Influencing factors on the safety and effectiveness of venom immunotherapy.

BACKGROUND AND OBJECTIVE: The safety profile of venom immunotherapy (VIT) is a relevant issue and considerable differences in safety and efficacy of VIT have been reported. The primary aim of this study was to evaluate the safety of ACE inhibitors and beta-blockers during VIT, which has already been published. For a second analysis, data concerning premedication and venom preparations in relation to systemic adverse events (AE) during the up-dosing phase and the first year of the maintenance phase were evaluated as well as the outcome of field stings and sting challenges. METHODS: The study was conducted as an open, prospective, observational, multicenter study. In total, 1,425 patients were enrolled and VIT was performed in 1,342 patients. RESULTS: Premedication with oral antihistamines was taken by 52.1% of patients during the up-dosing and 19.7% of patients during the maintenance phase. Taking antihistamines had no effect on the frequency of systemic AE (p=0.11) but large local reactions (LLR) were less frequently seen (OR: 0.74; 95% CI: 0.58-0.96; p=0.02). Aqueous preparations were preferentially used for up-dosing (73.0%) and depot preparations for the maintenance phase (64.5%). The type of venom preparation neither had an influence on the frequency of systemic AE nor on the effectiveness of VIT (p=0.26 and p=0.80, respectively), while LLR were less frequently seen when depot preparations were used (p<0.001). CONCLUSION: Pretreatment with oral antihistamines during VIT significantly reduces the frequency of LLR but not systemic AE. All venom preparations used were equally effective and did not differ in the frequency of systemic AE.

Variability of disease activity in patients with hereditary angioedema type 1/2: longitudinal data from the Icatibant Outcome Survey.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-1/2) is a chronic and debilitating disease. The unpredictable clinical course represents a significant patient burden. OBJECTIVE: To analyse longitudinal registry data from the Icatibant Outcome Survey (IOS) in order to characterize temporal changes in disease activity in patients with HAE-1/2. METHODS: Icatibant Outcome Survey (NCT01034969) is an international observational registry monitoring the clinical outcomes of patients eligible for icatibant treatment. The current analyses are based on data collected between July 2009 and July 2019. Retrospective data for attacks recorded in the 12 months prior to IOS enrolment and for each 12-month period up to 7 years were analysed. RESULTS: Included patients reported angioedema attacks without long-term prophylaxis (LTP; n = 315) and with LTP (n = 292) use at the time of attack onset. Androgens were the most frequently used LTP option (80.8%). At the population level, regardless of LTP use, most patients (52-80%) reporting <5 attacks in Year 1 continued experiencing this rate; similarly, many patients (25-76%) who reported high attack frequency continued reporting ≥10 attacks/year. However, year on year, 31-51% of patients experienced notable changes (increase/decrease of ≥5 attacks) in annual attack frequency. Of patients who reported an absolute change of ≥10 attacks from Year 1 to 2, 17-50% continued to experience a change of this magnitude in subsequent years. CONCLUSION: At the population level, attack frequency was generally consistent over 7 years. At the small group level, 28.8-34.5% of patients reported a change in attack frequency of ≥5 attacks from Year 1 to Year 2; up to half of these patients continued to experience this magnitude of variation in disease activity in later years, reflecting high intra-patient variability.

Immunological differences between insect venom-allergic patients with and without immunotherapy and asymptomatically sensitized subjects.

BACKGROUND: Currently available tests are unable to distinguish between asymptomatic sensitization and clinically relevant Hymenoptera venom allergy. A reliable serological marker to monitor venom immunotherapy (VIT) does also not exist. Our aim was to find reliable serological markers to predict tolerance to bee and vespid stings. METHODS: We included 77 asymptomatically sensitized subjects, 85 allergic patients with acute systemic sting reactions, and 61 allergic patients currently treated with VIT. Levels of sIgE and sIgG4 to bee and vespid venom, rApi m 1, and rVes v 5 were measured immediately after allergic sting reactions or before sting challenges and 4 weeks later. All sting challenges were tolerated. The inhibitory activity was determined using BAT inhibition and ELIFAB assay. RESULTS: Median sIgG4 levels were 96-fold higher in VIT patients (P < .001) while sIgE/sIgG4 ratios were consistently lower (P < .001). The ELIFAB assay was paralleled by low sIgE/sIgG4 ratios in VIT patients, showing markedly higher allergen-blocking capacity (P < .001). An almost complete inhibition of the basophil response was seen in all patients treated with vespid venom, but not in those treated with bee venom. Four weeks after the sting, sIgE and sIgG4 levels were increased in allergic and asymptomatically sensitized patients, but not in VIT patients. CONCLUSION: Immunological responses after stings varied in bee and vespid venom-allergic patients. In patients under VIT, sIgE and sIgG4 remained completely stable after sting challenges. Monitoring VIT efficacy was only possible in vespid venom allergy, and the sIgG4 threshold for rVes v 5 had the highest sensitivity to confirm tolerance. The BAT inhibition test was the most reliable tool to confirm tolerance on an individual basis.

