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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.

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.

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.

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

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.

In the setting of an acute cutaneous adverse drug reaction there is increasing interest in selected phenotypes and hosts to continue drug therapy, especially in settings in which there are limited therapeutic options. This concept of "treating through," defined as the continued use of a drug in the setting of, in particular maculopapular exanthema, potentially avoids unnecessary drug discontinuation. A review of the recent literature, historical viewpoints, and expert opinion are provided within to form recommendations and algorithms for a "treating-through" approach.

Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN) is a life-threatening cutaneous adverse drug reaction (cADR). Distinguishing SJS/TEN from nonsevere cADRs is difficult, especially in the early stages of the disease.To overcome this limitation, we developed a computer-aided diagnosis system for the early diagnosis of SJS/TEN, powered by a deep convolutional neural network (DCNN).We trained a DCNN using a dataset of 26,661 individual lesion images obtained from 123 patients with a diagnosis of SJS/TEN or nonsevere cADRs. The DCNN's accuracy of classification was compared with that of 10 board-certified dermatologists and 24 trainee dermatologists.The DCNN achieved 84.6% sensitivity (95% confidence interval [CI], 80.6-88.6), whereas the sensitivities of the board-certified dermatologists and trainee dermatologists were 31.3 % (95% CI, 20.9-41.8; P.0001) and 27.8% (95% CI, 22.6-32.5; P.0001), respectively. The negative predictive value was 94.6% (95% CI, 93.2-96.0) for the DCNN, 68.1% (95% CI, 66.1-70.0; P.0001) for the board-certified dermatologists, and 67.4% (95% CI, 66.1-68.7; P.0001) for the trainee dermatologists. The area under the receiver operating characteristic curve of the DCNN for a SJS/TEN diagnosis was 0.873, which was significantly higher than that for all board-certified dermatologists and trainee dermatologists.We developed a DCNN to classify SJS/TEN and nonsevere cADRs based on individual lesion images of erythema. The DCNN performed significantly better than did dermatologists in classifying SJS/TEN from skin images.

Background The diagnostic approach to drug hypersensitivity includes a detailed medical history, clinical examination, and skin testing and/or oral challenge with a culprit or alternative drug, depending on the type of reaction and the suspected drugs. Although skin testing is considered to be rather safe, cutaneous and systemic, including fatal, reactions have been described. Objectives To report 3 cases with generalized delayed reactions after skin testing with clindamycin, and to review the existing literature. Methods Thorough clinical examination, blood tests and prick, intradermal and patch tests were performed in 3 patients. Results All patients experienced generalized maculopapular exanthema after intradermal and patch testing with clindamycin and amoxicillin in the first patient, and clindamycin alone in the second and third patient. None of the patients showed immediate reactions to skin tests, while positive intradermal reactions after 24 h to amoxicillin and clindamycin were observed in the first patient, and positive intradermal reactions after 24 h to clindamycin were observed in the second and third patients. Conclusions Skin testing with clindamycin in the diagnosis of drug hypersensitivity carries some risk of adverse reactions. A stepwise and individual diagnostic work-up, considering potential risk factors, and testing in a specialized centre with emergency equipment available is highly recommended.

Allergy to beta-lactam antibiotics is a common condition and about 10% of patients report being allergic to penicillin. However, this diagnosis is largely overestimated. Two types of allergy should be distinguished and include immediate hypersensitivity that can lead to anaphylactic shock and delayed hypersensitivity, ranging from the most common maculopapular exanthema to severe bullous toxidermia or life-threatening DRESS. Allergy challenge with oriented skin tests according to the clinical features, supplemented with oral challenge in the absence of contraindication, will confirm or invalidate the diagnosis of beta-lactam allergy and will help to identify if necessary safe alternatives to beta-lactams.

Resume Le virus Zika (ZIKV), initialement identifie en 1947, est un Flavivirus re-emergent, principalement transmis par les piqures de moustiques du genre Aedes . Jusqu’aux recentes epidemies dans les iles du Pacifique et en Amerique centrale et du sud, il etait repute a l’origine d’une maladie benigne, asymptomatique dans la majorite des cas, ou avec des symptomes moderes non specifiques (fievre, eruption, conjonctivite, arthralgies…). Au cours de l’epidemie actuelle, d’une ampleur inedite, de nouveaux modes de transmission (transfusionnel, perinatal, sexuel) et des complications neurologiques severes telles que des malformations congenitales chez les fœtus de meres infectees et des syndromes de Guillain-Barre chez l’adulte ont ete mis en evidence. Cette situation, dans un contexte de potentielle pandemie mondiale a venir, a amene l’Organisation mondiale de la sante (OMS) a declarer l’infection a ZIKV urgence de sante publique de portee internationale en fevrier 2016.

