohort. METHODS: A retrospective data analysis of patients with suspected aeroallergen-dependent eczematous skin lesions was performed, who were patch tested in 15 Information Network of Departments of Dermatology-associated clinics between 2000 and 2015. Patients were stratified according to their atopic dermatitis (AD) status. RESULTS: The study group included 3676 patients (median age 41 years, 34.8% males, 54.5% AD). The most common aeroallergens causing positive patch test reactions were Dermatophagoides pteronyssinus (19.6%), Dermatophagoides farinae (16.9%), birch (6.2%), timothy grass (6.0%), cat dander (5.4%), mugwort (4.9%) and dog dander (4.6%). Reactions to other pollen allergen preparations, that is 5 grasses (3.2%), cocksfoot (2.1%) and plantain (1.6%), were less common. Positive patch test reactions to aeroallergens were consistently more frequent in patients with AD. These patients showed proportionally less dubious, follicular, irritant and weak positive reactions. Independent of AD status, a patient history of past or present allergic rhinitis was associated with an increased chance of a positive aeroallergen patch test reaction to pollen allergens. CONCLUSION: The aeroallergen patch test is a useful add-on tool in clinical routine, especially in patients with AD and/or respiratory allergy. A patch test series comprising Dermatophagoides pteronyssinus, Dermatophagoides farinae, birch, timothy grass, cat dander and mugwort seems to be suitable. Controlled studies with specific provocation and elimination procedures are required to further evaluate the diagnostic significance of the proposed screening series.

Meat allergy associated with galactosyl-α-(1,3)-galactose (α-Gal)-Closing diagnostic gaps by anti-α-Gal IgE immune profiling.

BACKGROUND: Glycoproteins and glycolipids of some mammalian species contain the disaccharide galactosyl-α-(1,3)-galactose (α-Gal). It is known that α-Gal is immunogenic in humans and causes glycan-specific IgG and also IgE responses with clinical relevance. α-Gal is part of the IgE-reactive monoclonal therapeutic antibody cetuximab (CTX) and is associated with delayed anaphylaxis to red meat. In this study, different α-Gal-containing analytes are examined in singleplex and multiplex assays to resolve individual sensitization patterns with IgE against α-Gal. METHODS: Three serum groups, α-Gal-associated meat allergy (MA) patients, idiopathic anaphylaxis (IA) patients with suspected MA, and non-meat-allergic healthy control individuals (HC), were analyzed via singleplex allergy diagnostics and a newly established immunoblot diagnostic system. The new dot blot detection system resolved individual IgE sensitization profiles for α-Gal-containing analytes CTX, bovine thyroglobulin (Bos d TG), and human serum albumin (HSA)-conjugated α-Gal. RESULTS: Singleplex allergy diagnostics using the α-Gal analytes CTX and Bos d TG confirms the history of MA patients in 91% and 88% of the cases, respectively. A novel dot blot-based assay system for the detection of IgE against α-Gal reveals individual IgE sensitization profiles for α-Gal-containing analytes. An α-Gal-associated IgE cross-reactivity profile (IgE against CTX, Bos d TG, and HSA-α-Gal) was identified, which is associated with MA. CONCLUSIONS: Detection of individual sensitization patterns with different α-Gal-containing analytes provides the basis for an individual allergy diagnosis for α-Gal-sensitized patients. Higher amounts of α-Gal in pork and beef innards compared to muscle meat as indicated by a higher staining intensity are a plausible explanation for the difference in allergic symptom severity.

Overcoming severe adverse reactions to venom immunotherapy using anti-IgE antibodies in combination with a high maintenance dose.

