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Tuberculosis (TB) is the most common, treatable and curable chronic infectious disease rampant in the developing countries. Anti-TB medications may be associated with several adverse effects including cutaneous reactions. Maculopapular exanthemas (MPE) are small cutaneous reddish macules and papules. Here we present 3 tuberculosis cases, treated with antitubercular therapy (ATT) enrolled in the outpatient department of Dermatology. Chief complaints were generalized rashes with itching and redness over the body. ATT was instantly stopped. Antihistamine, corticosteroid and topical emollients were administered to all the three patients. After 3 weeks, these patients recovered (dechallenge positive). For confirmation of ATT induced maculopapular rashes and to pin down the culprit drug, sequential rechallenge with individual ATT components was performed. Similar cutaneous eruptions were observed over the body with pyrazinamide in one case and with rifampicin in the other two cases (rechallenge positive). Symptoms of rechallenge resolved with antihistamine, steroids in 10 days. To restart ATT safely, re-challenge remains the best option and continue with alternative efficient anti-TB drugs as TB requires extensive therapy. Close, vigilant monitoring of ATT patients especially those on rifampicin and pyrazinamide must be done as these may precipitate MPE. Strict pharmacovigilance measures helps in early detection, timely management and prevent ATT induced ADRs. This is pivotal to promote safer drug utilization and help to achieve better prognostic outcomes. [ABSTRACT FROM AUTHOR]

Background: Penicillin-associated exanthems in the setting of infectious mononucleosis caused by Epstein-Barr virus (EBV) are often viewed as a transient event, not a true allergy. Recent evidence challenges this and suggests that a notable subset of patients retain penicillin hypersensitivity. Objective: We investigated the occurrence and predictors of persistent adulthood hypersensitivity in those with penicillin-associated rash occurring in the setting of EBV infection. Methods: Retrospective analysis of data of patients referred for penicillin allergy testing to an Australian tertiary-care hospital captured from 2015 to 2023 was carried out. Results: Of 2066 patients, 23 (1%) had penicillin-associated rash during an historic EBV infection; 16 (70%) were female; and median (interquartile range) age was 18 (16-20) years at index reaction and 38 (33.5-57) years at allergy testing. Skin prick testing and delayed intradermal testing to a penicillin panel were performed, followed by oral provocation challenge in those testing negative. Persistent sensitization was shown in 6 (26%) of 23; 4 (67%) of 6 positive delayed intradermal testing; and 3 (50%) of 6 had positive oral challenge test. Notably, 5 (83%) of 6 had a severe maculopapular exanthem with facial swelling, including 2 (33%) of 6 with probable drug reaction with eosinophilia and systemic symptoms (aka DRESS) during the index reaction, compared to 0 of 17 in patients tolerating penicillin on reexposure. Conclusion: This study highlights the requirement of allergy testing in adult patients reporting a penicillin-associated severe maculopapular exanthem in the setting of EBV, even if it occurred during childhood or adolescence.

The majority of viral rashes occurring during an antibiotic therapy are considered as a drug hypersensitivity reaction (DHR). Differentiating a viral rash versus a DHR is difficult or even impossible. In delayed DHRs the interplay between viruses and drugs is summarized according to the recent literature. The question is if the same reaction will again occur in case of drug re-exposure in absence of the concomitant viral infection because of persistent immune reactivity. Epstein Barr Virus (EBV) and Human Herpes virus 6 (HHV-6) models are analyzed in case of maculopapular exanthemas (MPEs) and drug reaction with eosinophilia and systemic symptoms (DRESS) over a course of drug therapy. MPEs are the most common skin manifestation during a viral infection and a concomitant drug therapy. In type IVb reactions to drugs a hapten/pro-hapten mechanism and a pharmacological interaction (p-i mechanism) are described as the 2 major ways to make T cells response functional. Rarely the altered repertoire model is involved. The Human Leukocyte Antigen (HLA) predisposition is an additional essential factor that can facilitate DHR. In MPEs rarely a DHR is confirmed by allergy testing. Severity and duration of MPEs, the presence of eosinophilia and systemic symptoms make more reliable the persistent nature of the reaction. Research on this topic is needed in order to provide the clinicians with instruments to decide when to suspect future reactions upon drug re-exposure even in the absence of a viral infection, because those patients should be investigated by a complete drug allergy work up.

