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Purpose: Surgical patients with a penicillin allergy label (PAL) are less likely to receive β-lactams for surgical site infection (SSI) prophylaxis and more likely to receive second-line antibiotics, which may increase the risk of SSI, drug toxicities, and associated costs. We assessed the impact of implementing a pharmacist-led quality improvement project to increase the use of cefazolin as a first-line agent in this population., Summary: After implementation of a pilot project in December 2021, all patients with a PAL and orders for preoperative antibiotics were risk stratified into high- or low-risk categories by a pharmacist. For the low-risk group, cefazolin was recommended. For the high-risk group, cefazolin was avoided and a second-line agent was administered. Our analysis compared 422 preintervention patients (August 15 to November 15, 2021) to 492 postintervention patients (December 15 to March 15, 2022). During the postintervention period, β-lactam usage increased (from 12.6% to 37.8%, P < 0.001), while usage of vancomycin (45.5% vs 29.5%, P < 0.001) and other second-line antibiotics (87.4% vs 62.2%, P < 0.001) declined. There were no adverse reactions reported in the preintervention cohort, with 2 potential adverse reactions reported after the intervention (0% vs 0.4%, P = 0.190). Medication costs based on claims data were 50% to 80% lower for patients receiving cefazolin., Conclusion: In our cohort, a pharmacy-led antibiotic selection algorithm for patients with a PAL receiving perioperative antimicrobial prophylaxis resulted in increased use of β-lactam antibiotics, decreased use of second-line antibiotics, and decreased costs without a significant change in the incidence of adverse reactions., (© American Society of Health-System Pharmacists 2023. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Since the advent of CT, iodinated contract media (ICM) has become one of the most regularly administered intravenous medications in clinical settings. Although considered generally safe, ICM is one of the most common causes of adverse drug reactions in clinical practice, accounting for more than 2 million adverse reactions worldwide. Currently, there are few useful tools to diagnose patient hypersensitivity, with the major limitation being the lack of consensus regarding the mechanisms of hypersensitivity to ICM. While there is an overwhelming abundance of literature pertaining to clinical features including incidence, symptomatology, and risk, few studies have further investigated the underlying mechanisms behind their clinical observations. Of the available literature discussing pathophysiology, most primary studies were completed over 20 years ago, since which the molecular characteristics of ICM have changed. Furthermore, many reviews mentioning pathophysiology fail to adequately emphasize the clinical importance of understanding the molecular pathways involved in hypersensitivity. In this review, we aim to emphasize the clinical relevance of pathophysiology as it relates to the prediction and diagnosis of hypersensitivity reactions to ICM. To this end, we will first briefly characterize hypersensitivity reactions to ICM with respect to epidemiology and clinical presentation. We will then present the existing evidence supporting various proposed mechanisms of hypersensitivity, highlighting the gaps that remain in the mechanistic delineation of both immediate and delayed reactions. Finally, we discuss the possibility of in vitro testing as a way to predict and diagnose hypersensitivity reactions, pending a more complete elucidation of mechanisms.

Purpose: The current evidence regarding iodine-containing compounds and iodine allergy cross-reactivity is reviewed., Summary: Iodine is an essential human nutrient found in the thyroid gland. It is used in the synthesis of the thyroid hormones thyroxine and triiodothyroxine. Patients who report having adverse reactions to iodine-containing substances are often labelled as having an "iodine allergy," which can result in delays in care or patients being denied essential iodinated contrast media (ICM) or other iodine-containing drugs. A literature review was conducted to evaluate the evidence regarding iodine allergy and iodine-containing drugs. Of 435 articles considered potentially appropriate for full review (plus 12 additional articles included on the basis of references from the eligible articles), 113 could not be obtained. After exclusion of 353 articles that did not meet all inclusion criteria, the remaining 81 articles were included in the review. The results of the literature review indicated that iodine has not been shown to be the allergen responsible for allergic reactions to iodinated contrast media, amiodarone, povidone-iodine, and other iodine-containing compounds., Conclusion: There is a lack of evidence to support cross-reactivity between iodine-containing compounds in so called iodine-allergic individuals., (© American Society of Health-System Pharmacists 2021. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Severe drug hypersensitivity reactions to antibiotics are rare but trimethoprim-sulfamethoxazole (TMP-SMX) is uniquely associated with numerous and varied manifestations including a reaction resembling septic shock, first observed in human immunodeficiency virus (HIV)/AIDS patients. Over the past 25 years about 20 cases have been reported and an association with the virus and related immune system dysregulation was assumed. However, recent reports in adults have recognized similar shock-like reactions in non-HIV infected individuals. Here we review severe TMP-SMX hypersensitivity reactions and within the context of these known reactions, describe three non-HIV infected adolescent patients with shock-like reactions to TMP-SMX observed in one institution over 1.5 years., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Recently, ustekinumab has been approved for the treatment of Crohn's disease and ulcerative colitis. Treatment is started with an intravenous induction dose, followed by a subcutaneous dosage. We present details of three patients with therapy-refractory Crohn's disease who experienced an immediate infusion reaction to intravenous administration of ustekinumab. In two of these patients a subsequent reaction to subcutaneous injections occurred. Clinical features and pathophysiology are discussed., (© The Author(s) 2020. Published by Oxford University Press on behalf of European Crohn’s and Colitis Organisation.)

