Guideline for allergological diagnosis of drug hypersensitivity reactions: S2k Guideline of the German Society for Allergology and Clinical Immunology (DGAKI) in cooperation with the German Dermatological Society (DDG), the Association of German Allergologists (ÄDA), the German Society for Pediatric Allergology (GPA), the German Contact Dermatitis Research Group (DKG), the German Society for Pneumology (DGP), the German Society of Otorhinolaryngology, Head and Neck Surgery, the Austrian Society of Allergology and Immunology (ÖGAI), the Austrian Society of Dermatology and Venereology (ÖGDV), the German Academy of Allergology and Environmental Medicine (DAAU), and the German Documentation Center for Severe Skin Reactions (dZh).

Not available.

A nontuberculous mycobacterium could solve the mystery of the lady from the Franciscan church in Basel, Switzerland.

BACKGROUND: In 1975, the mummified body of a female has been found in the Franciscan church in Basel, Switzerland. Molecular and genealogic analyses unveiled her identity as Anna Catharina Bischoff (ACB), a member of the upper class of post-reformed Basel, who died at the age of 68 years, in 1787. The reason behind her death is still a mystery, especially that toxicological analyses revealed high levels of mercury, a common treatment against infections at that time, in different body organs. The computed tomography (CT) and histological analysis showed bone lesions in the femurs, the rib cage, and the skull, which refers to a potential syphilis case. RESULTS: Although we could not detect any molecular signs of the syphilis-causing pathogen Treponema pallidum subsp. pallidum, we realized high prevalence of a nontuberculous mycobacterium (NTM) species in brain tissue sample. The genome analysis of this NTM displayed richness of virulence genes and toxins, and similarity to other infectious NTM, known to infect immunocompromised patients. In addition, it displayed potential resistance to mercury compounds, which might indicate a selective advantage against the applied treatment. This suggests that ACB might have suffered from an atypical mycobacteriosis during her life, which could explain the mummy's bone lesion and high mercury concentrations. CONCLUSIONS: The study of this mummy exemplifies the importance of employing differential diagnostic approaches in paleopathological analysis, by combining classical anthropological, radiological, histological, and toxicological observations with molecular analysis. It represents a proof-of-concept for the discovery of not-yet-described ancient pathogens in well-preserved specimens, using de novo metagenomic assembly.

[Cutaneous Vasculitides - Clinical Manifestations, Diagnosis, and Aetiology]. / Kutane Vaskulitiden.

Cutaneous Vasculitides - Clinical Manifestations, Diagnosis, and Aetiology Abstract. Vasculitides are a heterogeneous group of diseases that are classified differently, for example according to the size of the affected vessel or according to primary and secondary causes. The skin is most frequently affected; it can be involved both as single organ vasculitis and in the context of systemic forms. The combination of skin lesions, their anatomical location and information on the time course provide clues for a differential diagnosis. Purpura, blisters, necrosis, ulcerations and possibly a livedo are characteristic manifestations. Constitutional symptoms such as weight loss, exhaustion, fever, and arthralgias are indicative of a systemic form. It is important to differentiate vasculitides from vasculopathies, which can manifest similarly. The most common form in adults is cutaneous leukocytoclastic angiitis, in children IgA vasculitis (Schönlein-Henoch purpura). Various triggers are possible: infections, drugs, autoimmune diseases, and malignancies, whereby up to 50% remain etiologically unexplained. Skin biopsies and laboratory parameters, if necessary supplemented with imaging, are important steps in the clarification process. Treatment is primarily directed at the elimination of a possible triggering cause. Idiopathic cutaneous leukocytoclastic angiitis usually resolves spontaneously; treatment is symptomatic. In more severe cases, topical corticosteroids or calcineurin antagonists are primarily used. In case of therapeutic resistance, systemic immunosuppressants are recommended.

Use of intravenous iron and risk of anaphylaxis: A multinational observational post-authorisation safety study in Europe.