A considerable number of pediatric patients treated with beta-lactam (BL) antibiotics develop delayed onset of skin rashes during the course of treatment. Although the most frequent cause of these symptoms is infectious, many cases are labeled as allergic reactions to these drugs. BL allergy labels could have a negative impact, as they imply avoidance of this group of drugs and the use of second-line antibiotics, leading to a potential increase in adverse effects and the utilization of less effective therapies. This constitutes a major public health concern and economic burden, as the use of broad-spectrum antibiotics can result in multidrug-resistant organisms and prolonged hospital stays. Therefore, it is crucial to delabel patients during childhood to avoid false labeling in adult life. Although the label of BL allergy is among the most frequent causes of allergy referral, its management remains controversial, and new diagnostic perspectives are changing the paradigm of managing BL allergies in children. Traditionally, drug provocation testing (DPT) was exclusively performed in patients who had previously obtained negative results from skin tests (STs). However, the sensitivity of STs is low, and the role of in vitro testing in the pediatric population is not well defined. Recent studies have demonstrated the safety of direct DPT without prior ST or serum tests for pediatric patients who report a low-risk reaction to BLs, which is cost-effective. However, there is still a debate on the optimal allergic workup to be performed in children with a benign immediate reaction and the management of children with severe cutaneous adverse drug reactions. In this review, we will discuss the impact of the label of BL allergy and the role of the different tools currently available to efficiently address BL allergy delabeling in children.

Antibiotics, case series, children, cutaneous adverse drug reactions, drug hypersensitivity, maculopapular exanthema, patch test, DRESS syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis Keywords: antibiotics; case series; children; cutaneous adverse drug reactions; DRESS syndrome; drug hypersensitivity; maculopapular exanthema; patch test; Stevens-Johnson syndrome; toxic epidermal necrolysis EN antibiotics case series children cutaneous adverse drug reactions DRESS syndrome drug hypersensitivity maculopapular exanthema patch test Stevens-Johnson syndrome toxic epidermal necrolysis 373 376 4 09/08/22 20221001 NES 221001 Non-immediate cutaneous adverse drug reactions (CADRs) are mostly clinical manifestations of a Type IV hypersensitivity reaction.1,2 In children, diagnosing CADRs is a common challenge for physicians, as childhood rashes are more often due to viral infections but frequently mimic CADRs.1,2 A proper diagnosis and identification of the culprit drug avoids misdiagnosis, therefore, preventing unnecessary drug avoidance or replacement, and guides for potential alternatives reducing morbidity from CADRs.1-3 Patch tests (PT) are considered useful for diagnosing non-immediate CADRs, however, few paediatric studies have been published.2-6 This may be related to the lower incidence of CADRs in children, the lack of PT standardization especially for severe cutaneous adverse reactions (SCARs) and controversies on PT safety, particularly in this population.3-5,7 This study aimed to evaluate the sensitivity and safety of PT for paediatric CADRs. [Extracted from the article]

Abstract Background The relationship between the HLA-B*1502 gene and maculopapular exanthema (MPE) induced by antiepileptic drugs (AEDs) has not yet been elucidated. In this study, we investigated the association between AED-induced MPE (AED-MPE) and the HLA-B*1502 gene in patients in Northwest China. Methods We enrolled 165 subjects including nine patients with AED-MPE and 156 AED-tolerant patients as controls. HLA-B*1502 gene polymorphism was detected using digital fluorescence molecular hybridization (DFMH). The results of HLA genotyping were expressed as positive or negative for the HLA-B*1502 allele. An analysis of AED-MPE risk factors was performed using binary logistic regression, and differences in genotype frequencies between groups were assessed with the continuity correction chi-square test. Results We found that the HLA-B*1502 gene was a risk factor for AED-MPE (P = 0.028). The incidence of MPE induced by the two types of AEDs was different, and the incidence of aromatic AEDs use was higher that of non-aromatic AEDs use (P = 0.025). The comparison of the gene frequencies of the HLA-B*1502 allele between the two groups taking aromatic AEDs was also statistically significant (P = 0.045). However, there were no significant differences in terms of age, gender, ethnicity, or region in patients with MPE induced by AEDs. In addition, no association between the HLA-B1502 allele and CBZ- or OXC-induced MPE was found. Conclusions In northwestern China, the HLA-B*1502 allele was associated with aromatic AED-MPE. Since MPE can develop into Stevens–Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the HLA-B*1502 gene should be evaluated before administering AEDs.