BACKGROUND: An omalizumab treatment and a high maintenance venom dose may both help to prevent recurrent systemic allergic reactions (SAR) to venom immunotherapy (VIT). The effectiveness of this combination therapy, however, is unclear. OBJECTIVE: We wanted to explore the possibility whether a temporary treatment with the anti-IgE antibody omalizumab combined with a VIT using an elevated maintenance dose of >100 µg venom may establish a permanent tolerance of maintenance VIT. METHODS: For this retrospective case series, we scoured our institutional data base for patients who had had an insect venom allergy, and in whom it had not been possible to continue VIT because of repeated unstoppable SAR during maintenance VIT. Patients were divided into those who had received the combination therapy (omalizumab group) and those who had not received omalizumab because its costs could not be covered (controls). Guided by the total IgE level and by body weight, omalizumab had been given subcutaneously 5, 3 and 1 weeks before VIT had been restarted. Three to 6 months after an elevated maintenance dose (200-300 µg venom) had been reached, omalizumab had been stopped. RESULTS: Between 2006 and 2011, 15 patients had qualified for an off-label use of omalizumab: 10 patients had received the combination therapy, and 5 patients had remained without such a therapy. The combination therapy leads to a durable tolerance of VIT in all patients even after omalizumab had been discontinued (median of follow-up time 5.8 years, IQR 2.7-8.6 years). Sting challenge tests were tolerated by all of the re-stung omalizumab patients (n = 8). In all controls, VIT had to be stopped permanently due to repeated SARs (P < .001 vs omalizumab group). CONCLUSIONS AND CLINICAL RELEVANCE: Combining a temporary omalizumab therapy with an elevated maintenance dose seems a promising approach to achieve a tolerance of treatment in patients with a recurrent SAR to VIT.

Food-induced anaphylaxis and cofactors - data from the anaphylaxis registry.

Food allergens are frequent causes of anaphylaxis. In particular in children and adolescents they are the most frequent elicitors of severe allergic reactions, and in adults food allergens rank third behind insect venom and drugs. Since July 2006 severe allergic reactions from Germany, Austria, and Switzerland are collected in the anaphylaxis registry. Currently 78 hospitals and private practises are connected. From July 2006 until February 2009 1,156 severe allergic reactions were registered. Among children and adolescents (n = 187, age range from 3 months to 17 years) food allergens were the most frequent triggers, comprising 58% of cases. In the adult group (n = 968, 18 - 85 years) food allergens were in the third position (16.3%) behind insect venom and drugs. In children legumes (31%) and in particular peanuts were frequently responsible food allergens, followed by tree nuts (25%) with hazelnut being the most frequent elicitor. In adults fruits (13.4%) most often induced severe food-dependent anaphylaxis, but also animal products (12.2%); among these most frequently crustaceans and molluscs. Cofactors were often suspected in food-dependent anaphylaxis, namely in 39% of the adult group and in 14% of the pediatric group. In adults drugs (22%) and physical activity (10%) were reported to be the most frequent cofactors, in children physical activity was suspected in 8.7% and drugs in 2.6%. Concomitant diseases like atopic dermatitis, allergic asthma, or allergic rhinoconjunctivitis were reported in 78% of children and adolescents and in 67% of the adults. In conclusion, food-induced anaphylaxis, its cofactors and concomitant diseases are age-dependent. The data offers to identify risk factors of anaphylaxis.

Risk factors in Hymenoptera venom allergy.

. Risk factors should be part of the decision, of which patient should be offered venom immunotherapy (VIT) and how VIT should be performed. Risk factors for a severe systemic anaphylactic reaction (SAR) after a Hymenoptera field sting include a preceding less severe sting reaction, a wasp sting, an increased baseline serum tryptase concentration (BSTC), mastocytosis, older age, ACE inhibitor medication, and male gender. During VIT, treatment with honey bee venom is the most important risk factor for a SAR. Further risk factors include a high BSTC (for vespid VIT only), presence of venom specific IgE in serum, any antihypertensive medication during therapy, and an ultra-rush protocol for build-up. Treatment failure is more common in patients suffering from honey bee venom allergy, high BSTC (for vespid VIT only) or mastocytosis, and in those who had experienced side effects during VIT. Besides discontinuing antihypertensive medication or switching to a moderate type of dose increase during build-up, little can be done to minimize the risks associated with VIT. Increasing the maintenance dose may improve the efficacy of VIT. In patients with a particularly high risk for treatment failure, or in case of treatment failure, VIT should include an increased maintenance dose right from the beginning. Usually, 200 µg will be sufficient.

Effects of a structured educational intervention on knowledge and emergency management in patients at risk for anaphylaxis.