Background: Patients with reported β-lactam antibiotic allergies (BLAs) are more likely to receive broad-spectrum antibiotics and experience adverse outcomes. Data describing antibiotic allergies among solid organ transplant (SOT) and hematopoietic cell transplant (HCT) recipients are limited., Methods: We reviewed records of adult SOT or allogeneic HCT recipients from 1 January 2013 to 31 December 2017 to characterize reported antibiotic allergies at time of transplantation. Inpatient antibiotic use was examined for 100 days posttransplant. Incidence rate ratios (IRRs) comparing antibiotic use in BLA and non-BLA groups were calculated using multivariable negative binomial models for 2 metrics: days of therapy (DOT) per 1000 inpatient days and percentage of antibiotic exposure-days., Results: Among 2153 SOT (65%) and HCT (35%) recipients, 634 (29%) reported any antibiotic allergy and 347 (16%) reported BLAs. Inpatient antibiotics were administered to 2020 (94%) patients during the first 100 days posttransplantation; average antibiotic exposure was 41% of inpatient-days (interquartile range, 16.7%-62.5%). BLA patients had significantly higher DOT for vancomycin (IRR, 1.4 [95% confidence interval {CI}, 1.2-1.7]; P < .001), clindamycin (IRR, 7.6 [95% CI, 2.2-32.4]; P = .001), and aztreonam in HCT (IRR, 9.7 [95% CI, 3.3-35.0]; P < .001), and fluoroquinolones in SOT (IRR, 2.9 [95% CI, 2.1-4.0]; P < .001); these findings were consistent when using percentage of antibiotic exposure-days., Conclusions: Transplant recipients are frequently exposed to antibiotics and have a high prevalence of reported antibiotic allergies. Reported BLA was associated with greater use of β-lactam antibiotic alternatives. Pretransplant antibiotic allergy evaluation may optimize antibiotic use in this population., (© The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Purpose of the Study: This study investigates spontaneous adverse drug reactions (ADRs) to glucosamine and chondroitin in the Australian population between 2000 and 2011, with a primary focus on hypersensitivity reactions., Study Design: Case reports of ADR to glucosamine and chondroitin sent to the Therapeutic Goods Administration between 2000 and 2011 were obtained and analysed. The demographic information and severity of the ADR were recorded for individual ADR cases. These reactions were classified according to the Brown et al grading system for generalised hypersensitivity reactions. This included mild hypersensitivity reactions (generalised erythema, urticaria and angioedema) through to moderate hypersensitivity reactions (wheeze, nausea, vomiting, dizziness (presyncope), diaphoresis, chest or throat tightness and abdominal pain), and more severe reactions (hypotension, confusion and collapse)., Results: In this study of 366 ADRs to glucosamine and chondroitin preparations, 71.85% of cases (n=263) were found to have hypersensitivity reactions. Of these 263 cases, 92 cases were classified as mild (eg, pruritus, urticaria and lip oedema), 128 cases classified as moderate (such as dyspnoea, nausea and abdominal pain), and 43 cases classified as severe (including amnesia, gait disturbance, somnolence and hypotension). It is not clear whether the patients involved had a known shellfish allergy or underlying atopy., Conclusion: Results of this investigation support the need for clear labelling on glucosamine and chondroitin preparations to raise awareness of possible adverse events for those predisposed to allergy or atopy in response to shellfish., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The options for immunotherapy treatment are limited for treatment of hepatocellular carcinoma. In this case study, we report a case of successful alternation of one PD-1 inhibitor for another after a hypersensitivity reaction., Summary: Nivolumab (Opdivo, Bristol-Myers