Copyright of Revue Francaise d'Allergologie is the property of Elsevier B.V. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background: Patch tests (PTs) with two readings have been used for decades to identify the culprit drug in nonimmediate cutaneous adverse drug reactions (NICADRs), followed more recently by late reading of intradermal tests (IDTs). Some teams tend to perform PTs with only one reading before IDTs or even directly perform IDTs. Objectives: To evaluate the relevance of a late PT reading on day 4 (D4) in NICADRs. Methods: We retrospectively selected patients who had a PT for an NICADR between July 2014 and March 2020. Results: During the study period, 328 patients had a PT with available results. Among the 75 positive‐PT patients with available data for the two readings, 41 (54.7%) had positive results on D2 and D4 and 34 (45.3%) had negative results on D2 but positive results on D4. No patient had positive results on D2 and negative results on D4. Conclusion: This study shows that a D4 reading enhanced the PT‐positive results. A positive PT result allows for reducing the number of IDTs, which are more difficult and costly to perform. Our series suggests that a late PT reading at D4 should be performed for exploring NICADRs. [ABSTRACT FROM AUTHOR]

Background: The relationship between the HLA-B*1502 gene and maculopapular exanthema (MPE) induced by antiepileptic drugs (AEDs) has not yet been elucidated. In this study, we investigated the association between AED-induced MPE (AED-MPE) and the HLA-B*1502 gene in patients in Northwest China.Methods: We enrolled 165 subjects including nine patients with AED-MPE and 156 AED-tolerant patients as controls. HLA-B*1502 gene polymorphism was detected using digital fluorescence molecular hybridization (DFMH). The results of HLA genotyping were expressed as positive or negative for the HLA-B*1502 allele. An analysis of AED-MPE risk factors was performed using binary logistic regression, and differences in genotype frequencies between groups were assessed with the continuity correction chi-square test.Results: We found that the HLA-B*1502 gene was a risk factor for AED-MPE (P = 0.028). The incidence of MPE induced by the two types of AEDs was different, and the incidence of aromatic AEDs use was higher that of non-aromatic AEDs use (P = 0.025). The comparison of the gene frequencies of the HLA-B*1502 allele between the two groups taking aromatic AEDs was also statistically significant (P = 0.045). However, there were no significant differences in terms of age, gender, ethnicity, or region in patients with MPE induced by AEDs. In addition, no association between the HLA-B1502 allele and CBZ- or OXC-induced MPE was found.Conclusions: In northwestern China, the HLA-B*1502 allele was associated with aromatic AED-MPE. Since MPE can develop into Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN), the HLA-B*1502 gene should be evaluated before administering AEDs. [ABSTRACT FROM AUTHOR]

Copyright of Ginecología y Obstetricia de México is the property of Federacion Mexicana de Ginecologia y Obstetricia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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.

Keywords: drug reaction with eosinophilia and systemic symptoms; maculopapular exanthema; microRNAs EN drug reaction with eosinophilia and systemic symptoms maculopapular exanthema microRNAs 3279 3283 5 12/03/20 20201201 NES 201201 Abbreviations cADR atopic dermatitis DRESS drug reaction with eosinophilia and systemic symptoms HC healthy controls MiRNA microRNA MPE maculopapular exanthema PCA principal component analyses To the Editor, The diagnosis of drug reaction with eosinophilia and systemic symptoms (DRESS), is challenging due to its heterogeneous clinical presentation and complex natural course.1 It is therefore sometimes difficult, at an early stage, to differentiate between maculopapular exanthema (MPE) and DRESS due to overlapping clinical presentations.2,3 To better characterize cutaneous adverse drug reactions (cADRs), several approaches have been proposed. Briefly, skin and blood samples were obtained from MPE (n = 6) patients, DRESS (n = 6) patients and HCs (n = 6). Overall, these 34 miRNA-based signatures correctly separated MPE and DRESS patients, except for 2 MPE patients (E2 and E4; Table 1) with herpes viral replication, who had skin miRNA expression profiles more similar to DRESS. Only blood miR-185-3p was significantly higher in MPE compared to HC samples (FC x1.5, adjusted I P i -value.03) (Appendix S3), and none of the blood miRNAs were differentially expressed between DRESS and HC patients, probably due to small sample size. [Extracted from the article]

