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Background The diagnostic approach for beta-lactam (BL) drug hypersensitivity reactions (DHR) is based on the history, clinical signs, skin tests (ST), in vitro tests, and drug provocation tests (DPT). The aim of this study was to assess the performance of an allergy workup with ST in a real-world use. Methods In this cross-sectional study the rate of positive ST in subjects with suspected DHR to penicillins and cephalosporins was investigated. Of special interest were correlations of ST positivity: 1) to the time intervals between index reaction and the allergic work-up, 2) time interval from drug exposure to the onset of signs, 3) pattern of manifestation in delayed DHR and involvement of test area in the index reaction, and 4) potential advantage of patch testing in delayed DHR. Results 175 patients were included between January 2018 and April 2019 (63.4% female), 45 (25.7%) with immediate DHR manifestation and 130 with delayed DHR manifestation (74.3%). A total of 44 patients (25.1%) had a positive ST (immediate DHR 37.8% versus 20.0% in delayed DHR). ST positivity decreased in both groups after 3 years from 47.8% [95%CI 29.2–67] to 23.5% [95%CI 9.6–47.3] in immediate DHR and 23.0% [95%CI 15-4-32.9] to 12.9% [95%CI 5.1–28.9] in delayed DHR. The proportion of positive ST was higher in patients with more severe forms of delayed DHR, and in subjects with a shorter latency period of onset of symptoms after drug exposure: 0-3d: 29.5% [95%CI 19.6–41.9] vs. >3d: 11.6% [95%CI 6.0–21.2]). No sensitization was shown in delayed urticaria or angioedema. ST done outside the skin area involved during the index reaction were negative in all cases (0/38 vs. 26/84 in cases with involved area). The combination of patch test and intradermal test (IDT) revealed an additional positive result in 2/77 cases. Additional in vitro testing reduced the proportion of negative test results to 72%. Conclusion In most patients with negative test results, we could not clarify the cause of the BL-associated adverse events even with further investigations (including DPT). How to prevent new drug-induced adverse events in such patients has hardly been investigated yet. Corresponding cohort studies could improve the data situation.

Human leukocyte antigen (HLA) encoded by the HLA gene is an important modulator for immune responses and drug hypersensitivity reactions as well. Genetic polymorphisms of HLA vary widely at population level and are responsible for developing severe cutaneous adverse drug reactions (SCARs) such as Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS), maculopapular exanthema (MPE). The associations of different HLA alleles with the risk of drug induced SJS/TEN, DRESS and MPE are strongly supportive for clinical considerations. Prescribing guidelines generated by different national and international working groups for translation of HLA pharmacogenetics into clinical practice are underway and functional in many countries, including Thailand. Cutting edge genomic technologies may accelerate wider adoption of HLA screening in routine clinical settings. There are great opportunities and several challenges as well for effective implementation of HLA genotyping globally in routine clinical practice for the prevention of drug induced SCARs substantially, enforcing precision medicine initiatives.

Nonimmediate drug hypersensitivity reactions (niDHRs) range from mild-type maculopapular exanthema (MPE) to severe type Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with unentirely clarified pathogenesis. This study sought to explore whether complement components participated in niDHRs. The participants comprised of three groups as follows: MPE (n = 65), SJS/TEN (n = 13, contains 7 SJS, 2 SJS-TEN overlap and 4 TEN), and equal healthy controls (n = 78). Skin pathological changes were confirmed by hematoxylin and eosin staining. The mRNA and protein levels of complement components were assessed. In the MPE group, there were no alterations in complement components at the protein and mRNA levels found except for a decrease in factor H mRNA. In the SJS/TEN group, up-regulated levels of C3aR and C5aR mRNA and down-regulated factor H mRNA levels in blood were noted. A lower plasma protein level of C3, Factor H and a higher level of C3a, C5, C5a, C5b-9, Factor B (p