DRESS syndrome (drug rash with eosinophilia and systemic symptoms) or drug hypersensitivity syndrome, presents a prevalence of 2% to 3% among the in-hospital population. In the present case, patients admitted to the intensive care unit (ICU) after intracranial surgery presented generalized facial edema, maculopapular exanthema and scaly erythroderma. During intra-buccal inspection, multiple ulcerated lesions with bleeding were observed at the lowest stimulation on the lips and oral mucosa at various localization sites. Laboratory tests revealed eosinophilia, thrombocytopenia, leukocytosis, and elevation of TGO, TGP, and CPK levels. In view of the clinical picture, it was found to be DRESS syndrome. The treatment of oral lesions consisted of cleaning, crust removal, and low-intensity laser therapy with red light. After 10 sessions of laser therapy, ulcerated lesions were resolved. The patient was discharged and has been under follow-up for 7 months.

BACKGROUND: Misdiagnosis of amoxicillin (clavulanic acid) (AX(/CL)) hypersensitivity has serious consequences. A drug challenge (DC) is the final diagnostic to affirm or infirm AX(/CL) hypersensitivity. However, uncertainties remain whether a prolonged drug challenge (pDC) should benefit the diagnosis of a nonimmediate AX(/CL) hypersensitivity. OBJECTIVE: To assess the added value of a standardized 7-day pDC in the diagnosis of nonimmediate or unclear penicillin hypersensitivity. METHODS: A total of 132 patients with a history of a nonimmediate hypersensitivity reaction or an unclear reaction to AX(/CL) or an undefined penicillin with a negative diagnostic workup including a single-day DC (DC) with AX(/CL) were selected. In all these patients, an additional pDC with AX(/CL) was planned. Thirteen patients started the pDC immediately after the DC. To ensure that hypersensitivity symptoms manifesting during the pDC course do not result from the DC, in the remaining 119 patients, the pDC was scheduled after a washout of 1 week. RESULTS: A total of 128 patients (12 without washout, 116 with washout) completed the pDC. Three patients reacted with a mild maculopapular exanthema. However, the value of a pDC was evidenced in only 1 patient who reacted during her pDC after an uneventful washout. In 2 patients pDC was cancelled because they reacted during the washout. CONCLUSIONS: A pDC is of limited added value to the diagnostic algorithms of nonimmediate hypersensitivity reaction or unclear hypersensitivity reactions to AX(/CL). In our hands, the traditionally recommended diagnostic algorithm that offers a 1-day DC as a final diagnostic in patients with negative workup for AX(/CL) is appropriate. (C) 2019 American Academy of Allergy, Asthma & Immunology.

Background Antiepileptic drugs (AEDs) can cause hypersensitivity reactions in children. These reactions are mainly cutaneous, self-limiting, and benign, but life-threatening severe cutaneous adverse reactions can occur. Infections can lead to skin eruptions and mimic drug hypersensitivity reactions, if a drug is taken at the same time. The aims of our study were to confirm or rule out the diagnosis of hypersensitivity reactions to AEDs in children and to detect an infection which mimics these reactions. Methods A prospective survey was conducted in a group of 100 children with histories of hypersensitivity reactions to AEDs by performing patch tests, delayed-reading intradermal test, and, in case of negative results, challenge test. In all children, a study was performed to detect infections by viruses or Mycoplasma pneumoniae. Results Maculopapular exanthema and delayed-appearing urticaria were the most reported hypersensitivity reactions to AEDs. Sixty-six (66%) of 100 children had confirmed hypersensitivity reactions to AEDs. Fifty-nine children had positive patch test. No children had positive challenge tests. The most common AEDs causing hypersensitivity reactions were carbamazepine (45.4%) and lamotrigine (43.6%). Thirty-two children had positive tests for viruses or M pneumoniae, and nine of them had also a positive allergy work-up. Conclusion Considering that there are no specific tests to distinguish between a viral infection and hypersensitivity reactions to AEDs in the acute phase, a diagnostic work-up should be performed in all children with suspected hypersensitivity reactions to AEDs, as well as infectious agent study, to remove a false label of hypersensitivity.