Objective: This study aimed to describe the genetic and clinical risk factors associated with phenytoin‐induced cutaneous adverse drug reactions (PHT‐induced cADRs) in Thai patients. Method: A retrospective case‐control study was conducted among 88 PHT‐ cADRs (25 SJS/TEN, 37 DRESS/DIHS and 26 MPE) compared to 70 PHT‐tolerant controls during 2008‐2017. Genotyping was performed by Taqman RT‐PCR (EPHX1 337 T > C, EPHX1 416A > G and CYP2C9*3), pyrosequencing (UGT1A1*28, UGT1A1*6) and polymerase chain reaction‐sequence‐specific oligonucleotide probe (HLA‐B). Chi‐squared test and binary logistic regression were used to identify factors associated with PHT‐cADRs. Results: Multivariate analysis showed that HLA‐B*46:01 was significantly associated with all PHT‐induced cADRs (OR 2.341; 95% CI, 1.078‐5.084; P =.032). Age of ≥60 years showed a significant association with PHT‐induced SJS/TEN (OR 3.600; 95% CI, 1.214‐10.672; P =.021). CYP2C9*3 was almost reaching statistically associated with an increased risk of PHT‐induced SJS/TEN (OR 4.800; 95% CI, 0.960‐23.990; P =.056). While HLA‐B*56:02/04 was found to have a significant association with PHT‐induced DRESS/DIHS (OR 29.312; 95% CI, 1.213‐707.994; P =.038). Moreover, female gender and HLA‐B*40:01 were associated with an increased risk of PHT‐induced MPE at OR 5.734; 95% CI, 0.910‐58.351; P =.042 and OR 3.647; 95% CI, 1.193‐11.147; P =.023, respectively. Conclusion: Both clinical (advanced age, female gender) and genetic factors (HLA‐B*46:01, CYP2C9*3, HLA‐B*56:02/04 and HLA‐B*40:01) contributed to the risk of PHT‐induced cADRs. Further studies with larger sample size may be warranted to confirm these findings and also the influence of EPHX1 gene. [ABSTRACT FROM AUTHOR]

Background: Drug‐induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4+ T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint inhibitor Tim3 and its physiological ligand galectin‐9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3‐Gal9 axis on the development of MPE induced by drugs. Methods: Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT‐qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3‐Gal9 axis on monocyte‐derived dendritic cell (moDC) maturation and T‐cell proliferation were determined by flow cytometry. Results: The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3+ Th1 proliferation, although Treg proliferation increased. Conclusion: This study showed the involvement of the Tim3‐Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions. [ABSTRACT FROM AUTHOR]