BACKGROUND: Structured educational programmes for patients at risk for anaphylaxis have not yet been established. Patients and caregivers often lack adequate skills in managing the disease. METHODS: To investigate effects of structured patient education intervention on knowledge, emergency management skills and psychological parameters in patients with previous episodes of anaphylaxis and caregivers of affected children 95 caregivers (11 male, 84 female, mean age 37 years) of affected children and 98 patients (32 male, 66 female, mean age 47.5 years) were randomly assigned to an intervention (IG) or control group (CG) in a multicentre randomized controlled trial. The IG received two 3-h schooling modules of group education; the CG received standard auto-injector training only. Knowledge of anaphylaxis and emergency management competence in a validated training anaphylaxis situation as main outcome measures as well as secondary psychological parameters were assessed at baseline and 3 months after intervention. RESULTS: In comparison with controls, the intervention led to significant improvement of knowledge from baseline to 3-month follow-up (caregivers: IG 3.2/13.2 improvement/baseline vs CG 0.7/12.6; P < 0.001; patients: IG 3.9/10.8 vs 1.3/12.6; P < 0.001). Moreover, emergency management competence was increased after intervention as compared to controls (caregivers: IG 8.6/11.2 vs CG 1.2/10.8; P < 0.001; patients: 7.1/11.0 vs 1.1/11.1; P < 0.001). Intervention showed significant reduction of caregiver anxiety (-1.9/8.4 vs -0.7/7.5; P < 0.05). There were no significant changes in the depression scores. CONCLUSION: Structured patient education programmes may be beneficial in the management of anaphylaxis by increasing patients' empowerment to prevent and treat the disease.

[Sting challenge: indications and execution]. / Stichprovokation: Indikation und Durchführung.

BACKGROUND: Venom immunotherapy (VIT) is a highly effective treatment for Hymenoptera venom allergy. However, VIT treatment may fail to protect against systemic reactions. Many in vitro parameters as well as skin test reactivity change during the course of VIT; however, similar to the pre-treatment situation, there is no in vitro parameter, which reliably indicates the clinical reactivity of a sensitized patient. Sting challenge with the culprit insect is the only tool which reveals clinical reactivity. OBJECTIVES: To define the indications, contraindications and performance of sting challenge tests. MATERIAL AND METHODS: Review of the literature. RESULTS: Sting challenge tests are not recommended for individuals who are not being treated with VIT, and are also not recommended as a routine diagnostic method for patients who have stopped VIT. Indications of sting challenge are identification of patients who are not protected, and quality of life issues. Major contraindications of sting challenge are repeated side effects or a field sting reaction during maintenance VIT, and unstable medical disease. Risk factors for treatment failure are mastocytosis, bee venom allergy, repeated side effects of VIT, and ACE inhibitors. Protection rate is significantly better in patients who are treated with elevated venom dose, with double VIT, and longer treatment duration. CONCLUSIONS: For the majority of patients quality of life will significantly improve after tolerated sting challenge. A sting challenge test is particularly important in those patients who are at increased risk due their increased risk of treatment failure. If in patients with risk factors for treatment failure, VIT is done with elevated dose or if no risk factors are present, a sting challenge may not be needed. VIT with an elevated dose may prevent or correct treatment failure.

Atopic dermatitis, STAT3- and DOCK8-hyper-IgE syndromes differ in IgE-based sensitization pattern.

BACKGROUND: Increased serum IgE levels are characteristic but not specific for allergic diseases. Particularly, severe atopic dermatitis (AD) overlaps with hyper-IgE syndromes (HIES) regarding eczema, eosinophilia, and increased serum IgE levels. HIES are primary immunodeficiencies due to monogenetic defects such as in the genes DOCK8 and STAT3. As it is not known to date why allergic manifestations are not present in all HIES entities, we assessed the specificity of serum IgE of AD and HIES patients in the context of clinical and immunological findings. METHODS: Clinical data, skin prick tests, specific IgE to aero- and food allergens, and T helper (Th) subpopulations were compared in AD and molecularly defined HIES patients. RESULTS: Total serum IgE levels were similarly increased in STAT3-HIES, DOCK8-HIES, and AD patients. The ratio of aeroallergen-specific IgE to total IgE was highest in AD, whereas DOCK8-HIES patients showed the highest specific serum IgE against food allergens. Overall, clinical allergy and skin prick test results complied with the specific IgE results. Th2-cell numbers were significantly increased in DOCK8-HIES and AD patients compared to STAT3-HIES patients and controls. AD patients showed significantly higher nTreg-cell counts compared to STAT3-HIES and control individuals. High Th17-cell counts were associated with asthma. Specific IgE values, skin prick test, and T-cell subsets of STAT3-HIES patients were comparable with those of healthy individuals except decreased Th17-cell counts. CONCLUSION: Hyper-IgE syndromes and atopic dermatitis patients showed different sensitization pattern of serum IgE corresponding to the allergic disease manifestations and Th-cell subset data, suggesting a key role of DOCK8 in the development of food allergy.