PURPOSE: This post-authorisation safety study estimated the risk of anaphylaxis in patients receiving intravenous (IV) iron in Europe, with interest in iron dextran and iron non-dextrans. Studies conducted in the United States have reported risk of anaphylaxis to IV iron ranging from 2.0 to 6.8 per 10 000 first treatments. METHODS: Cohort study of IV iron new users, captured mostly through pharmacy ambulatory dispensing, from populations covered by health and administrative data sources in five European countries from 1999 to 2017. Anaphylaxis events were identified through an algorithm that used parenteral penicillin as a positive control. RESULTS: A total of 304 210 patients with a first IV iron treatment (6367 iron dextran), among whom 13-16 anaphylaxis cases were identified and reported as a range to comply with data protection regulations. The pooled unadjusted incidence proportion (IP) ranged from 0.4 (95% confidence interval [CI], 0.2-0.9) to 0.5 (95% CI, 0.3-1.0) per 10 000 first treatments. No events were identified at first dextran treatments. There were 231 294 first penicillin treatments with 30 potential cases of anaphylaxis (IP = 1.2; 95% CI, 0.8-1.7 per 10 000 treatments). CONCLUSION: We found an IP of anaphylaxis from 0.4 to 0.5 per 10 000 first IV iron treatments. The study captured only a fraction of IV iron treatments administered in hospitals, where most first treatments are likely to happen. Due to this limitation, the study could not exclude a differential risk of anaphylaxis between iron dextran and iron non-dextrans. The IP of anaphylaxis in users of penicillin was consistent with incidences reported in the literature.

European Surveillance System on Contact Allergies (ESSCA): Characteristics of patients patch tested and diagnosed with irritant contact dermatitis.

BACKGROUND: Irritant contact dermatitis (ICD) is caused by the acute locally toxic effect of a strong irritant, or the cumulative exposure to various weaker physical and/or chemical irritants. OBJECTIVES: To describe the characteristics of patients with ICD in the population patch tested in the European Surveillance System on Contact Allergies (ESSCA; www.essca-dc.org) database. METHODS: Data collected by the ESSCA in consecutively patch-tested patients from January 2009 to December 2018 were analyzed. RESULTS: Of the 68 072 patients, 8702 were diagnosed with ICD (without concomitant allergic contact dermatitis [ACD]). Hand and face were the most reported anatomical sites, and 45.7% of the ICD was occupational ICD (OICD). The highest proportions of OICD were found in metal turners, bakers, pastry cooks, and confectionery makers. Among patients diagnosed with ICD, 45% were found sensitized with no relevance for the current disease. CONCLUSIONS: The hands were mainly involved in OICD also in the subgroup of patients with contact dermatitis, in whom relevant contact sensitization had been ruled out, emphasizing the need for limiting irritant exposures. However, in difficult-to-treat contact dermatitis, unrecognized contact allergy, or unrecognized clinical relevance of identified allergies owing to incomplete or wrong product ingredient information must always be considered.

Patch test results with the European baseline series and additions thereof in the ESSCA network, 2015-2018.

BACKGROUND: Clinical surveillance of the prevalence of contact allergy in consecutively patch tested patients is a proven instrument to continually assess the importance of contact allergens (haptens) assembled in a baseline series. OBJECTIVES: To present current results from the European Surveillance System on Contact Allergies, including 13 countries represented by 1 to 11 departments. METHODS: Anonymized or pseudonymized patch test and clinical data from various data capture systems used locally or nationally as transferred to the Erlangen data centre were pooled and descriptively analysed after quality control. RESULTS: In the 4 years (2015-2018), data from 51 914 patients patch tested with the European baseline series (EBS) of contact allergens were analysed. Contact allergy to nickel was most frequent (17.6% positive), followed by contact allergy to fragrance mix I (6.9%), methylisothiazolinone (MI; 6.2%), and Myroxylon pereirae resin (balsam of Peru; 5.8%). CONCLUSIONS: While the prevalence of MI contact allergy decreased substantially following regulatory intervention, the persistently high levels of allergy to metals, fragrances, other preservatives, and rubber chemicals point to problems needing further research and, potentially, preventive efforts. Results with national additions to the baseline series provide important information on substances possibly to be considered for inclusion in the EBS.

Indium and iridium: Two rare metals with a high rate of contact sensitization.