Squibb) has been Food and Drug Administration (FDA) approved for a variety of malignancies, including a recent approval for hepatocellular carcinoma (HCC). Infusion-related reactions occur in less than 1% of patients, and although such reactions are rare, recognition of infusion-related reactions induced by nivolumab is an important aspect of its usage. The PD-1 checkpoint inhibitor pembrolizumab is also FDA approved for subsequent-line therapy in treatment of HCC. Thus far, approximately 0.2% of patients experienced severe infusion-related reaction in studies using pembrolizumab. A 70-year-old male with HCC had an infusion reaction to nivolumab that presented as facial flushing, dyspnea, and back pain. The patient received prompt administration of diphenhydramine and hydrocortisone, which led to the amelioration of symptoms and allowed the patient to complete his immunotherapy treatment. For the third dose of nivolumab, the patient received premedications prior to treatment, including diphenhydramine, hydrocortisone, and famotidine. During his infusion, the patient experienced facial flushing, coughing, chest tightness, and an itchy throat. The patient again received diphenhydramine and hydrocortisone to treat infusion-related symptoms and his therapy was discontinued. Because of the nivolumab infusion-related reaction, nivolumab was discontinued, and the patient was started on pembrolizumab. The patient tolerated pembrolizumab without any subsequent infusion-related reactions. Prompt recognition and attention to immunotherapy infusion-related reactions could potentially prevent the fatal complication of anaphylaxis with immune checkpoint inhibitors. In this report, we describe the successful transition from one anti-PD-1 therapy to another for continued immunotherapy treatment without any subsequent infusion reactions., Conclusion: A patient with HCC was successfully treated with pembrolizumab after experiencing adverse effects with nivolumab., (© American Society of Health-System Pharmacists 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Didecyldimethylammonium chloride (DDAC) is an antimicrobial dialkyl-quaternary ammonium compound used in industrial and commercial products. Clinical data suggest that DDAC exposure elicits multiple types of hypersensitivity reactions; here, we confirm this observation in a BALB/c murine model. To examine the immunological mechanism behind this mixed-type response and the potential involvement of type 2 innate lymphoid cells (ILC2s), we assessed early immune responses in the skin following topical DDAC exposure (0.125% and 0.5%). DDAC exposure resulted in a rapid and dramatic increase in the Th2-skewing and ILC2-activating cytokine thymic stromal lymphopoietin. Correspondingly, dermal ILC2s were activated 24 h after DDAC exposure, resulting in increased expression of CD25, ICOS and KLRG1, and decreased CD127 throughout 7 days of exposure. Following ILC2 activation, the Th2 cytokine IL-4 was elevated compared with control mice in total ear protein lysate (0.5% DDAC). Rag2-/- mice were used to determine a functional role for ILC2s in DDAC-induced sensitization. ILC2s from Rag2-/- mice were similarly activated by DDAC and, importantly, produced significant levels of IL-4 and IL-5 in the skin (0.5% DDAC). These data indicate that ILC2s contribute to early Th2 immune responses following DDAC exposure. ILC2s have been previously implicated in allergic responses, but to our knowledge have not been thoroughly investigated in chemical sensitization. These results indicate that following DDAC exposure, skin ILC2s become activated and produce Th2 cytokines, providing a possible mechanism for the development of the mixed-type allergic responses commonly observed with chemical sensitizers., (Published by Oxford University Press on behalf of the Society of Toxicology 2019.)