Randomized controlled trials define shape of dose response for Pollinex Quattro Birch allergoid immunotherapy.

BACKGROUND: The Birch Allergoid, Tyrosine Adsorbate, Monophosphoryl Lipid A (POLLINEX® Quattro Plus 1.0 ml Birch 100%) is an effective, well-tolerated short course subcutaneous immunotherapy. We performed 2 phase II studies to determine its optimal cumulative dose. METHODS: The studies were conducted in Germany, Austria and Poland (EudraCT numbers: 2012-004336-28 PQBirch203 and 2015-000984-15 PQBirch204) using a wide range of cumulative doses. In both studies, subjects were administered 6 therapy injections weekly outside the pollen season. Conjunctival Provocation Tests were performed at screening, baseline and 3-4 weeks after completing treatment, to quantify the reduction in Total Symptom Scores (as the primary endpoint) with each cumulative dose. Multiple Comparison Procedure and Modeling analysis was used to test for the dose response, shape of the curve and estimation of the median effective dose (ED50 ), a measure of potency. RESULTS: Statistically significant dose responses (P < .01 & .001) were seen, respectively. The highest cumulative dose in PQBirch204 (27 300 standardized units [SU]) approached a plateau. Potency of the PQBirch was demonstrated by an ED50 2723 SU, just over half the current dose. Prevalence of treatment-emergent adverse events was similar for active doses, most being short-lived and mild. Compliance was over 85% in all groups. CONCLUSION: Increasing the cumulative dose of PQBirch 5.5-fold from 5100 to 27 300 SU achieved an absolute point difference from placebo of 1.91, a relative difference 32.3% and an increase in efficacy of 50%, without compromising safety. The cumulative dose response was confirmed to be curvilinear in shape.

The EAACI/GA²LEN/EDF/WAO guideline for the definition, classification, diagnosis and management of urticaria.

This evidence- and consensus-based guideline was developed following the methods recommended by Cochrane and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) working group. The conference was held on 1 December 2016. It is a joint initiative of the Dermatology Section of the European Academy of Allergology and Clinical Immunology (EAACI), the EU-founded network of excellence, the Global Allergy and Asthma European Network (GA²LEN), the European Dermatology Forum (EDF) and the World Allergy Organization (WAO) with the participation of 48 delegates of 42 national and international societies. This guideline was acknowledged and accepted by the European Union of Medical Specialists (UEMS). Urticaria is a frequent, mast cell-driven disease, presenting with wheals, angioedema, or both. The lifetime prevalence for acute urticaria is approximately 20%. Chronic spontaneous urticaria and other chronic forms of urticaria are disabling, impair quality of life and affect performance at work and school. This guideline covers the definition and classification of urticaria, taking into account the recent progress in identifying its causes, eliciting factors and pathomechanisms. In addition, it outlines evidence-based diagnostic and therapeutic approaches for the different subtypes of urticaria.

Problems and challenges of predatory journals.

The companies publishing predatory journals are an emerging problem in the area of scientific literature as they only seek to drain money from authors without providing any customer service for the authors or their readership. These predatory journals try to attract new submissions by aggressive email advertising and high acceptance rates. But in turn, they do not provide proper peer review, and therefore, the scientific quality of submitted articles is questionable. This is important because more and more people, including patients, are reading such journals and rely on the information they provide. Consequently, predatory journals are a serious threat to the integrity of medical science, and it is crucial for scientists, physicians and even patients to be aware of this problem. In this review, we briefly summarize the history of the open access movement, as well as the rise of and roles played by predatory journals. In conclusion, young and inexperienced authors publishing in a predatory journal must be aware of the damage of their reputation, of inadequate peer review processes and that unprofitable journals might get closed and all published articles in that journal might be lost.