BACKGROUND: Humans are exposed to a variety of metals on a daily basis, and nickel is the most frequent contact allergen. Little is known about the frequency of sensitization to indium and iridium. OBJECTIVES: Study the prevalence of indium and iridium sensitization and evaluate the optimal patch test conditions. METHODS: A total of 364 patients were patch tested at the allergy unit of the University Hospital of Basel. Pure metals, metal chlorides, and metal sulfates were applied in petrolatum or water in Inert Quadrate (IQ) test chambers for 2 days and read twice at day (D) 2, and between D4 and D7. RESULTS: Eleven patients reacted to indium salts (3.0%), 13 to iridium salts (3.6%), and one reacted to both salts. None of the patients reacted to pure metals. Nineteen of the 23 patients who reacted either to indium or iridium showed concomitant positive reactions to other metals, mainly nickel and palladium. CONCLUSION: This retrospective clinical study provides insight into the prevalence and test conditions of two rarely tested metal allergens in a large patient cohort. A considerable number of indium- or iridium-positive subjects had co-sensitization to other metals.

Towards a more precise diagnosis of hypersensitivity to beta-lactams - an EAACI position paper.

A recent survey of the European Academy of Allergy and Clinical Immunology (EAACI) Drug Allergy Interest Group (DAIG) on how European allergy specialists deal with beta-lactam (BL) hypersensitivity demonstrated a significant heterogeneity in current practice, suggesting the need to review and update existing EAACI guidelines in order to make the diagnostic procedures as safe and accurate, but also as cost-effective, as possible. For this purpose, a bibliographic search on large studies regarding BL hypersensitivity diagnosis was performed by an EAACI task force, which reviewed and evaluated the literature data using the GRADE system for quality of evidence and strength of recommendation. The updated guidelines provide a risk stratification in BL hypersensitivity according to index reaction(s), as well as an algorithmic approach, based on cross-reactivity studies, in patients with a suspicion of BL hypersensitivity and an immediate need for antibiotic therapy, when referral to an allergist is not feasible. Furthermore, the update addresses availability and concentrations of skin test (ST) reagents, ST and drug provocation test (DPT) protocols, and diagnostic algorithms and administration of alternative BL in allergic subjects. Specifically, distinct diagnostic algorithms are suggested depending on risk stratification of the patient into high and low risk based on the morphology and chronology of the reaction, immediate (ie, occurring within 1-6 hours after the last administered dose) or nonimmediate (ie, occurring more than 1 hour after the initial drug administration), and the reaction severity. Regarding the allergy workup, the main novelty of this document is the fact that in some low-risk nonimmediate reactions ST are not mandatory, especially in children. For DPT, further studies are necessary to provide data supporting the standardization of protocols, especially of those regarding nonimmediate reactions, for which there is currently no consensus.

Controversies in drug allergy: Testing for delayed reactions.

Controversies exist with regard to in vivo approaches to delayed immunologically mediated adverse drug reactions, such as exanthem (maculopapular eruption), drug reaction with eosinophilia and systemic symptoms, acute generalized exanthematous pustulosis, Stevens-Johnson syndrome/toxic epidermal necrolysis, and fixed drug eruptions. In particular, widespread differences exist between regions and practice on the availability and use of intradermal and patch testing, the standard drug concentrations used, the use of additional drugs in intradermal and patch testing to help determine cross-reactivity, the timing of testing in relation to the occurrence of the adverse drug reaction, the use of testing in specific phenotypes, and the use of oral challenge in conjunction with delayed intradermal and patch testing to ascertain drug tolerance. It was noted that there have been advances in the science of delayed T cell-mediated reactions that have shed light on immunopathogenesis and provided a mechanism of preprescription screening in the case of HLA-B*57:01 and abacavir hypersensitivity and HLA-B*15:02 and carbamazepine Stevens-Johnson syndrome/toxic epidermal necrolysis in Southeast Asian subjects. Future directions should include the collaboration of large international networks to develop and standardize in vivo diagnostic approaches, such as skin testing and patch testing, combined with ex vivo and in vitro laboratory approaches.

Metal hypersensitivity in patients with orthopaedic implant complications-A retrospective clinical study.