Predictors of clinical effectiveness of Hymenoptera venom immunotherapy.

BACKGROUND: Treatment failure during venom immunotherapy (VIT) may be associated with a variety of risk factors, of which the relative importance is unknown. OBJECTIVE: Our aim was to evaluate the association of baseline serum tryptase concentration (BTC), mastocytosis in the skin (MIS) and of other parameters with the frequency of objective systemic reactions during in-hospital sting challenge (SC). METHODS: In this observational retrospective study, we enrolled 1532 patients (1609 cases due to double SC) with established honeybee or vespid venom allergy who had undergone VIT and a subsequent SC. Data were collected on various putative risk factors. Adult-onset MIS and/or a BTC > 20.0 µg/L was defined as clinical indicators of systemic mastocytosis. Relative rates were calculated with logistic regression models. RESULTS: Ninety-eight patients (6.4%) presented with MIS and/or BTC > 20.0 µg/L. 104 cases (6.5%) developed objective generalized symptoms during SC. In the absence of MIS, a BTC ≤ 20 µg/L did not increase the risk for VIT failure. The most important factors associated with a worse outcome were ACE inhibitor medication (OR 5.24, 95% CI 1.83-13.00, P < 0.001), honeybee venom allergy (OR 5.09, 95% CI 3.17-8.15, P < 0.001), systemic allergic reaction during VIT (OR 3.07, 95% CI 1.79-5.14, P < 0.001), and a substantial likelihood to suffer from SM (OR 2.74, 95% CI 1.37-5.22, P = 0.003), whereas a double VIT (OR 0.51, 95% CI 0.27-0.90, P = 0.027) and a longer duration of therapy (OR 0.68 per treatment month, 95% CI 0.50-0.93, P = 0.017) reduced the failure rate. CONCLUSION: The magnitude of therapeutic success correlates with type of venom, duration of therapy, and venom dose. Adult-onset MIS and/or a BTC > 20 µg/L is a significant, albeit not the strongest determinant for VIT failure. According to its odds ratio, ACE inhibitor therapy appears to be associated with the highest risk for VIT failure.

IgE-mediated hypersensitivity reactions to cannabis in laboratory personnel.

BACKGROUND: There have been sporadic reports of hypersensitivity reactions to plants of the Cannabinaceae family (hemp and hops), but it has remained unclear whether these reactions are immunologic or nonimmunologic in nature. OBJECTIVE: We examined the IgE-binding and histamine-releasing properties of hashish and marijuana extracts by CAP-FEIA and a basophil histamine release test. METHODS: Two workers at a forensic laboratory suffered from nasal congestion, rhinitis, sneezing and asthmatic symptoms upon occupational contact with hashish or marijuana, which they had handled frequently for 25 and 16 years, respectively. Neither patient had a history of atopic disease. Serum was analyzed for specific IgE antibodies to hashish or marijuana extract by research prototype ImmunoCAP, and histamine release from basophils upon exposure to hashish or marijuana extracts was assessed. Results were matched to those of 4 nonatopic and 10 atopic control subjects with no known history of recreational or occupational exposure to marijuana or hashish. RESULTS: Patient 1 had specific IgE to both hashish and marijuana (CAP class 2), and patient 2 to marijuana only (CAP class 2). Controls proved negative for specific IgE except for 2 atopic individuals with CAP class 1 to marijuana and 1 other atopic individual with CAP class 1 to hashish. Stimulation of basophils with hashish or marijuana extracts elicited histamine release from basophils of both patients and 4 atopic control subjects. CONCLUSIONS: Our results suggest an IgE-related pathomechanism for hypersensitivity reactions to marijuana or hashish.