Objectives: The objective of this study is to identify risk factors for hypersensitivity reaction (HSR) to tocilizumab (TCZ) in systemic juvenile idiopathic arthritis (sJIA)., Methods: Clinical records of 40 patients with sJIA administered TCZ at one center were retrospectively reviewed. Patients were divided into HSR or non-HSR groups depending on the presence of HSR between the first and third TCZ administrations; clinical and laboratory assessments, including serum cytokine profile, were compared., Results: Five patients displayed HSR following the third TCZ administration. They were significantly younger, shorter, and lighter, with a higher peak body temperature than non-HSR patients following the third administration. Their serum C-reactive protein (CRP) level was undetectable following the first administration but detectable by the third administration. Before the third administration, the white blood cell counts and serum levels of CRP and sTNFRII were significantly higher in the HSR group than in the non-HSR group. The serum levels of interleukin-18 and -6 before the third TCZ administration were higher and lower than those before the first administration in the HSR and non-HSR groups, respectively., Conclusion: Patients with sJIA having a younger age, shorter stature, and lighter weight and those showing increased disease activity in the early period of TCZ administration may be at higher risk of TCZ-induced HSR.

Allergy to insulin occurs in approximately 2% of patients treated with insulin. However, major guidelines fail to emphasize this serious adverse effect. In this article, we report on a 61 year old ethnic Filipino man who developed urticaria and pruritus with a swollen tongue, which necessitated a visit to the emergency department. His clinical diagnosis was confirmed by a high titer of anti-insulin antibodies. His condition was successfully managed by discontinuing insulin and by treatment with oral hypoglycemic agents, with no additional adverse reactions. At the most recent follow-up visit, his antibody titer had fallen; however, that titer has not normalized. Also, the patient currently does not have uticaria.

Background: Atopic dermatitis is a chronic inflammatory skin disease that may require systemic therapy. Ciclosporin A (CsA) is a widely used, potent immunosuppressant but it is not effective in all patients with atopic dermatitis, and side-effects limit its use. Dupilumab, a fully human anti-interleukin 4 receptor-alpha monoclonal antibody, inhibits signaling of IL-4 and IL-13, key drivers of Type 2/Th2-mediated inflammation, and is approved in the U.S.A. and the European Union for the treatment of inadequately-controlled moderate-to-severe atopic dermatitis in adults., Objectives: To evaluate efficacy and safety of dupilumab with concomitant topical corticosteroids (TCS) in adults with atopic dermatitis with inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable., Methods: In this 16-week, double-blind, randomized, placebo-controlled, phase III trial, patients were randomized 1 : 1 : 1 to subcutaneous dupilumab 300 mg weekly (qw) or every 2 weeks (q2w) or placebo. All received concomitant medium-potency TCS from Week -2 through Week 16; dosage could be tapered if lesions cleared, or stopped for adverse reactions to TCS., Results: In total, 390 patients were screened, 325 were randomized, and 318 completed the trial. Treatment groups had similar baseline characteristics. Significantly more patients in the dupilumab qw + TCS and q2w + TCS groups achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index at Week 16 vs. the placebo + TCS group (primary end point) (59·1% and 62·6% vs. 29·6%, respectively; P < 0·001 vs. placebo + TCS, both doses). Other clinical outcomes and atopic dermatitis symptoms were significantly improved in the dupilumab qw + TCS and q2w + TCS groups, including pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and quality of life (QoL). Treatment groups had similar overall rates of adverse events (qw + TCS, q2w + TCS and placebo + TCS groups: 69·1%, 72·0% and 69·4%, respectively) and serious adverse events (1·8%, 1·9% and 1·9%, respectively). Conjunctivitis was more frequent with dupilumab + TCS; skin infections were more frequent with placebo + TCS., Conclusions: Dupilumab + TCS significantly improved signs and symptoms of atopic dermatitis and QoL in adults with a history of inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable. No new safety signals were identified., (© 2017 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Aspirin hypersensitivity is not a rare condition among patients with acute coronary syndrome. However, despite the publication of several successful desensitization protocols, the procedure is not as widespread as expected. We present a cohort of patients with acute coronary syndrome undergoing aspirin desensitization to evaluate its short- and long-term efficacy and safety and to reinforce data from previous studies., Methods: Of 1306 patients admitted to our Coronary Care Unit between February 2011 and February 2013, 24 (1.8%) had a history of aspirin hypersensitivity. All 24 patients underwent an eight-dose aspirin desensitization protocol (0.1, 0.3, 1, 3, 10, 25, 50 and 100 mg of aspirin given by mouth every 15 minutes) after premedication with antihistamines and corticosteroids or antileucotrienes. Previously prescribed β blockers and angiotensin-converting enzyme inhibitors were not discontinued. All patients were desensitized within 72 hours of admission. Those requiring urgent catheterization (five patients with ST segment elevation myocardial infarction) were desensitized within 12 hours of catheterization and the remainder before catheterization., Results: All patients were successfully desensitized and only one presented with an urticarial reaction. The five patients with ST segment elevation myocardial infarction were treated with abciximab until desensitization was complete. All but one patient underwent catheterization and 20 underwent percutaneous coronary intervention, most (66%) with the implantation of a bare metal stent. At follow-up (a minimum of 6-24 months), only two patients had discontinued aspirin, both due to gastrointestinal bleeding, and no hypersensitivy reaction had occurred., Conclusions: Aspirin desensitization is effective and safe in unstable patients with acute coronary syndrome in both the short and long term.