Purpose: To report a childhood case of tumor necrosis factor receptor-associated periodic syndrome (TRAPS) carrying the R92Q variant with a vision-threatening bilateral panuveitis.Methods: Case report and review of the literature.Results: A 7-year-old boy presented with an active bilateral panuveitis and a macular rash associated with fever. Fundus examination showed two choroidal lesions on the posterior pole of the right eye, and fluorescein angiography revealed early hypofluorescence and late hyperfluorescence of the lesions, which were hyper-autofluorescent. Extensive clinical laboratory analyses ruled out autoimmune diseases and systemic infection. The only remarkable finding was a positive IgG for herpes simplex 1. He underwent two successive diagnostic pars plana vitrectomies as well as cataract and glaucoma surgeries. Genetic analysis revealed a mutation in the TNFRSF1A gene, and the patient was diagnosed with TRAPS-associated bilateral panuveitis. He was treated with adalimumab and has been free of active inflammation since then.Conclusions: We present here the first case reported of panuveitis in a patient with TRAPS. This finding stresses the increasing importance of genetic analysis in search of autoinflammatory diseases to establish an adequate diagnosis and treatment in cases of uveitis of unknown etiology. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Multiple drug hypersensitivity (MDH) is a syndrome that develops as a consequence of massive T-cell stimulations and is characterized by long-lasting drug hypersensitivity reactions (DHR) to different drugs. The initial symptoms are mostly severe exanthems or drug rash with eosinophilia and systemic symptoms (DRESS). Subsequent symptoms due to another drug often appear in the following weeks, overlapping with the first DHR, or months to years later after resolution of the initial presentation. The second DHR includes exanthema, erythroderma, DRESS, Stevens-Johnson syndrome/ toxic epidermal necrolysis (SJS/TEN), hepatitis, and agranulocytosis. The eliciting drugs can be identified by positive skin or in vitro tests. The drugs involved in starting the MDH are the same as for DRESS, and they are usually given in rather high doses. Fixed drug combination therapies like sulfamethoxazole/trimethoprim or piperacillin/tazobactam are frequently involved in MDH, and 30-40% of patients with severe DHR to combination therapy show T-cell reactions to both components. The drug-induced T-cell stimulation appears to be due to the p-i mechanism. Importantly, a permanent T-cell activation characterized by PD-1+/CD38+ expression on CD4+/CD25 low T cells can be found in the circulation of patients with MDH for many years. In conclusion, MDH is a drug-elicited syndrome characterized by a long-lasting hyperresponsiveness to multiple, structurally unrelated drugs with clinically diverse symptoms. [ABSTRACT FROM AUTHOR]

Background The introduction of pegylated interferon (PEG- IFN)-α in the treatment of chronic hepatitis C has led to an increase in sustained virological response. Despite reduced immunogenicity of the pegylated form in comparison with native interferon ( IFN)-α, a high frequency of adverse cutaneous reactions has been reported with pegylated IFN-α. Here, we aimed to investigate the immunological mechanisms underlying pegylated IFN-α-induced drug eruptions. Methods Hepatitis C patients suffering from drug eruptions in association with administration of pegylated interferons were enrolled in the study ( n = 22). Subjects were tested for sensitivity to pegylated IFN-α2a, pegylated IFN-α2b, or ribavirin using intradermal, scratch, and/or patch tests, as well as lymphocyte activation tests ( LATs). Skin biopsies obtained from pegylated IFN-α-associated exanthemas, as well as from localized inflammatory skin reactions at pegylated IFN-α injection sites, were analyzed for the expression of relevant chemokines by quantitative real-time PCR and immunohistochemistry. Results A subset of patients suffering from pegylated IFN-α-associated exanthemas displayed positive intradermal tests to PEG- IFNs but not to conventional IFN (11/22). In selected patients, this observation correlated with the presence of pegylated IFN-specific T cells (3/11). Chemokine profiles of inflammatory skin reactions at the injection sites reflected an IFN-α-signature, whereas lesional skin of exanthemas showed induction of TH2-associated chemokines. Conclusions Our results indicate that specific sensitizations are one cause of exanthemas under therapy with PEG- IFNs. Clinical proof-of-concept analyses demonstrate that affected patients may benefit from a switch to conventional, nonpegylated drugs, enabling IFN-α therapy continuation without drug-associated skin eruptions. [ABSTRACT FROM AUTHOR]