Comparing acquired angioedema with hereditary angioedema (types I/II): findings from the Icatibant Outcome Survey.

Icatibant is used to treat acute hereditary angioedema with C1 inhibitor deficiency types I/II (C1-INH-HAE types I/II) and has shown promise in angioedema due to acquired C1 inhibitor deficiency (C1-INH-AAE). Data from the Icatibant Outcome Survey (IOS) were analysed to evaluate the effectiveness of icatibant in the treatment of patients with C1-INH-AAE and compare disease characteristics with those with C1-INH-HAE types I/II. Key medical history (including prior occurrence of attacks) was recorded upon IOS enrolment. Thereafter, data were recorded retrospectively at approximately 6-month intervals during patient follow-up visits. In the icatibant-treated population, 16 patients with C1-INH-AAE had 287 attacks and 415 patients with C1-INH-HAE types I/II had 2245 attacks. Patients with C1-INH-AAE versus C1-INH-HAE types I/II were more often male (69 versus 42%; P = 0·035) and had a significantly later mean (95% confidence interval) age of symptom onset [57·9 (51·33-64·53) versus 14·0 (12·70-15·26) years]. Time from symptom onset to diagnosis was significantly shorter in patients with C1-INH-AAE versus C1-INH-HAE types I/II (mean 12·3 months versus 118·1 months; P = 0·006). Patients with C1-INH-AAE showed a trend for higher occurrence of attacks involving the face (35 versus 21% of attacks; P = 0·064). Overall, angioedema attacks were more severe in patients with C1-INH-HAE types I/II versus C1-INH-AAE (61 versus 40% of attacks were classified as severe to very severe; P < 0·001). Median total attack duration was 5·0 h and 9·0 h for patients with C1-INH-AAE versus C1-INH-HAE types I/II, respectively.

Questionable diagnostic benefit of the commercially available panel of bee venom components.

For many years, only the major allergen rApi m 1 has been available on the ImmunoCAP system for routine diagnosis of bee venom (BV) allergy. Now, there are five components available, and we aimed to detect the sensitivity and specificity of rApi m 1, 2, 3, 5, and 10 in BV-allergic patients. We further evaluated the sensitivity of rApi m 1 and 2 of an alternative platform and investigated possible differences in the sensitization profile between monosensitization and clinically relevant double sensitization. Analysis of the whole panel of BV allergens of the CAP system still resulted in a lower sensitivity than analysis of the combination of rApi m 1 and 2 of the Immulite (71.6% vs 85.8%). Sensitization rate of rApi m 5 was more than doubled in double-sensitized patients, while there was no difference for rApi m 2. The benefit of the commercially available panel of BV components is questionable, due to the insufficient sensitivity and still unavailable important cross-reacting allergens.

Long-term safety of icatibant treatment of patients with angioedema in real-world clinical practice.

The Icatibant Outcome Survey (IOS) is an observational study monitoring safety and effectiveness of icatibant in the real-world setting. We analyzed safety data from 3025 icatibant-treated attacks in 557 patients (enrolled between July 2009 and February 2015). Icatibant was generally well tolerated. Excluding off-label use and pregnancy, 438 patients (78.6%) did not report adverse events (AEs). The remaining 119 (21.4%) patients reported 341 AEs, primarily gastrointestinal disorders (19.6%). Of these, 43 AEs in 17 patients (3.1%) were related to icatibant. Serious AEs (SAEs) occurred infrequently. A total of 143 SAEs occurred in 59 (10.6%) patients; only three events (drug inefficacy, gastritis, and reflux esophagitis) in two patients were considered related to icatibant. Notably, no SAEs related to icatibant occurred in patients with cardiovascular disease, nor in those using icatibant at a frequency above label guidelines. Additionally, no major differences were noted in AEs occurring in on-label vs off-label icatibant users.

The Icatibant Outcome Survey: experience of hereditary angioedema management from six European countries.