Background: Formaldehyde is a well-known contact sensitizer. Formaldehyde releasers are widely used preservatives in skincare products. It has been found that formaldehyde at concentrations allowed by the European Cosmetics Directive can cause allergic contact dermatitis. However, we still lack information on whether formaldehyde at low concentrations affects dermatitis in formaldehyde-allergic individuals., Objectives: To study the effects of low concentrations of formaldehyde on irritant contact dermatitis in formaldehyde-allergic individuals., Methods: Fifteen formaldehyde-allergic individuals and a control group of 12 individuals without contact allergy to formaldehyde and formaldehyde releasers were included in the study. The individuals performed the repeated open application test (ROAT) during 4 weeks with four different moisturizers releasing formaldehyde in concentrations that had been determined as > 40, 20-40, 2·5-10 and 0 p.p.m. by the chromotropic acid (CA) spot test. Dimethyloldimethylhydantoin was used as a formaldehyde releaser in the moisturizers. The ROAT was performed on areas of experimentally induced sodium lauryl sulfate dermatitis. The study was double blind, controlled and randomized., Results: Nine of the 15 formaldehyde-allergic individuals had reappearance or worsening of dermatitis on the areas that were treated with moisturizers containing formaldehyde. No such reactions were observed in the control group (P < 0·001) or for the moisturizers without formaldehyde in the formaldehyde-allergic individuals (P < 0·001)., Conclusions: Our results demonstrate that the low concentrations of formaldehyde often found in skincare products by the CA method are sufficient to worsen an existing dermatitis in formaldehyde-allergic individuals., (© 2015 British Association of Dermatologists.)

Vemurafenib and dabrafenib are both orally bioavailable small molecule agents that block mitogen activated protein kinase signalling in patients with melanoma and BRAF(V600E) mutation. Generalized hypersensitivity reactions to vemurafenib or dabrafenib have not been described. Continuing vemurafenib or dabrafenib therapy despite hypersensitivity reaction is especially important in patients with melanoma and BRAF(V600E) mutation, in whom this mutation plays a critical role in tumour growth. Desensitization protocols to overcome hypersensitivity reactions by gradual reintroduction of small amounts of the offending drug up to full therapeutic doses are available for many anti-cancer agents, including vemurafenib but, to the best of our knowledge, have not been reported for dabrafenib. We describe a patient with metastatic melanoma who developed Type I hypersensitivity reaction to vemurafenib and to subsequent treatment with dabrafenib, and who was successfully treated by drug desensitization which allowed safe prolonged continuation of dabrafenib. The development of hypersensitivity reactions for both dabrafenib and vemurafinib in the current case could be because these drugs have a similar chemical structure and cause a cross-reactivity. However, hypersensitivity reaction to a non-medicinal ingredient shared by the two drugs is also possible. Oral desensitization appears to be an option for patients with hypersensitivity Type I to dabrafenib. This approach may permit clinicians to safely administer dabrafenib to patients who experience hypersensitivity reactions to this life-prolonging medication., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Platinum agents are drugs used for various types of cancer. With increased frequency of administration of platinum agents, hypersensitivity reactions appear more frequently, occurring in over 25% of cases from the seventh cycle or second line onward. It then becomes difficult to conduct treatment using these agents. Various approaches have been investigated to address hypersensitivity reactions to platinum agents. Desensitization, which gradually increases the concentration of the anticancer drug considered to be the antigen until the target dosage, has been reported as being particularly effective, with a success rate of 80-100%. The aims of this paper are to present the current findings regarding hypersensitivity reactions to platinum agents and to discuss attempts of using desensitization against hypersensitivity reactions worldwide., (© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Objective: Administration of infliximab is associated with a well-recognised risk of infusion reactions. Lack of a mechanism-based rationale for their prevention, and absence of adequate and well-controlled studies, has led to the use of diverse empirical administration protocols. The aim of this study is to perform a systematic review of the evidence behind the strategies for preventing infusion reactions to infliximab, and for controlling the reactions once they occur., Methods: We conducted extensive search of electronic databases of MEDLINE [PubMed] for reports that communicate various aspects of infusion reactions to infliximab in IBD patients., Results: We examined full texts of 105 potentially eligible articles. No randomised controlled trials that pre-defined infusion reaction as a primary outcome were found. Three RCTs evaluated infusion reactions as a secondary outcome; another four RCTs included infusion reactions in the safety evaluation analysis; and 62 additional studies focused on various aspects of mechanism/s, risk, primary and secondary preventive measures, and management algorithms. Seven studies were added by a manual search of reference lists of the relevant articles. A total of 76 original studies were included in quantitative analysis of the existing strategies., Conclusions: There is still paucity of systematic and controlled data on the risk, prevention, and management of infusion reactions to infliximab. We present working algorithms based on systematic and extensive review of the available data. More randomised controlled trials are needed in order to investigate the efficacy of the proposed preventive and management algorithms., (© European Crohn’s and Colitis Organistion 2015.)