Whenever a cutaneous adverse drug reactions (cADR) is suspected, it is important to establish the dermatological diagnosis, since reaction patterns may differ in causality, time latency between the beginning of drug use and reaction onset, and prognosis. Few epidemiologic studies have been performed on frequent non-life-threatening cADR, such as maculopapular exanthema, fixed drug eruption, and urticaria. For rare but life-threatening severe cutaneous adverse reactions, e.g., Stevens-Johnson syndrome/toxic epidermal necrolysis, acute generalized exanthematous pustulosis, and drug reaction with eosinophilia and systemic symptoms, several epidemiologic studies have been or are currently performed. They allow for estimation of incidence rates, demographic data, and drug risks.

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.

Background β-Lactam antibiotics are the most common trigger of reactions in children with most of them being nonimmediate (85.5%), but proven allergy after the allergological workup is between 7% and 10%. There is no agreement on how to perform the provocation tests in these types of hypersensitivity reactions. Objective To determine whether or not repeated doses of the β-lactams are required to reproduce a nonimmediate reaction in children. Methods This is a retrospective observational study. We included children under 14 years who were referred for a nonimmediate reaction to β-lactams. All patients underwent a 1-day hospital provocation and were kept under observation at home during the following days for at least the time elapsed between the first dose and the symptoms of the index reaction. If no reaction was triggered, the patient resumed the provocation at home with 2 daily therapeutic doses for an equal of interval time. Results Ninety-seven patients were included in the study. A positive reaction was recorded in 14 of them (14.4%). The short hospital provocation triggered 3 immediate reactions and 8 delayed reactions. The home rechallenge developed 1 immediate reaction and 2 delayed reactions. Conclusions Nonimmediate reactions to β-lactams in children may be triggered with a 1-day provocation test. We suggest to perform a 1-day provocation test followed by an observational period of at least the time interval of the index reaction. If this challenge is negative, an extended home provocation could subsequently be carried out.

Resume Introduction Nous rapportons le premier cas de necrolyse epidermique toxique (NET) survenue sous vemurafenib. Observation Une femme de 75 ans etait traitee par vemurafenib pour un melanome de stade IV porteur de la mutation BRAF V600E. Elle presentait brutalement de la fievre, un erytheme maculo-papuleux diffus prurigineux, un �deme palpebral, une bulle palmaire, une conjonctivite, une cheilite et des erosions muqueuses. L'evolution se faisait vers un decollement touchant 50 % de la surface cutanee. La biopsie cutanee montrait une dermatose lichenoide, focalement vesiculeuse avec de nombreux polynucleaires eosinophiles. L'etude en immunofluorescence directe (IFD) etait negative. Le vemurafenib etait le seul medicament imputable. Nous concluions a une NET au vemurafenib. Discussion Il s'agit a notre connaissance du premier cas rapporte de NET au vemurafenib mais cet effet indesirable, quoique deja decrit dans l'etude BRIM-3, semble rare en pratique clinique. Dans la litterature, d'autres reactions cutanees severes ont ete decrites. Parmi elles, un cas de syndrome de Stevens-Johnson chez une patiente sous vemurafenib, precedemment traitee par ipilimumab. De maniere plus frequente, les reactions cutanees a type d'efflorescence de lesions hyperkeratosiques benignes parfois accompagnees d'authentiques carcinomes epidermoides ou keratoacanthomes sont rapportees et justifient une surveillance cutanee reguliere des patients traites par vemurafenib. Conclusion Devant l'apparition d'un exantheme maculo-papuleux sous vemurafenib, la poursuite du traitement doit etre reevaluee puisque le risque d'evolution plus grave, comme ici, une NET, n'est pas nul. ________________________________________ Summary Background Herein we report the first case of toxic epidermal necrolysis (TEN) occurring with use of vemurafenib. Patients and methods A 75-year-old female patient was being treated with vemurafenib for stage IV melanoma with BRAF V600E mutation. She suddenly presented fever, diffuse pruriginous maculopapular erythema, palpebral edema, palmar bulla, conjunctivitis, cheilitis and mucosal ulceration. The condition progressed towards detachment affecting 50% of the skin area. Cutaneous biopsy revealed lichenoid dermatosis, chiefly vesicular with numerous eosinophils. Direct immunofluorescence (IFD) was negative. Vemurafenib was the only drug to which the reaction was ascribable and we concluded on vemurafenib-induced TEN. Discussion To our knowledge, this is the first reported case of vemurafenib-induced TEN, but this adverse effect, although already described in the BRIM-3 study, appears rare in clinical practice. Other severe skin reactions have been described in the literature. These include a case of Stevens-Johnson syndrome in a female patient treated with vemurafenib and previously receiving ipilimumab. A more common occurrence is cutaneous reactions involving efflorescence of benign hyperkeratotic lesions, occasionally accompanied by authentic epidermal carcinoma or keratoacanthoma, and requiring regular dermatological monitoring of patients treated with vemurafenib. Conclusion If maculopapular exanthema occurs under vemurafenib, continuation of this treatment should be reassessed since the risk of progression to a more serious condition such as TEN, as seen in the present case, cannot be ruled out. Mots cles " Vemurafenib; " Necrolyse epidermique toxique; " Syndrome de Lyell; " Melanome Keywords " Vemurafenib; " Toxic epidermal necrolysis; " Lyell's syndrome; " Melanoma