To characterize human leukocyte antigen (HLA) loci as risk factors in aromatic antiepileptic drug-induced maculopapular exanthema (AED-MPE). A case-control study was performed to investigate HLA loci involved in AED-MPE in a southern Han Chinese population. Between January 2007 and June 2019, 267 patients with carbamazepine (CBZ), oxcarbazepine (OXC), or lamotrigine (LTG) associated MPE and 387 matched drug-tolerant controls from six centers were enrolled. HLA-A/B/C/DRB1 genotypes were determined using sequence-based typing. Potential risk alleles were validated by meta-analysis using data from different populations and in silico analysis of protein-drug interactions. HLA-DRB1*04:06 was significantly associated with OXC-MPE (p = 0.002, pc = 0.04). HLA-B*38:02 was associated with CBZ-MPE (p = 0.03). When pooled, HLA-A*24:02, HLA-A*30:01, and HLA-B*35:01 additionally revealed significant association with AED-MPE. Logistic regression analysis showed a multiplicative interaction between HLA-A*24:02 and HLA-B*38:02 in CBZ-MPE. Meta-analysis of data from different populations revealed that HLA-24*:02 and HLA-A*30:01 were associated with AED-MPE (p = 0.02 and p = 0.04, respectively). In silico analysis of protein-drug interaction demonstrated that HLA-A*24:02 and HLA-A*30:01 had higher affinities with the three aromatic AEDs than the risk-free HLA-A allele. HLA-DRB1*04:06 showed relatively specific high affinity with S-monohydroxy derivative of OXC. HLA-DRB1*04:06 is a specific risk allele for OXC-induced MPE in the Southern Han Chinese. HLA-A*24:02, possibly HLA-A*30:01, are common risk factors for AED-MPE. The multiplicative risk potential between HLA-A*24:02 and HLA-B*38:02 suggests that patients with two risk alleles are at greater risk than those with one risk allele. Inclusion of these HLA alleles in pre-treatment screening would help estimating the risk of AED-MPE.

Evolocumab is a relatively new monoclonal antibody designed to decrease low-density lipoproteins via the inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9). It is used alone or in combination with other lipid-lowering agents. Evolocumab was associated with adverse events of skin rashes in clinical trials. We describe a rare case of maculopapular exanthema in a female patient with hyperlipidemia, which was treated with evolocumab. The patient was a 60-year-old female with hyperlipidemia who experienced a maculopapular rash after she was administered the second dose of evolocumab subcutaneously. The rash occurred on her torso and upper extremities and was associated with pruritus and mild wheezing. The hypersensitivity reaction was treated with antihistamines and with the discontinuation of evolocumab. The skin eruption cleared within 10 days. In conclusion, medical professionals should be aware of evolocumab skin hypersensitivity reactions, which could demand the cessation of the evolocumab treatment.

The immunomodulatory effects of regulatory T cells (Tregs) and co-signaling receptors have gained much attention, as they help balance immunogenic and immunotolerant responses that may be disrupted in autoimmune and infectious diseases. Drug hypersensitivity has a myriad of manifestations, which ranges from the mild maculopapular exanthema to the severe Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and drug reaction with eosinophilia and systemic symptoms/drug-induced hypersensitivity syndrome (DRESS/DIHS). While studies have identified high-risk human leukocyte antigen (HLA) allotypes, the presence of the HLA allotype at risk is not sufficient to elicit drug hypersensitivity. Recent studies have suggested that insufficient regulation by Tregs may play a role in severe hypersensitivity reactions. Furthermore, immune checkpoint inhibitors, such as anti-CTLA-4 or anti-PD-1, in cancer treatment also induce hypersensitivity reactions including SJS/TEN and DRESS/DIHS. Taken together, mechanisms involving both Tregs as well as coinhibitory and costimulatory receptors may be crucial in the pathogenesis of drug hypersensitivity. In this review, we summarize the currently implicated roles of co-signaling receptors and Tregs in delayed-type drug hypersensitivity in the hope of identifying potential pharmacologic targets.

Macrolides are one of the most widely used antibiotics, but the mechanisms underlying macrolide allergy have not been clearly elucidated. Diffuse maculopapular exanthema caused by clarithromycin is extremely rare, of which clinical images have not been reported. Here, we report a case of a 55-year-old Japanese female who was treated with oral clarithromycin and lysozyme hydrochloride due to odontogenic maxillary sinusitis. On the 15th day after starting both drugs, she suffered from diffuse maculopapular exanthema, which worsened despite the discontinuation of lysozyme hydrochloride and the introduction of treatment with oral and topical corticosteroids and oral levocetirizine. Clarithromycin was discontinued and an intravenous corticosteroid introduced on the 19th day. A lymphocyte transformation test was positive for clarithromycin but negative for lysozyme hydrochloride. Although adverse effects of clarithromycin are extremely rare, physicians should be aware of clarithromycin as a potential cause of a type IV allergic reaction.