Unlabelled: Botulinum toxin is a widely used treatment with satisfactory results, and it is relatively safe in the doses used for cosmetic procedures. The authors report a case of allergic reaction to Chinese botulinum toxin serotype A (CBTX-A). Although this is a rare adverse event, it is nonetheless clinically relevant to healthcare professionals. A 44-year-old woman presented to the authors' hospital complaining of dynamic wrinkles. CBTX-A was used to treat her. Minutes after application, she developed urticarial plaques proximal to the injection site. The patient had an allergic reaction, as documented by a positive skin test, which was controlled by the administration of antihistamines and systemic corticosteroids. This report is intended to guide healthcare professionals faced with this type of adverse event regarding how to proceed without hindering the delivery and effectiveness of the treatment. When performed by a qualified health professional, this treatment brings excellent results in the vast majority of cases., Level of Evidence: 5 Risk., (© 2015 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.)

Background: Although long treatment courses of outpatient antimicrobials are often used in pediatric patients, few data exist regarding the frequency of adverse events (AEs) associated with these medications., Methods: We performed a retrospective cohort study of all patients seen in the Infectious Diseases clinic at a tertiary referral children's hospital from August 1, 2009 to August 1, 2011. We included patients who received ≥14 days of oral or intravenous antibiotic, antiviral, or antifungal medications. Patients receiving only prophylactic medications or human immunodeficiency virus treatment were excluded., Results: Three hundred thirty-five subjects met inclusion criteria, with a median age of 7.4 years at start of therapy. The cohort was predominantly male (60%), white (54%), and previously healthy (59%). A majority (88.4%) of subjects were treated for bacterial infections. β-Lactam agents were the most commonly used antimicrobial class (210 subjects; 62.7%), followed by clindamycin (86; 25.7%), rifampin (76; 22.7%), and vancomycin (62; 18.5%). Overall, 107 (31.9%) subjects experienced 151 distinct AEs. The most common individual AE noted was diarrhea (44; 29.1% of all AEs). Serious AEs developed in 42 (12.5%) subjects, including allergic reactions (15; 11.3% of all AEs), venous catheter-related complications (14; 13.0% of those with catheters), neutropenia (9; 3.0%), renal insufficiency (7; 2.5%), and hepatotoxicity (3; 1.1%). Rates of AEs were similar between those on oral and intravenous antimicrobials., Conclusions: In our study population, patients on prolonged oral or intravenous outpatient antimicrobials experienced AEs frequently. These findings support the need for close monitoring of pediatric patients on prolonged antimicrobial therapy and vigilance for unwanted effects of these medications., (© The Author 2014. Published by Oxford University Press on behalf of the Pediatric Infectious Diseases Society. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Background: A 30-min application of a hair dye product containing 2% p-phenylenediamine (PPD) to subjects diagnostically graded +, showed that 12 of 18 reacted; eight of 18 with a true + and four of 18 with a doubtful (?+) response, whereas six of 18 did not react at all. In vitro skin-binding experiments showed that for diagnostic patch test conditions the measured exposure level (MEL) is more than 10-fold higher than the MEL for hair dyeing conditions., Objective: To further analyse the limited elicitation response of the diagnostically + graded subjects to a PPD hair dye product, under standardized test conditions mimicking product usage, by varying exposure time and dose., Methods: A hair dye model formulation containing 2% PPD, applied for 30, 45 and 60 min and a diagnostic PPD TRUE test(®) were applied to assess elicitation responses to increasing PPD exposure levels. Grading was performed according to International Contact Dermatitis Research Group guidelines., Results: Six subjects were available for this follow-up study. One of six subjects responded with a + elicitation response to the hair dye model applied for 60 min. Four of the five remaining subjects elicited a + response to the PPD TRUE test(®) applied subsequently, while one of five responded doubtfully., Conclusions: Increasing the PPD exposure time twofold--resulting in a 5-6% increase of sensitivity of this hair dye model test--or further extending the exposure time 48-fold, was found sufficient to increase the MEL above the thresholds needed to elicit individuals with a + diagnostic PPD patch test who did not react to typical hair dye use conditions with a MEL of about 6·8 μg cm⁻². This analysis confirms that consideration of the MEL is a useful tool to better characterize thresholds of elicitation than consideration of the applied dose alone., (© 2014 British Association of Dermatologists.)