BACKGROUND: Hypersensitivity to metals as a cause of implant-related complications has been a subject of controversy. Projections indicate an increase in the frequency of joint replacements of between 300% and 600% by the year 2030; therefore, this issue is of considerable interest. OBJECTIVE: To evaluate sensitization to implant materials in patients with implant-related complications, to identify allergens, and to clarify whether hypersensitivity is a relevant cause. METHODS: Patients with implant-related complications or a positive history of contact allergy and planned total joint replacements referred for allergological investigation between 2004 and 2017 were retrospectively analysed. RESULTS: In total, 311 patients were included. A positive patch test reaction to a metal was seen in 64.4% of preoperative patients and in 54.6% of patients with implant-related complications. Common alloy metals such as cobalt, chromium and titanium gave positive reactions in up to 2.9% of patients with implant-related complications. None of the patients with skin changes had a positive patch test reaction to an implant metal. CONCLUSION: Other factors, such as the type of replaced joint and mechanical stress, seem to be more relevant for implant-related complications. Sensitization to metals or other materials seems to rarely play a role, and is overestimated.

Delayed-type allergy to cobalt-comparison of a flow cytometric lymphocyte proliferation test with patch testing.

BACKGROUND: The patch test is the standard procedure for diagnosing delayed-type sensitization. If a patch test is not possible, the flow cytometric lymphocyte proliferation test (LPT), which determines the number and type of cells responding to a specific antigen in vitro, might be considered as an alternative. OBJECTIVES: Our aim was to establish a flow cytometric LPT for the detection of delayed-type allergic responses to cobalt, and to determine the correlation between stimulation indices (SIs) in LPT and the grade of patch test reactions. With the patch test as a diagnostic reference, we also assessed the sensitivity and specificity of the LPT. METHODS: Fifty-four patients patch tested with the baseline series including cobalt (CoCl2 ) were additionally tested with the flow cytometric LPT with CoCl2 . RESULTS: There was a significant correlation between the results of both tests: rs = 0.43; P = .001. The LPT with CoCl2 showed a sensitivity of 52.6% and a specificity of 85.7%. Corresponding to the low sensitivity of the LPT, high likelihood ratios for a positive patch test reaction were reached only in cases of strong lymphocyte proliferation (SI ≥ 10). CONCLUSIONS: In cases of clearly increased SIs, the flow cytometric LPT with CoCl2 gives relevant diagnostic information, and represents a valuable alternative to patch testing.

European Surveillance System on Contact Allergies (ESSCA): polysensitization, 2009-2014.

BACKGROUND: Polysensitization, defined as being allergic to three or more haptens from the European baseline series, is considered to reflect increased susceptibility to developing a contact allergy, and is likely to be associated with an impaired quality of life. OBJECTIVES: To evaluate the prevalences of polysensitization across Europe and to analyse factors associated with polysensitization. METHODS: Patch test data collected by the European Surveillance System on Contact Allergies (ESSCA; www.essca-dc.org) in consecutively patch tested patients from January 2009 to December 2014, comprising 11 countries and 57 departments, were retrospectively analysed. RESULTS: A total of 86 416 patients were available for analysis, showing a standardized prevalence of polysensitization of 7.02%, ranging from 12.7% (Austria) to 4.6% (Italy). Allergen pairs with the strongest association are reported for the total population, for South Europe, and for North/Central Europe. Overall, polysensitized patients showed a higher percentage of extreme (+++) positive patch test reactions than oligosensitized patients. Female sex, occupational dermatitis and age > 40 years were risk factors for polysensitization. CONCLUSIONS: The varying prevalences of polysensitization across Europe most likely reflect differences in patient characteristics and referral patterns between departments. Known risk factors for polysensitization are confirmed in a European dermatitis population.

Delayed-type hypersensitivity to oral and parenteral drugs.