Purpose of Review Quinolones are a group of synthetic antibiotics widely use as first-line treatment for many infections. There has been an increase in the incidence of hypersensitivity reactions to quinolones in recent years, likely due to increased prescription. The purpose of this review is to summarize the clinical pictures, the methods used for diagnosing and the management of allergic reactions to quinolones. Recent Findings Allergic reactions to quinolones can be immediate or delayed, being anaphylaxis and maculopapular exanthema respectively the most frequent clinical entities. A precise diagnosis is particularly difficult since clinical history is often unreliable, skin tests can induce false-positive results, and commercial in vitro test are not well validated. Therefore, drug provocation testing is considered the gold standard to establish diagnosis, which is not a risk-free procedure. Cross-reactivity between quinolones is difficult to predict due to the small number of patients included in the few published studies. Moreover, hypersensitivity to quinolones has also been associated with beta-lactam and neuromuscular blocking agent allergies, although further studies are needed to understand the underlying mechanisms. Avoidance of the culprit quinolone is indicated in patients with a diagnosis of hypersensitivity to these drugs. When quinolone treatment is the only therapeutic option available, desensitization is necessary. Summary This review summarizes the complex diagnostic approach and management of allergic reactions to quinolones.

In the article “Genetic variation in CFH predicts phenytoin-induced maculopapular exanthema in European-descent …

Glioblastoma is the most common form of primary brain cancer. Its treatment involves surgery, radiotherapy, and chemotherapy with temozolomide (TMZ), which is an oral alkylating agent. To the best of our knowledge, few dermatologic side effects of TMZ have been described. We report two cases of cutaneous drug eruption caused by TMZ during and after radiochemotherapy treatment. In the first case, all tests were negative, but the clinical history and the time of onset supported an allergy to TMZ. In the second case, an allergy to TMZ was proved by a positive lymphocyte activation test. In this context, our study is one of a very few trying to determine dermatologic side effects by applicable tests used in routine practice.

Dursun, A. Berna/0000-0002-6337-6326 WOS: 000346025100001 PubMed: 25685161 Background: Allopurinol is an effective urate-lowering drug that is well tolerated by the majority of patients. Patients with chronic renal insufficiency have an increased risk of hypersensitivity reactions with allopurinol. Case presentation: 75 year old male patient with gout, renal insufficiency, history of metastatic colorectal carcinoma status post-resection was referred to Allergy clinic for a maculopapular eruption that developed 1 week after initiating therapy with allopurinol. the rash resolved with discontinuation of allopurinol. However, his serum urate level rose to 19.9 mg/dl. We initially proposed a slow 4 week oral allopurinol desensitization. the treating nephrologist felt it was critical to lower urate more rapidly. As a result, we modified the dose and standard 4 week protocol down to 2 weeks. A suspension of allopurinol was prepared by the allergy nurse practitioner with a 300 mg allopurinol tablet. the sensitization protocol was modified as a starting dose of 0.3 mg escalating to a final dose of 300 mg/day in 2 weeks. There was no reaction during or after the desensitization. the patient's urate level normalized (6.3 mg/dl) and has continued on 300 mg allopurinol daily without reaction. Conclusion: A 2 week modified allopurinol desensitization protocol is a safe alternative for elderly patients with multiple comorbidities.

Apart from gastroenteritis, rotavirus has been rarely implicated with some cutaneous disorders such as generalized maculopapular exanthema, infantile acute hemorrhagic edema and Gianotti-Crosti syndrome. We report a 30-month old toddler boy who developed erythematous macular skin eruptions during the course of rotavirus gastroenteritis. To our knowledge, this is the first case in the literature reporting rotavirusrelated macular erythematous lesions in a pediatric patient. We therefore would like to share our experience, to keep rotavirus infection in the differential diagnosis of children with gastroenteritis and erythematous eruption. Keyword: Rotavirus, gastroenteritis, child, erythema.