[Skin tests for diagnostics of allergic immediate-type reactions. Guideline of the German Society for Allergology and Clinical Immunology]. / Hauttests zur Diagnostik von allergischen Soforttyp-Reaktionen. Leitlinie der Deutschen Gesellschaft für Allergologie und klinischen Immunologie (DGAKI).

Skin tests in patients with IgE-mediated immediate type allergy are performed with the intention to establish a contact between allergens and skin mast cells. The latter carry specific IgE antibodies on their surface. If mast cells get activated, mediators (mainly histamine) are released which induce a visible skin reaction (wheal and erythema).[nl]Skin tests are indicated, if an immediate type allergic disease is suspected. Systemic anaphylactic reactions at skin testing are very rare. However, it is necessary to take them into account and to provide emergency treatment. Relative contraindications comprise skin diseases in the test area, poor general condition and insufficiently treated severe asthma. If tests are used, which have a higher risk for a systemic anaphylactic reaction, pregnancy or beta-blocker therapy, are further contraindications.[nl]Skin test application does not depend on patient age. However, in pre-school age tests are reluctantly performed. It is essential to consider the half-life of drugs which may interfere with the test result, and which have to be discontinued early enough before testing. After anaphylactic reactions there may be a refractory period. Therefore, tests should not be done within the first week after such reactions. Skin prick tests are the procedures of first choice, intradermal tests are more sensitive than prick tests. Skin tests are performed at the flexor side of the forearm. As intradermal tests are more inconvenient, testing can be also done at a less susceptible site of the body (upper back).[nl]It is recommended to use standardized test extracts. However, if standardised extracts are not available or do not yield suitable test results, one may switch to other preparations. If the patient shows a positive reaction to a non-standardized substance, control tests should be performed in healthy subjects in order to exclude an unspecific reaction.[nl]The reaction is read after 15 to 20 min. Skin tests are regarded positive if the mean wheal diameter is ≥ 3 mm at the prick test, and ≥ 5 mm at the intradermal test.[nl]Skin test results may be negative although patients are allergic. If a skin test is positive, one will have to distinguish reactions, which are clinically relevant, from those, which are not. History and/or challenge tests help to clarify the relevance of a sensitization. Usually, a clinically irrelevant sensitization does not lead to practical consequences.

[Standards and pitfalls of in-vitro diagnostics of Hymenoptera venom allergy]. / Standards und Fallstricke der In-vitro-Diagnostik der Insektengiftallergie.

In patients with a history of anaphylactic sting reactions, in-vitro tests are performed in order to demonstrate venom sensitization to the causative venom. Measurement of specific IgE-antibodies (sIgE) to the natural composite venom represents the standard in-vitro method to demonstrate venom sensitization. If sensitization to the composite venom cannot be demonstrated, one may determine sIgE to recombinant allergen compounds, in order to demonstrate sensitization to molecular venom allergens. Moreover, several cellular tests are available to confirm venom sensitization. Herein basophils, which carry cell-bound sIgE, can be used to produce a confirmatory response upon incubation with venom allergens. Reactions to both honey bee and vespid venom may either indicate true double sensitization or cross sensitization. The identification of antibodies cross-reacting to venoms and to other allergen sources does not exclude clinical relevance. Elevated baseline serum tryptase is a risk factor for severe systemic reactions after a field sting and during venom immunotherapy (VIT), the latter in particular for VIT with vespid venom. Serum tryptase measurement should, therefore, be included into routine diagnostics of venom allergy. The measurement of IgG-antibodies specific to venom is not recommended for routine work-up. None of the mentioned in-vitro tests, which may be used before, during or after VIT, allow, however, a precise prognosis with respect to future sting reactions, or to side effects and to the efficacy of VIT, respectively. To validate the reason for a VIT, one should also consider patient history and results of other tests.

Serum concentration of baseline mast cell tryptase: evidence for a decline during long-term immunotherapy for Hymenoptera venom allergy.