BackgroundCutaneous adverse drug reactions frequently present as a benign maculopapular exanthema (MPE) with a rapid healing. Sometimes systemic signs are present, which could represent a more severe or systemic MPE (sMPE) or even be the initial phase of a drug reaction with eosinophilia and systemic symptoms (DRESS). Histopathology associated with MPE, sMPE and DRESS has not been well characterized.ObjectivesTo study the cutaneous histopathological changes associated with MPE, sMPE and DRESS.MethodsA retrospective clinicopathological analysis of 13 cases of MPE, 13 of sMPE and 45 of DRESS, collected in one centre from 2005 to 2013.ResultsThe number of histopathological changes per section increased gradually from MPE to sMPE and DRESS. Prevalence of spongiosis, dermal lymphocytes, eosinophils and neutrophils did not differ between MPE, sMPE and DRESS. Keratinocyte damage, rare in MPE, was regularly found in sMPE and frequent in DRESS. The density of the inflammatory infiltrate increased progressively from MPE to sMPE and DRESS. Atypical lymphocytes were absent in MPE, present in sMPE and more frequent in DRESS. Deep dermal involvement and leukocytoclastic vasculitis were only observed in DRESS.LimitationsThis was a retrospective study.ConclusionsNumerous histopathological changes per section in drug-induced exanthema should alert for a more severe form of cutaneous adverse drug reactions, i.e. DRESS.

Purpose of review The purpose of this review is to examine in detail the new advances in the pathomechanisms and diagnosis of immediate and nonimmediate hypersensitivity reactions to quinolones, as well as analyze cross-reactivity among different quinolones. Recent findings Hypersensitivity reactions to quinolones, especially anaphylactic reactions, have become more common in the past decade. This phenomenon could be related to their increased consumption. Although attempts have been made to standardize skin testing, the diagnosis of immediate hypersensitivity reactions to quinolones is mainly based on drug provocation. Some in-vitro, radioimmunoassay and basophil activation tests have also been used for diagnostic purposes, with results indicating that they could be complementary to in-vivo tests. Cross-reactivity seems to exist between first and second-generation quinolones, with lower levels with the third and fourth generations. However, no general rules exist for predicting cross-reactivity and it needs to be analyzed patient by patient. Nonimmediate hypersensitivity reactions also exist, especially maculopapular exanthema and fixed drug eruptions, and a T-cell mechanism has been demonstrated. Summary Over the past decade the number of hypersensitivity reactions to quinolones has increased. These reactions can be severe and diagnosis difficult to confirm. Although new in-vitro tests hold promise, drug provocation testing remains the most frequently used and reliable diagnostic method.

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

The initial symptoms of an HIV-1 infection were observed in four patients. The following were characteristic for the acute primary phase: (a) initial maculopapular exanthema, especially of the trunk, with occasional transition into a papulovesical appearance; (b) involvement of the oral mucosa, often of aphthous character; and (c) general malaise with fever and lymphadenopathy. The observed cutaneous changes had, on one hand, features of a Coxsackie or mononucleosis exanthema, on the other of secondary syphilis. In three patients seroconversion occurred within 2-6 weeks, the fourth failed to return for follow-up. The listed acute primary symptoms can be used as the earliest indicators of an HIV-1 infection having occurred.

Adverse drug reactions (ADRs) place a large economic strain on our health care system and prevent the use of key medications by many individuals. A subset of ADRs show evidence of mediation by the human leukocyte antigen (HLA) molecules, and numerous associations between specific ADRs and particular HLA alleles or subgroups have been identified. Here we discuss the current models for interaction of small molecule drugs with the HLA and the supporting evidence in the context of antigen-processing and presentation.