Background: Hypersensitivity to nonsteroidal anti-inflammatory drugs (NSAIDs) can affect children, with the mechanism proposed being inhibition of the cyclooxygenase enzyme-1 (COX-1). In these patients nonchemically related NSAIDs, including COX-2 inhibitors, can induce the reaction, hampering treatment of fever and inflammatory processes., Objectives: To analyse retrospectively tolerance to etoricoxib, a selective COX-2 inhibitor, and to meloxicam, a preferential COX-2 inhibitor, in children with hypersensitivity to NSAIDs., Methods: Clinical records of children (aged 1-14 years) diagnosed with hypersensitivity reactions to NSAIDs from January 2006 to January 2013 were included. The diagnosis was confirmed by oral drug provocation test (DPT) with the culprit NSAIDs and acetylsalicylic acid (ASA). Tolerance to paracetamol, etoricoxib and meloxicam was also evaluated., Results: The study included 41 children with a positive DPT with ASA and the culprit NSAID. DPT with paracetamol and etoricoxib was negative in all children, although two (4.9%) children developed a reaction after the administration of meloxicam., Conclusions: These data indicate that both etoricoxib and meloxicam are good alternatives for treatment in older children with hypersensitivity to NSAIDs., (© 2013 British Association of Dermatologists.)

Background: Our understanding of whether the use of acetaminophen and/or antibiotics in early life can cause allergic diseases in later childhood remains inconclusive. The objective of this study was to investigate the temporal relationship between exposure to acetaminophen and/or antibiotics in early life and the development of allergic diseases in later childhood, using two independent birth cohorts derived from the National Health Insurance Research Database (NHIRD) in Taiwan., Methods: The authors conducted a prospective birth cohort study of 263 620 children born in 1998 and 9910 children born in 2003, separately, from the NHIRD. Exposure status of acetaminophen and/or antibiotics and potential confounding factors were included in the analyses. Cox proportional hazards models were applied to determine the temporal relationship between acetaminophen and/or antibiotic exposure and the development of allergic diseases., Results: We observed a positive relationship between acetaminophen and/or antibiotic exposure during the 1st year of life and the subsequent development of the three examined allergic diseases (atopic dermatitis, asthma and allergic rhinitis) in the 1998 birth cohort, but the observed relationship of drug exposure in the 2003 cohort, especially for atopic dermatitis and asthma, was lower than for those in the 1998 cohort and was not statistically significant., Conclusions: Our findings provide suggestive evidence that the temporal effect of exposure to acetaminophen and/or antibiotics influences the development of common allergic diseases in later childhood. Further functional studies and/or animal studies are needed to better understand the underlying regulatory mechanisms driving this important clinical and public health issue.

Chlorhexidine is a low molecular weight occupational sensitizer that can cause different delayed and immediate-type allergic reactions including anaphylaxis. It is widely used as an antiseptic and disinfectant and not only in the occupational environment as it is present in toothpaste, mouthwash, nose and eye drops and ointments. We present three cases of occupationally exposed workers with airway allergy to chlorhexidine. The role of chlorhexidine as an occupational allergen was confirmed by placebo-controlled specific inhalative challenge tests monitored by spirometry and analysis of induced sputum (influx of eosinophils after provocation has been observed). One of these patients presented with a systemic reaction with ordinary environment exposure. These findings are a reminder to clinicians of chlorhexidine's ability to cause various hypersensitivity reactions and the potential risk of this widely used antiseptic.

There is increasing evidence that epigenetic regulation of gene expression plays a pivotal role in the orchestration of immune and allergic responses. Such regulatory mechanisms have potentially important implications for the acquisition of sensitization to chemical and drug allergens; and in determining the vigor, characteristics, and longevity of allergic responses. Importantly, the discovery of long-lasting epigenetic alterations in specific immunoregulatory genes provides a mechanistic basis for immune cell memory, and thereby the potential of chemical allergens to influence the subsequent orientation of the adaptive immune system. In this article, we consider the implications of epigenetic mechanisms for the development of sensitization to chemical and drug allergens and the form that allergic reactions will take.