BACKGROUND: Baseline serum mast cell tryptase concentration (BTC) is thought to reflect the constitutive mast cell load or activity of an individual patient. Little is known about the individual stability of BTC during long-term venom immunotherapy (VIT). OBJECTIVE: To investigate the intra-individual stability of BTC over time in patients with Hymenoptera venom allergy. METHODS: Three hundred and two patients were studied. BTC was measured before and at least twice during VIT. At least 4 weeks lay between BTC measurements and the most recent field sting, in-hospital sting, or preceding venom injection. Multifactorial mixed linear models were used to analyse BTC changes over time. RESULTS: Median observation time was 4.2 years (range 2-12 years). Before VIT, the median BTC was 6.8 microg/L (range 1.14-177 microg/L). The median coefficient of variation (CV) over time was 15.3% (range 1.9-63.8%). The median CV was significantly smaller in patients presenting with an elevated BTC (>11.4 microg/L) than in patients with a normal BTC (11.4%, range 2.6-39.5%; vs. 17.6%, range 1.9- 63.8%; P<0.001). During VIT and after adjusting for age and gender, we found a slight but significant decrease of BTC over time (2.5% per year, 95% confidence interval 2.0-3.0%, P<0.001). CONCLUSION: Individual variation of BTC during VIT does not rise when BTC is increased before therapy. VIT is associated with a small, but continuous decrease of BTC over time possibly indicating a dampened mast cell function or a decline in mast cell burden.

Experimental inhalation of fragrance allergens in predisposed subjects: effects on skin and airways.

BACKGROUND: Exposure to fragrances is increasingly encountered in the environment. Some fragrances are known to be important skin and potential airway sensitizers. OBJECTIVES: We investigated whether patients with contact allergy to isoeugenol (ISO) or hydroxyisohexyl-3-carboxaldehyde (HICC) would react to inhalation exposure at the level of the airways and skin. METHODS: Eleven patients sensitized to ISO and 10 patients sensitized to HICC were exposed for 60 min to 1000 microg m(-3) of these compounds in an exposure chamber at rest, and to geraniol 1000 microg m(-3) as a control. Patients wore protective clothing to prevent skin exposure. Assessments were performed prior to exposure, and immediately, 2, 5, 24 and 72 h afterwards. RESULTS: There were no significant changes in lung function but a tendency towards an increased bronchial hyper-responsiveness after exposure to any of the compounds. Laboratory parameters of inflammation did not indicate responses. Single patients reported respiratory symptoms unrelated to objective measures. In contrast, the observed skin symptoms corresponded to the patients' specific sensitization. Four patients reported symptoms compatible with delayed-type hypersensitivity, and two demonstrated a flare after ISO. On re-exposure they did not respond to a lower, more realistic level of ISO. CONCLUSION: Inhalation of high concentrations of fragrance contact allergens apparently poses a risk for some patients of developing manifest haematogenic contact dermatitis, while the changes in the respiratory tract are limited to symptoms in some subjects without objective changes.

[Venom immunotherapy. Side effects and efficacy of treatment]. / Insektengifthyposensibilisierung. Nebenwirkungen und Therapieerfolg.

Venom immunotherapy (VIT) protects patients with Hymenoptera venom anaphylaxis from subsequent potentially life-threatening reactions. The most important side effect are systemic anaphylactic reactions (SAR). Compared to the administration of aqueous extracts according to a rush protocol, the frequency of systemic and also local side effects will be lower if depot extracts are used and a slow conventional dose schedule is used, as compared to rush desensitization with aqueous extracts. However, protection often has to be achieved rapidly, and adequate surveillance of sufficient duration is hardly feasible in outpatients. Therefore, VIT according to rush schedules in inpatients remains indispensable. Pre-treatment with H(1)-blocking antihistamines reduces frequency and intensity of local and mild systemic adverse reactions during VIT. Up to 25% of patients again develop a SAR when re-stung while on VIT with the usual maintenance dose of 100 microg venom. Patients with honeybee venom allergy or with mastocytosis are at a higher risk for treatment failure. Almost all of them will become fully protected by increasing the maintenance dose, 200 microg venom being sufficient in most cases. Patients with significant risk factors may be treated from the beginning with an elevated maintenance dose, particularly when they are allergic to honeybee venom.