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.

Developing a cosmetic series: Results from the ESSCA network, 2009-2018.

BACKGROUND: There is considerable variability across European patch test centres as to which allergens are included in local and national cosmetics series. OBJECTIVES: To propose a standardized, evidence-based cosmetic series for Europe based on up-to-date analysis of relevant contact allergens. METHODS: We collated data from the European Surveillance System on Contact Allergies (ESSCA) from 2009 to 2018 to determine which cosmetic allergens produce a high yield of contact allergy. Contact allergens with a prevalence of >0.3% that were considered relevant were included. Rare contact allergens were excluded if deemed no longer relevant or added to a supplemental cosmetic series for further analysis. RESULTS: Sensitization prevalences of 39 cosmetic contact allergens were tabulated. Thirty of these allergens yielded >0.3% positive reactions and are therefore included in our proposed European cosmetic series. Six were considered no longer relevant and therefore excluded. Three were included in a supplementary European cosmetic series. An additional nine allergens were included in either the core or supplemental European cosmetic series following literature review. CONCLUSION: We have derived a potential European cosmetic series based upon the above methods. This will require ongoing investigation based upon the changing exposure profiles of cosmetic allergens as well as new and evolving substances.

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.

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.

Structured diagnostic assessment of hand eczema in cleaning workers.

Hand dermatitis is a widespread problem among cleaners. In most cases, it is caused by a combination of wet work and contact with irritants, which can result in irritant (toxic) contact dermatitis. In some cases, the irritant contact eczema then evolves into allergic contact dermatitis, although not all cases of allergic contact dermatitis are preceded by irritant contact dermatitis. This mini-review proposes a two-step diagnostic algorithm based on patch testing, which can be used if allergic contact dermatitis is suspected in cleaning workers. As a first step, we recommend performing the DKG standard series (German Contact allergy research group, DKG), the DKG rubber series, both DKG "further fragrances" series as well as the DKG preservative and disinfectant series. If there are clear hints of an occupational contact dermatitis, the first step can also involve testing patients' own products alongside the standardized tests. In a second step (at the latest), if standardized tests do not suffice to identify the culprit allergen and there is well-founded suspicion, we recommend testing the patients' own products. If necessary, the second step can also include testing the individual contact allergens contained in the screening mixes that are part of the standard series.

Genetic variants associated with T cell-mediated cutaneous adverse drug reactions: A PRISMA-compliant systematic review-An EAACI position paper.

Drug hypersensitivity reactions (DHRs) are associated with high global morbidity and mortality. Cutaneous T cell-mediated reactions classically occur more than 6 hours after drug administration and include life-threatening conditions such as toxic epidermal necrolysis, Stevens-Johnson syndrome, and hypersensitivity syndrome. Over the last 20 years, significant advances have been made in our understanding of the pathogenesis of DHRs with the identification of human leukocyte antigens as predisposing factors. This has led to the development of pharmacogenetic screening tests, such as HLA-B*57:01 in abacavir therapy, which has successfully reduced the incidence of abacavir hypersensitivity reactions. We have completed a PRISMA-compliant systematic review to identify genetic associations that have been reported in DHRs. In total, 105 studies (5554 cases and 123 548 controls) have been included in the review reporting genetic associations with carbamazepine (n = 31), other aromatic antiepileptic drugs (n = 24), abacavir (n = 11), nevirapine (n = 14), trimethoprim-sulfamethoxazole (n = 11), dapsone (n = 4), allopurinol (n = 10), and other drugs (n = 5). The most commonly reported genetic variants associated with DHRs are located in human leukocyte antigen genes and genes involved in drug metabolism pathways. Increasing our understanding of genetic variants that contribute to DHRs will allow us to improve diagnosis, develop new treatments, and predict and prevent DHRs in the future.

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.

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.

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.

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

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

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.

Chronic hand eczema: A prospective analysis of the Swiss CARPE registry focusing on factors associated with clinical and quality of life improvement.