Objective To systematically review evidence on genetic risk factors for carbamazepine (CBZ)-induced hypersensitivity reactions (HSRs) and provide practice recommendations addressing the key questions: (1) Should genetic testing for HLA-B15:02 and HLA-A31:01 be performed in patients with an indication for CBZ therapy to reduce the occurrence of CBZ-induced HSRs? (2) Are there subgroups of patients who may benefit more from genetic testing for HLA-B15:02 or HLA-A31:01 compared to others? (3) How should patients with an indication for CBZ therapy be managed based on their genetic test results? Methods A systematic literature search was performed for HLA-B15:02 and HLA-A31:01 and their association with CBZ-induced HSRs. Evidence was critically appraised and clinical practice recommendations were developed based on expert group consensus. Results Patients carrying HLA-B15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) in populations where HLA-B15:02 is common, but not CBZ-induced hypersensitivity syndrome (HSS) or maculopapular exanthema (MPE). HLA-B15:02-positive patients with CBZ-SJS/TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B15:02 is rare among Caucasians or Japanese; no HLA-B15:02-positive patients with CBZ-SJS/TEN have been reported so far in these groups. HLA-A31:01-positive patients are at increased risk for CBZ-induced HSS and MPE, and possibly SJS/TEN and acute generalized exanthematous pustulosis (AGEP). This association has been shown in Caucasian, Japanese, Korean, Chinese, and patients of mixed origin; however, HLA-A31:01 is common in most ethnic groups. Not all patients carrying either risk variant develop an HSR, resulting in a relatively low positive predictive value of the genetic tests. Significance This review provides the latest update on genetic markers for CBZ HSRs, clinical practice recommendations as a basis for informed decision making regarding the use of HLA-B15:02 and HLA-A31:01 genetic testing in patients with an indication for CBZ therapy, and identifies knowledge gaps to guide future research. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. © 2014 International League Against Epilepsy.

Investigators at the Taipei Medical University Hospital and other centers in Taiwan conducted a case-control study in 2002-2014 among 105 cases with phenytoin-related severe cutaneous adverse reactions (n = 61 Stevens-Johnson syndrome/toxic epidermal necrolysis and n = 44 drug reactions with eosinophilia and systemic symptoms), 78 cases with maculopapular exanthema, 130 phenytoin-tolerant control participants, and 3655 population controls from Taiwan, Japan, and Malaysia.

Chloramphenicol is a broad spectrum antibiotic that acts by inhibiting protein synthesis. Though systemic use is rare, their topical preparations are commonly used. Allergic reaction due to chloramphenicol ear drops are less reported. Here, we have reported a maculopapular exanthema due to use of chloramphenicol ear drops.

Results Ninety patients were evaluated, 54 male, with a median age of 6 years. Personal history of atopy was reported in 65 and previous DHR in 9. Cutaneous manifestations were observed in 86 – urticaria and/or angioedema in 71 and macular or maculopapular exanthema in 15. Other symptoms reported were: respiratory (25), gastrointestinal (8), cardiovascular (5). The interval between dose and reaction was less than 1 hour in 38 subjects. Mild reaction was observed in 32 patients and moderate in 55. Fever and/or viral infection were present in 61 patients during or just before the reaction. The majority of subjects were treated in emergency units (79). More than one drug was suspected as a trigger in 50 children (NSAIDs in 50%, beta-lactam antibiotics in 31% and other antibiotics in 8.5%). Sixteen skin tests (prick and intradermal) were performed and were all negative but one with amoxicilin. Drug provocation tests were positive in 4 of 51 tests NSAIDs 29 (4 positive), beta-lactam antibiotics 20 and others 4. Sixty-one reactions were possible or probable related with the suspected drug, but in 25 this relation was unlikely.

Background Immune-mediated cutaneous adverse drug reactions (CADR) present under different clinical patterns, some different from the main phenotypes of CADR. Our objective is to characterize manifestations and culprit drugs in CADR that required hospitalization, particularly exanthema associated with few systemic symptoms without fulfilling the European DRESS criteria (MP/DR).

Editor,—We examined a 33-year-old woman with a week long history of a progressively inflamed left eye who showed oculoglandular conjunctivitis and a marginal corneal ulcer. Three days later she presented with fever and cutaneous maculopapular exanthema. The patient revealed that 2 weeks earlier a jet of blood had splashed into her left eye as she accidentally crushed a tick on her dog. Blood samples from the patient were positive to the Weil–Felix test; therefore, Mediterranean spotted fever was diagnosed. Systemic and topical treatment with tetracyclines was successful. The possibility that spotted fever may be acquired through the eye should be kept in mind. ### CASE REPORT A previously healthy 33-year-old woman was admitted with a week long history of a progressively painful and inflamed left eye. She had eyelid erythema and swelling, mucopurulent discharge, marked conjunctival hyperaemia, …