BACKGROUND: Hereditary angioedema (HAE) due to C1-inhibitor deficiency (C1-INH-HAE) is a rare, potentially fatal, bradykinin-mediated disease. Icatibant is a bradykinin B2 receptor antagonist originally approved in 2008 in the European Union and 2011 in the United States as an acute therapy option for HAE attacks in adults. OBJECTIVE: To compare demographics, disease characteristics and treatment outcomes of icatibant-treated HAE attacks in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey across six European countries: Austria, France, Germany, Italy, Spain and the UK. METHODS: The Icatibant Outcome Survey [IOS; Shire, Zug, Switzerland (NCT01034969)] is an international observational study monitoring the safety and effectiveness of icatibant. Descriptive, retrospective analyses compared IOS country data derived during July 2009-April 2015. RESULTS: Overall, 481 patients with C1-INH-HAE provided demographic data. A significant difference across countries in age at onset (P = 0.003) and baseline attack frequency (P < 0.001) was found although no significant differences were found with respect to gender (majority female; P = 0.109), age at diagnosis (P = 0.182) or delay in diagnosis (P = 0.059). Icatibant was used to treat 1893 attacks in 325 patients with majority self-administration in all countries. Overall, significant differences (all P < 0.001) were found across countries in time to treatment [median 1.8 h; median range: 0.0 (Germany-Austria) to 4.4 (France) h], time to resolution [median 6.5 h; median range: 3 (Germany-Austria) to 12 (France) h] and attack duration [median 10.5 h; median range: 3.1 (Germany-Austria) to 18.5 (France) h]. CONCLUSION: These data form the first European cross-country comparison of disease characteristics and icatibant use in patients with C1-INH-HAE who are enrolled in IOS. International variation in icatibant practice and treatment outcomes across the six European countries assessed highlight the need to further investigate the range of country-specific parameters driving regional variations in icatibant use.

Updated evidence-based (S2e) European Dermatology Forum guideline on topical corticosteroids in pregnancy.

BACKGROUND: Topical corticosteroids may be needed for treating skin conditions in pregnancy. Nevertheless, only limited data on the fetal effects of topical corticosteroids are available. OBJECTIVE: To update an evidence-based guideline on the safe use of topical corticosteroids in pregnancy. METHODS: A guideline subcommittee of the European Dermatology Forum updated the guideline by adding and appraising new evidence. RESULTS: The current best evidence from 14 observational studies with 1 601 515 study subjects found no significant associations between maternal use of topical corticosteroids of any potency and some adverse pregnancy outcomes including mode of delivery, birth defect, preterm delivery and fetal death. However, maternal use of potent/very potent topical corticosteroids, especially in large amounts, is associated with an increase in the risk of low birthweight. CONCLUSION: Mild/moderate topical corticosteroids should be preferred to potent/very potent ones in pregnancy. The well-known topical side-effects of corticosteroids on the mother's side need to be considered as well.

[Allergic contact dermatitis of the scalp]. / Kontaktallergien der Kopfhaut.

Contact allergy represents an important differential diagnosis to other skin diseases of the scalp. The typical efflorescences, spreading in the periphery, pruritus, and the clinical history support the differential diagnosis. Since the scalp is particularly resistant to contact dermatitis, allergens applied to this area often produce dermatitis of the eyelids, ears and neck. Nevertheless, potent allergens such as para-phenylendiamine can also cause severe reactions of the scalp. The most important allergens eliciting contact allergy of the scalp are found in bleaches and dyes, shampoos and conditioners, products for perm waves and straighteners as well as topical drugs. Besides active ingredients or drugs, vehicles and preservative agents represent additional allergens. The use of topical steroids and oral antihistamines usually results in rapid resolution of the dermatitis, systemic steroids are only necessary in severe cases. Epicutaneous patch testing on the basis of available series combined with the ingredients of the suspected elicitors confirms the diagnosis and facilitates allergen avoidance as well as the selection of alternative products.

Hymenoptera stings in the head region induce impressive, but not severe sting reactions.

Stings in the head region are considered to be a risk factor for severe systemic reactions to hymenoptera stings. We supposed that stings in skin areas, which are well supplied with blood, lead to more severe reactions and tested our hypothesis in 847 patients with confirmed hymenoptera venom allergy. However, symptom severity was independent from sting site: only 16.3% of patients with severe reactions were stung on the head (P = 0.017). But we confirmed age > 40 years (P < 0.001) as well as elevated basal tryptase levels (P = 0.001) as risk factors. Taking antihypertensive drugs seemed to have an influence: 41.7% of patients taking antihypertensive drugs experienced a severe reaction compared to 29.5% of patients, not taking such drugs (P = 0.019). However, considering patients' age in regression analysis, taking antihypertensive drugs had no effect on symptom severity (P = 0.342). Importantly, in most patients with severe reactions, cutaneous signs were absent (P < 0.001).