Background: Selective cyclooxygenase (COX) 2 nonsteroidal anti-inflammatory drugs (NSAIDs) have been associated with a general lower incidence of side effects compared with nonselective NSAIDs. Postmarketing information has highlighted the need to reassess the risk evaluation for specific organs, including the skin. Objective: A prospective databank to record all cases of adverse cutaneous reactions associated with the use of COX inhibitors was conducted at the Centre for Drug Surveillance of the Dermatology Department of Cagliari University. Material and Methods: An intensive surveillance program from November 2000 to October 2004, adopting the World Health Organization Collaborating Centre for Drug Monitoring causality assessment criteria and algorithm. Results: Seventeen cases, 4 male and 13 female, were studied. None had previously presented any drug intolerance or allergy. Clinical manifestations were mainly maculopapular exanthema followed by urticaria-angioedema. A severe case of leukocytoclastic vasculitis was also observed. Responsible drugs were celecoxib (13 cases; 76%), rofecoxib (3 cases; 18%), and etoricoxib (1 case; 6%). All cases recovered with drug withdrawal. Causality was probable for all eruptions, except for the fixed drug eruption, for which causality was certain. Discussion: Although most cases were associated with celecoxib, the observation of severe eruptions owing to rofecoxib and etoricoxib in this prospective study is consistent with a class effect of COX inhibitors on the skin, which merits further studies to explain the fine underlying mechanisms.

In a 58-year-old hospitalized woman with gonarthrosis a leech therapy was applied to both knee joints. In the evening of the following day she observed strong pruritus in the area of the leech bites; in addition a maculopapular exanthema appeared on the torso and her lower extremities. The allergic reaction lasted four days. Administration of antihistamines only led to a slight improvement of the symptoms. A full restitution could only be achieved after a systemic dose of glucocorticoids on the fourth day after leech therapy. Eight days before beginning of the leech therapy a five-day antibiotic therapy with trimethoprim and sulfamethoxazole (Cotrim forte®) had been administered to treat an uncomplicated urinary infection. Allergic reactions are well-known complications of these antibiotics and of leech therapy. The four-day duration of the allergic reaction after leech therapy, however, was untypical. In order to explain these symptoms, a prick test and an epicutaneous test for the antibiotic components were executed five weeks after the leech therapy. Furthermore, a second leech therapy was administered and a lymphocyte transformation test (LTT) was carried out. The results of the LTT showed a sensitization for sulfamethoxazole and a possible sensitization for trimethoprim, the results of the epicutaneous test showed a positive reaction to sodium lauryl sulfate, a component of the antibiotic. In the area of the leech bites a clear local skin reaction was observed. These results suggest a drug exanthema, in all probability triggered by the leech therapy.

We report a 45-year old man who developed maculopapular exanthema on the inferior cervical folder, axillae and umbilicus, as well as erythema multiforme-like lesions on the wrists after the introduction in his work of pao ferro (Machaerium scleroxylon). Patch tests were positive to pao ferro and ebony. This case highlights the importance of patch tests for the confirmation of the culprit agent in occupational dermatoses and also to identify other occupational allergens that the patient should avoid. Tropical woods contain quinones that could explain the possible cross-reactions between woods belonging to different families.

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.

A maculopapular exanthema developed in a 60-year-old man with coronary heart disease while being treated for angina with the calcium antagonist diltiazem. Epicutaneous and scratch tests were positive, both for the immediate type (type I) and the delayed type (type IV), proving that the drug had caused the allergic reaction. The exanthema quickly disappeared once the drug had been discontinued. Anti-anginal treatment was continued without further complications with nifedipine.

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.

Beta-lactam antibiotics (BLs) are the most frequent cause of hypersensitivity reactions mediated by specific immunological mechanisms, with two main types, IgE reactions or T-cell-dependent responses. From a practical point of view, these reactions can be classified into immediate, for those appearing within 1 h after drug intake, and non-immediate, for those appearing at least 1 h after and usually within 24 h of BL administration. The clinical symptoms differ according to this classification. Urticaria and anaphylaxis are the most frequently recorded symptoms in immediate reactions and maculopapular exanthema and delayed urticaria in non-immediate reactions. Although the exact diagnostic approach differs depending on the underlying mechanism, it is based on the performance of skin testing, laboratory tests, and drug provocation tests.

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).