Adverse drug reactions (ADRs) are common and are a major problem in drug therapy. Patients experience unnecessary morbidity and mortality whilst many effective drugs are withdrawn because of ADRs in a minority of patients. Recent studies have demonstrated significant associations between human leukocyte antigens (HLA) and predisposition to ADRs such as drug-induced skin injury (DISI) and drug-induced liver injury (DILI). HLA-B*58:01 has been significantly associated with allopurinol-induced hypersensitivity. Associations between HLA and carbamazepine hypersensitivity reactions demonstrate both ethnicity and phenotype specificity; with HLA-B*15:02 associated with Stevens-Johnson syndrome and toxic epidermal necrolysis in South East Asian patients only whilst HLA-A*31:01 is associated with all phenotypes of hypersensitivity in multiple ethnicities. Studies of ximelagatran, an oral direct thrombin inhibitor withdrawn because of hepatotoxicity, found associations between HLA-DRB1*07:01 and HLA-DQA1*02:01 and ximelagatran DILI. Interestingly, HLA-B*57:01 is associated with both abacavir DISI and flucloxacillin DILI but the reasons for the different phenotype of ADR remains unknown. Pharmacogenetic screening for HLA-B*57:01 prior to abacavir therapy has significantly reduced the incidence of abacavir hypersensitivity syndrome in clinical practice. No other HLA associations have been translated into clinical practice because of multiple reasons including failure to replicate, inadequate sample sizes, and our lack of understanding of pathophysiology of ADRs. Here, we review genetic associations that have been reported with ADRs and discuss the challenges that scientists, clinicians, pharmaceutical industry and regulatory agencies face when attempting to translate these associations into clinically valid and cost-effective tests to reduce the burden of ADRs in future. [ABSTRACT FROM AUTHOR]

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-B*15:02 and HLA-A*31:01 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-B*15:02 or HLA-A*31:01 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-B*15:02 and HLA-A*31:01 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-B*15:02 are at strongly increased risk for CBZ-induced Stevens-Johnson syndrome/toxic epidermal necrolysis ( SJS/ TEN) in populations where HLA-B*15:02 is common, but not CBZ-induced hypersensitivity syndrome ( HSS) or maculopapular exanthema ( MPE). HLA-B*15:02-positive patients with CBZ- SJS/ TEN have been reported from Asian countries only, including China, Thailand, Malaysia, and India. HLA-B*15:02 is rare among Caucasians or Japanese; no HLA-B*15:02-positive patients with CBZ- SJS/ TEN have been reported so far in these groups. HLA-A*31:01-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-A*31:01 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-B*15:02 and HLA-A*31:01 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 . [ABSTRACT FROM AUTHOR]

Abstract: Background: Increasing studies reported genetic susceptibility to drug hypersensitivity reactions, as exemplified by the HLA-A*31:01 and HLA-B*15:02 association with carbamazepine (CBZ)-induced hypersensitivity reactions, such as maculopapular exanthema (MPE), drug rash with eosinophilia and systemic symptoms (DRESS), and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). Objective: To carry out a comprehensive analysis on the clinical spectrum and HLA genotype–phenotype correlations in CBZ-induced hypersensitivity reactions. Methods: We analyzed the clinical information of 194 patients with CBZ hypersensitivity (51 MPE, 23 DRESS, 112 SJS/TEN, and 8 cases with other phenotypes), and 152 CBZ-tolerant controls. All are Han Chinese. We examined the HLA-A/HLA-B genotypes, gene dosage, and drug dosage effects. Results: CBZ-SJS/TEN showed the strongest association with the HLA-B*15:02 allele (Pc=5.8×10−43; odds ratio (OR) (95% CI)=97.6(42.0–226.8)), in which HLA-B*15:02 was identified in all patients (25/25) with SJS/TEN with >5% body surface area (BSA) skin detachment, but lost its 100% association (85.1%, 74/87) in SJS with <5% BSA detachment. In contrast, HLA-B*40:01 showed negative association with CBZ-induced SJS/TEN ((Pc=8.3×10−5; OR (95% CI)=0.22(0.1–0.4)). By comparison, CBZ-induced MPE/DRESS had no association with HLA-B*15:02, but linked to HLA-A*31:01 (Pc=2.7×10−3; OR (95% CI)=6.86(2.4–19.9), and HLA-B*51:01 (Pc=0.01; OR (95% CI)=4.56(2.0–10.5)). No gene dosage or CBZ dosage effects was observed. Conclusion: This study reported the different strength of HLA association with CBZ hypersensitivity in Han Chinese. With the increasing application of pharmacogenetic markers, the HLA genotype–phenotype correlations and the results of the test need to be carefully interpreted for CBZ-induced hypersensitivity reactions. [Copyright &y& Elsevier]