Purpose: Two cases of successful desensitization to docetaxel after severe hypersensitivity reactions are reported., Summary: Two patients with gynecological malignancies (uterine leiomyosarcoma and ovarian adenocarcinoma) experienced severe hypersensitivity reactions with docetaxel, including flushing, numbness, sharp radiating pain, severe nausea and vomiting, apnea, and unresponsiveness. Both patients received ondansetron before docetaxel. One patient received dexamethasone, diphenhydramine, and famotidine premedication before docetaxel, as she had previously reacted to paclitaxel. Docetaxel infusions were stopped, and the reactions were treated with diphenhydramine and dexamethasone (one patient also received famotidine). After resolution of symptoms, the docetaxel was not reinitiated due to the nature of the reactions. For the next cycle, both patients received a graded drug challenge or desensitization. Both were pre-medicated with dexamethasone, diphenhydramine, and famotidine. The docetaxel was given as infusions of 0.1%, 1%, and 10% of the dose, with each infusion given over one hour. After this, the remainder of the dose was infused over one hour. Both patients tolerated this desensitization well and completed a total of three and four cycles each. The first patient to receive the desensitization did complain of chest pain during the first desensitization, and the infusion rate was decreased to administer the drug over two hours. After she tolerated two cycles of two-hour infusions, the infusion rate was increased to administer each docetaxel infusion over one hour., Conclusion: Two patients who had severe hypersensitivity reactions to docetaxel successfully received further docetaxel doses via a desensitization procedure that involved the sequential administration of solutions containing increasing concentrations of the drug.

A 61 year old woman with active luminal Crohn's disease was successfully treated with infliximab induction therapy followed by 5 infusions every 8 weeks. However, symptoms returned in the weeks preceding the 7th and 8th infusions. The 9th infusion was therefore given only 4 weeks after the 8th infusion, but an acute severe anaphylactoid reaction occurred immediately after start of the infusion. Anti-infliximab IgG antibody concentration was high (100 U/ml) prior to the 8th infusion and up to 1 year after infliximab discontinuation (81 U/ml). Anti-infliximab IgE antibodies were not found, and the anti-infliximab antibodies did not cross react with adalimumab. One week after the anaphylactoid reaction to infliximab, adalimumab therapy was initiated. Twelve days after the first adalimumab administration (80 mg), a delayed hypersensitivity reaction occurred. This was likely caused by rapidly generated anti-adalimumab IgG antibodies (45 U/ml), as these antibodies appeared to be specific for adalimumab in that infliximab failed to compete with adalimumab/anti-adalimumab antibody binding ex vivo. In conclusion, immunogenicity to infliximab and adalimumab may be associated with both acute anaphylactoid reactions and delayed hypersensitivity reactions. Reactions may be precipitated by newly induced specific anti-drug antibodies rather than by cross-reactivity of previously generated antibodies., (Copyright © 2011 European Crohn's and Colitis Organisation. Published by Elsevier B.V. All rights reserved.)

Our aim was to evaluate real-world safety and effectiveness in a 6-month postmarketing surveillance study covering all Japanese patients with rheumatoid arthritis (RA) who received etanercept during a 2-year period. Data for 13,894 patients (1334 sites) enrolled between March 2005 and April 2007 were collected. Adverse events (AEs) and serious adverse events (SAEs) were reported in 4336 (31.2%) and 857 (6.2%) patients, respectively. The most frequent AEs were injection site reactions (n = 610, 4.4%) and rash (n = 339, 2.4%), whereas pneumonia (n = 116, 0.8%) and interstitial lung disease (n = 77, 0.6%) were the most frequent SAEs. Significant improvement in the proportion of patients with a good European League Against Rheumatism (EULAR) response was observed from week 4 (17.6%) to week 24 (31.6%) (p < 0.001); 84.3% of patients had good or moderate EULAR responses at week 24. The percentage of patients achieving remission increased significantly from week 4 (9.3%) to week 24 (18.9%) (p < 0.001). Patients with early moderate RA were less likely to experience SAEs and were more likely to achieve remission compared with patients with more severe disease. The safety and effectiveness of etanercept was demonstrated in Japanese patients in one of the largest observational trials conducted thus far in RA patients treated with biologics.