BACKGROUND: Hand eczema (HE) is common and may follow a chronic disease course. So far, prospective studies investigating the risk factors for disease progression as a prerequisite for targeted prevention are scarce. OBJECTIVE: To evaluate the overall association of HE-associated factors with clinical and quality of life (QoL) improvement during a follow-up of 2 years. METHODS: Data of the prospective patient cohort (N = 199) followed by the Swiss chronic HE (CHE) registry on long-term patient management (CARPE-CH) were analysed by means of both classic regression and semantic map analyses. RESULTS: Both severity of HE and QoL significantly improved over the period of 2 years (P < .001). However, 20% of patients had moderate to severe HE after 2 years of follow-up. As factors associated with an unfavourable CHE clinical course and QoL, environmental exposures, male sex, occupational skin disease, job loss or change at baseline, allergic contact dermatitis, a chronic disease course, palmar localization and widespread eczema were identified. CONCLUSIONS: Analysis of prospective data from CARPE-CH shows a complex pattern of associations among variables as shown by semantic map and classic statistical analyses. Factors related to occupational exposure had the highest impact on CHE.

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.

The risk of Stevens-Johnson syndrome and toxic epidermal necrolysis in new users of antiepileptic drugs.

OBJECTIVE: Older antiepileptic drugs (AEDs) are known to cause Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN). However, evidence for newer AED is sparse. We quantified risks of SJS/TEN in association with use of all AEDs in the United Kingdom. METHODS: In a matched case-control study of 480 previously validated SJS/TEN cases (1995-2013) we used conditional logistic regression to calculate odds ratios (ORs) with 95% confidence intervals (CIs), and calculated absolute risks of SJS/TEN within separate cohorts of new users of 28 AEDs. We assessed causality between drugs and SJS/TEN in each exposed case, using an adapted version of the algorithm of drug causality for epidermal necrolysis (ALDEN) score. RESULTS: We observed a strong association between SJS/TEN and new use of carbamazepine (OR 92.57, 95% CI 19.89-∞), phenytoin (OR 49.96, 95% CI 10.13-∞), and lamotrigine (OR 26.90, 95% CI 4.88-∞), where causality, according to the ALDEN score, was very probable or probable for most exposed cases. Absolute risks for SJS/TEN were highest for phenytoin (45.86 cases/100,000 exposed), lamotrigine (44.17 cases/100,000 exposed), and carbamazepine (20.38 cases/100,000 exposed). Despite increased ORs for valproate (40,941 exposed), gabapentin (116,037 exposed), pregabalin (59,967 exposed), and clobazam (4,300 exposed), ALDEN suggested no causal association. There were no observed cases of SJS/TEN among new users of levetiracetam (n = 96,77), clonazepam (n = 18,075), or topiramate (n = 11,307). SIGNIFICANCE: The results of our study are consistent with those of previous studies of SJS/TEN, which found increased risks of SJS/TEN in new use of carbamazepine, phenytoin, and lamotrigine. Despite frequent use, no ALDEN-score confirmed cases were observed in new users of valproate, gabapentin, pregabalin, levetiracetam, topiramate, or clonazepam.

Validation of Stevens-Johnson syndrome or toxic epidermal necrolysis diagnoses in the Clinical Practice Research Datalink.

PURPOSE: To evaluate the validity of recorded diagnoses of Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in the Clinical Practice Research Datalink (CPRD). METHODS: We identified patients with a diagnosis of SJS or TEN between 1995 and 2013 in the CPRD. We reviewed information from patient records, free text, and hospital episode statistics (HES) data, and excluded patients with no indication of a secondary care referral. Remaining patients were classified as probable, possible, or unlikely cases of SJS/TEN by two specialised clinicians or based on pre-defined classification criteria. We quantified positive predictive values (PPV) for all SJS/TEN patients and for patients categorised as 'probable/possible' cases of SJS/TEN, based on a representative subsample of 118 patients for whom we had unequivocal information (original discharge letters or HES data). RESULTS: We identified 1324 patients with a diagnosis of SJS/TEN, among whom 638 had a secondary care referral recorded. Of those, 565 were classified as probable or possible cases after expert review. We calculated a PPV of 0.79 (95% CI, 0.71-0.86) for all SJS/TEN patients with a recorded secondary care referral, and a PPV of 0.87 (95% CI, 0.81-0.93) for probable/possible cases. After excluding 14 false positive patients, our study population consisted of 551 SJS/TEN patients. CONCLUSIONS: Diagnoses of SJS/TEN are recorded with moderate diagnostic accuracy in the CPRD, which was substantially improved by additional expert review of all available information. We established a large population-based SJS/TEN study population of high diagnostic validity from the CPRD. Copyright © 2016 John Wiley & Sons, Ltd.