Highlights: [•] To date, little is known about the genetic mechanisms of carbamazepine (CBZ) and lamotrigine (LTG)-induced mild rash. [•] A larger group of patients from Han Chinese were included in this study. [•] The HLA-A*0201 or HLA-DRB1*1405 carriers may have a higher risk for CBZ-induced MPE than the non-carriers. [•] The existence of the two alleles, HLA-DRB1*0301 and HLA-B*5801, may decrease the potential risk for CBZ-induced MPE. [•] HLA-A*3001 and HLA-B*1302 may be two risk alleles for LTG-induced MPE, but HLA-A*3303 may be a protective allele. [Copyright &y& Elsevier]

Delayed reactions to iodine contrast media (CM) account for 1-3% of patients with adverse reactions to iodine CM. The cellular and molecular mechanisms of these reactions remain poorly documented. Although most of these reactions are T cell mediated, the involvement of dendritic cells (DC) has not been investigated sufficiently. To determine whether the T cell response to iodixanol requires DC as antigen-presenting cell and, more particularly, to evaluate the changes induced by iodixanol on DC maturation and in vitro production of cytokines after drug stimulation in patients with maculopapular exanthema. Peripheral blood lymphocytes, immature monocyte-derived DC (imDC) and skin biopsies were obtained from patients with delayed reactions to iodixanol and tolerant subjects. We studied the consequences of the interaction between DC, lymphocytes and iodixanol by phenotype analysis, proliferation and cytokine production. A T-cell-mediated reaction was evidenced in patient biopsies, with a lymphocyte-rich, peri-vascular infiltrate. Iodixanol induced maturation of imDC from patients but not from controls, with expression of the co-stimulatory markers CD83, CD86 and CD40 and an increase in mean fluorescence intensity of CD80, CD86 and HLA-DR. In the absence of DC, positive cell proliferation to iodixanol was detected in only one patient while the addition of DC produced a positive test in five of the six patients. Similarly, the increase in cytokines (IFN-γ, IL-2, IL-6, IL-1b and TNF-α) was higher when imDC were introduced into the culture together with the culprit drug. These results provide evidence for a DC-mediated mechanism in delayed allergic reactions to CM, influencing T cell proliferation and cytokine production. These new insights will be helpful for designing immunotherapeutic strategies and in vitro diagnostic tests of CM-delayed reactions. Cite this as: C. Antunez, A. Barbaud, E. Gomez, S. Audonnet, S. Lopez, R.-M. Guéant-Rodriguez, I. Aimone- Gastin, F. Gomez, M. Blanca and J.-L. Guéant, Clinical & Experimental Allergy, 2011 (41) 657-664. [ABSTRACT FROM AUTHOR]

&bgr;-lactam antibiotics are the agents most frequently implied in immune drug adverse reactions. These can be classified as immediate or nonimmediate according to the time interval between the last drug administration and their onset. Mechanisms of immediate IgE-mediated reactions are widely studied and are therefore better understood. Nonimmediate reactions include a broad number of clinical entities like mild maculopapular exanthemas, the most common, and other less frequent but more severe reactions such as Stevens–Johnson syndrome, toxic epidermal necrolysis, acute exanthematic pustulosis or cytopenias. These nonimmediate reactions are mainly mediated by T cells but the precise underlying mechanisms are not well elucidated. This fact complicates the allergological evaluation of patients with this type of reaction and available tests have demonstrated poor sensitivity and specificity. INSET: Key issues. [ABSTRACT FROM AUTHOR]

Background: Maculopapular exanthema (MPE) is the most frequent clinical manifestation of nonimmediate allergic reactions to drugs and T helper 1 (Th1) cytokines and CD4+ T cells have been shown to play an important role in its pathogenesis. We assessed the role of cytokines and chemokines and their receptors in the pathogenesis of MPE. Methods: We evaluated skin biopsies and peripheral CD4+ and CD8+ T cells from 27 patients during the acute phase of the reaction and 26 exposed controls. Semiquantitative real-time PCR was performed to determine the expression of cytokines and chemokines and their receptors and immunohistochemistry was used to determine the same chemokines and their receptor proteins in skin. Results: There was a high expression of the Th1 cytokines interferon-γ ( P = 0.006) and tumor necrosis factor-α ( P = 0.022) in skin and CD4+ T cells ( P = 0.007 and P = 0.005, respectively); and of the Th1 chemokines CXCL9 ( P = 0.005) and CXCL10 ( P = 0.028) in the skin, while their receptor CXCR3 was increased in skin ( P = 0.006) and CD4+ T cells ( P = 0.03). Homing chemokine receptors were also increased: CCR6 in skin ( P = 0.026) and CD4+ T cells ( P = 0.016), and CCR10 only in CD4+ T cells ( P = 0.016), as well as their ligands, CCL20 and CCL27, in skin alone. Immunohistochemistry confirmed these results. Conclusions: These data show significant differences in the expression of chemokines and chemokine receptors, related with a Th1 profile, in both skin biopsies and peripheral CD4+ T cells in patients with drug-induced MPE. [ABSTRACT FROM AUTHOR]