Adverse drug reactions of the delayed type rank among the most common dermatoses and are predominantly characterized by exanthematous macular or maculopapular eruptions. However, approximately 2 % of affected individuals develop severe or even life-threatening systemic immune reactions associated with organ involvement, requiring immediate diagnosis and treatment. Numerous drugs are capable of eliciting delayed-type hypersensitivity reactions, with antibiotics, anticonvulsant drugs, and the xanthine oxidase inhibitor allopurinol being the most common. Apart from genetic susceptibility, predisposing factors for the development of drug hypersensitivity reactions include high drug doses, polypharmacy, long treatment duration, female gender, as well as acute or chronic infections.

Allergic contact dermatitis caused by a new temporary blue-black tattoo dye - sensitization to genipin from jagua (Genipa americana L.) fruit extract.

BACKGROUND: Temporary tattoos made with an extract of the jagua fruit (Genipa americana L.) are becoming increasingly popular. It is claimed that it is 'dermatologically tested' and does not contain p-phenylenediamine. Extracts of jagua and gardenia fruits have been used by indigenous people in South America, as well as in traditional Chinese medicine, for centuries. Genipin is currently used for its cross-linking effect in the manufacture of polysaccharides, and is being investigated for its anti-inflammatory and other properties. OBJECTIVES: To report the presence of the allergenic substance genipin in a self-administered temporary tattoo dye made from the fruit juice of jagua (Genipa americana L.). PATIENTS AND METHODS: A 39-year-old female who repeatedly applied 'completely natural and 100% safe' Earth Jagua® tattoo, obtained via the internet, to her left hand developed allergic contact dermatitis within 6 weeks. Analysis of the dye showed the presence of geniposide and genipin. RESULTS: Patch tests with the dye and with its main components, including genipin, gave strong positive reactions to the latter. There was no sensitization to other ingredients or p-amino compounds. CONCLUSIONS: We report an extensively evaluated case of allergic contact dermatitis caused by a temporary Earth Jagua® tattoo. The allergen identified is genipin, a substance that is increasingly used for tattoos and as a therapeutic agent in medicine. This could result in an increase in the number of allergic reactions in the future.

Thaumatin and gum arabic allergy in chewing gum factory workers.

Thaumatin is a sweetener and flavor modifier commonly used in the food industry. Likewise, gum arabic is widely used as a food stabilizer and thickening agent. We report here that a powder mixture composed of 10% thaumatin and 90% gum arabic led to allergic symptoms in the upper airways in occupationally exposed individuals: four of eight workers of a chewing gum factory exposed to this powder mixture had pronounced rhinitis. A positive skin prick test result for pure thaumatin was obtained in all four individuals with rhinitis of whom two also had a positive skin prick test result for pure gum arabic and gum arabic-specific IgE. Subsitution of a powdered thaumatin with a liquid form reduced symptoms among the rhinitic workers. Although gum arabic is a well-known potential allergen, we were unable to find prior documentation of allergic symptoms to thaumatin when it is used in the food industry.

Food allergy to the carbohydrate galactose-alpha-1,3-galactose (alpha-gal): four case reports and a review.

Until recently, food allergies to mammalian meats have been considered to be very rare. The observation that patients not previously exposed to the monoclonal chimeric antibody cetuximab suffered from severe anaphylaxis upon first exposure, led to the identification of galactose-alpha-1,3-galactose as a new relevant carbohydrate allergen. These patients later often suffered from anaphylactic reactions to red meat. Epidemiological data indicated that bites by the tick Amblyomma americanum in the USA, later also by Ixodes species in other continents, resulted in sensitisation to alpha-gal. On the other hand, in African patients with parasitic disorders, a high prevalence of anti-alpha-gal IgE, without clinical relevance, has been reported. In our four cases, one patient with a late onset of meat allergy had a history of a tick bite. The other three patients had symptoms from childhood or at a juvenile age. This indicates that in some patients, other ways of sensitisation may also take place. However, in patients without atopy, tick bite-induced IgE to alpha-gal may be more relevant. Diagnosis is based on a history of delayed onset of anaphylaxis. Skin tests with commercially available meat test solutions are often equivocal or negative; skin tests with raw meat and particularly pork kidney are more sensitive. Determination of specific IgE to alpha-gal is commercially available. The highest sensitivity is observed with skin and basophil activation tests with cetuximab which is, however, limited by its high costs.