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

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

[Mucosal diseases from an allergological perspective]. / Schleimhauterkrankungen aus allergologischer Sicht.

The oral allergy syndrome is one of the most common form of food allergy and manifests as contact urticaria of the oral mucosa after consumption of cross reacting foods. Whereas allergic contact stomatitis often occurs due to dental materials, allergic contact cheilitis is usually a reaction due to topical therapeutics like herpes ointments or lip care products. As late type reactions are more frequent than immediate type reactions in the anogenital mucosa, contact dermatitis in this area should be identified via epicutaneous testing. In case of contact urticaria at the genital mucosa, a semen allergy or a latex allergy should be given due consideration as a possible cause. Angioedemas, which are mostly common histamine mediated, usually prefer skin areas with loose connective tissue such as the oral or genital mucosa. Fixed drug eruption also occurs preferentially in these areas. Bullous drug-induced skin reactions (e.g., SJS and TEN) are characterized by severe hemorrhagic, erosive affections of mucous membranes.

Anaphylaxis with clonal mast cells in normal looking skin - a new entity?

BACKGROUND: Patients with elevated basal tryptase (sBT) >15 µg/l and anaphylaxis may have an underlying mastocytosis. A monoclonal mast cell activation syndrome with aberrant mast cells (MC) at extracutaneous sites has been described in patients with severe hypotension or anaphylaxis. METHODS: As MC in patients with elevated sBT might be altered in the skin as well, we studied MC in normal neck skin in anaphylaxis and urticaria patients with elevated sBT. RESULTS: A mean of 93.1 (SD 19.1) MC/mm² was counted in normal neck skin in 14 patients with anaphylaxis, 84.0 (SD 13.6) in seven patients with urticaria, 142.0 (SD 24.0) in two patients with eczema, 124.4 (SD 43.2) in five patients with systemic mastocytosis (SM) in comparison with autopsy skin (39.1 MC/mm², SD 12.4). In five of 14 (35.7%) of the anaphylaxis and three of five (60%) SM patients more than 25% of MC were spindle shaped and expressed CD25 antigen. CONCLUSIONS: We could show for the first time that the normal skin can harbour clonal MC in anaphylaxis patients. Analogous to the criteria for mastocytosis, we suggest a skin score criteria including an elevated number of MC, spindle shape, CD25 expression, c-Kit mutation and sBT values >20 µg/l. In patients with anaphylaxis and elevated sBT, skin should be biopsied and, as with the approach for mastocytosis diagnosis in the bone marrow, MC should be analysed for their number, clonality and c-Kit mutation. This approach should be confirmed in further studies. Patients with aberrant skin MC should be handled as mastocytosis patients.

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

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

MACVIA-ARIA Sentinel NetworK for allergic rhinitis (MASK-rhinitis): the new generation guideline implementation.

Several unmet needs have been identified in allergic rhinitis: identification of the time of onset of the pollen season, optimal control of rhinitis and comorbidities, patient stratification, multidisciplinary team for integrated care pathways, innovation in clinical trials and, above all, patient empowerment. MASK-rhinitis (MACVIA-ARIA Sentinel NetworK for allergic rhinitis) is a simple system centred around the patient which was devised to fill many of these gaps using Information and Communications Technology (ICT) tools and a clinical decision support system (CDSS) based on the most widely used guideline in allergic rhinitis and its asthma comorbidity (ARIA 2015 revision). It is one of the implementation systems of Action Plan B3 of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). Three tools are used for the electronic monitoring of allergic diseases: a cell phone-based daily visual analogue scale (VAS) assessment of disease control, CARAT (Control of Allergic Rhinitis and Asthma Test) and e-Allergy screening (premedical system of early diagnosis of allergy and asthma based on online tools). These tools are combined with a clinical decision support system (CDSS) and are available in many languages. An e-CRF and an e-learning tool complete MASK. MASK is flexible and other tools can be added. It appears to be an advanced, global and integrated ICT answer for many unmet needs in allergic diseases which will improve policies and standards.