Non-immediate reactions to iodine contrast media (ICM) affect 2–5% of patients receiving these agents. We studied the immunological mechanisms involved in patients with a confirmed non-immediate reaction, maculopapular exanthema, after administration of ICM. The diagnosis was carried out by skin testing or drug provocation test. The immunological study was performed in sequential peripheral blood mononuclear cells taken from the onset of the reaction by flow cytometry and in skin biopsy by immunohistochemistry, with specific recognition by the lymphocyte transformation test (LTT) with different ICM. Flow cytometry showed an increase in the different activation markers [CD69, CD25 and human leucocyte antigen D-related (HLA-DR)] and the skin homing receptor [cutaneous lymphocyte-associated antigen (CLA)] in CD4 lymphocytes, whereas perforin was higher in the CD8 lymphocytes. The skin biopsy showed a perivascular mononuclear infiltrate composed of CD4 lymphocytes, expressing CD25, HLA-DR and CLA, with eosinophils. Intradermal skin tests and the LTT were positive to several ICM, including the culprit agent in four and three patients, respectively, with negative results in all 10 tolerant controls. We showed that a specific immunological mechanism was implicated in patients with non-immediate reactions to ICM. Moreover, the positive results in skin tests and lymphocyte proliferation tests indicated that an important cross-reactivity exists. [ABSTRACT FROM AUTHOR]

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Studies on the epidemiology of common adverse cutaneous drug reactions have rarely been reported, since they can only be successfully conducted in clinics of internal medicine employing consultant dermatologists and having a comprehensive or intensive system of monitoring. Between 1974 and 1993, the adverse skin reactions occurring in divisions of general internal medicine of three different hospitals were monitored by a computerized comprehensive system. The "drug-monitoring patient" was defined as the recipient of at least one drug during hospitalization. The relationship of the skin reactions to drug causality in these patients had to be either definite (proven by re-exposure) or probable (drug relation greater than that of nondrug causality). The skin reactions were classified into four diagnostic groups. Maculopapular exanthema, urticaria, and vasculitis were the three main groups. The fourth group comprised cases of nonhomogeneous but clinically well-defined special exanthema. For selected drugs and years of observation, special emphasis was placed on the study of time patterns (reaction time, exposure time). A total of 1317 definite or probable drug-induced skin reactions occurred during the hospitalization of 48,005 consecutively admitted "drug-monitoring patients": 1201 cases of maculopapular exanthema, 78 cases of urticaria, 18 cases of cutaneous vasculitis, and 20 cases of special exanthema (five of erythema multiforme minor, six of fixed eruption, one of photosensitivity reaction, and eight of acneiform eruption). The main drugs involved did not differ for the three main types of skin reactions, penicillins ranking in the first place, followed by sulfonamides--most often combined with trimethoprim--and in the third place nonsteroidal anti-inflammatory drugs. The reaction time (time from last drug exposure to first skin manifestation) for urticaria showed a relevant proportion of the acute type (within 1 h) and most of the subacute type (1-24 h). For maculopapular exanthema, the subacute or, rarely, the latent type (1-8 days, exceptionally more than 8 days) predominated. For aminopenicillins, the rate of occurrence of skin reactions increased with increasing exposure time up to 12 days, and then markedly diminished. Possibly due to the tendency to withdraw suspected drugs even in the case of minor (e.g., maculopapular) skin reactions, no severe events such as erythema multiforme major/Stevens-Johnson syndrome or toxic epidermal necrolysis occurred. [ABSTRACT FROM AUTHOR]