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Background: Anaphylaxis-like reactions developing within a few minutes are the most frequent complications of subcutaneous or submucosal injections of local anaesthetics (LAs), and topically applied LAs are potential contact allergens. In addition, injected LAs have been reported to induce delayed reactions, including local inflammation at the injection site, and various general symptoms., Objectives: To assess the frequency and symptoms of late-type hypersensitivity occurring several hours after LA injections., Methods: We retrospectively evaluated clinical data and test results from all patients referred to our allergy clinic in a period of 20 years for diagnostic work-up of LA-associated late-type reactions., Results: Of 202 patients reporting symptoms with onset at least 1 hour after LA injection, 40 had cutaneous inflammation confined to the injection site, and 162 reported various systemic symptoms. LA hypersensitivity could be excluded in all patients with systemic complaints by means of skin testing and subsequent subcutaneous provocation. In 8 of the 40 patients (20%) with local inflammatory reactions, late-type allergic LA hypersensitivity was confirmed., Conclusions: Late-type LA allergy commonly causes inflammatory skin reactions confined to the injection site. Conversely, LAs are highly unlikely to trigger delayed systemic symptoms such as urticarial or exanthematous skin eruptions., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Nexplanon® is an etonogestrel implant with a long-acting contraceptive effect. Although several studies underlined its safety profile, its implant can rarely lead to moderate or severe adverse event. Here, we presented a case of delayed-type hypersensitivity reaction against Nexplanon® that resolved after its removal., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Introduction: Hypersensitivity reactions to beta-lactams (BLs) are often reported in children, with amoxicillin and, to a lesser extent, cephalosporins being the most frequent drugs involved. Although many of these children are considered to be allergic, a careful evaluation only confirms a low percentage., Objectives: To analyse the clinical data, sensitization profile and diagnostic methods used in a large group of children with a clinical history of hypersensitivity reactions to BLs., Methods: The study included children aged 1-14 yr with symptoms suggestive of hypersensitivity to BLs from January 2006-December 2012. Diagnosis was confirmed from a clinical history, specific IgE determination, skin testing and, if necessary, a drug provocation test (DPT)., Results: Of a total of 783 patients studied, only 62 (7.92%) were confirmed as being allergic, 9 (14.52%) with immediate and 53 (85.48%) with non-immediate reactions. In those with immediate reactions, 2 (22.22%) were diagnosed by in vitro test, 2 (22.22%) by skin testing and 5 (55.56%) by DPT; in those with non-immediate reactions, 2 (3.77%) were diagnosed by skin testing and 51 (96.23%) by DPT. In all cases, DPT was positive to the culprit drug (29 AX-CLV, 26 AX, 1 cefixime and 1 cefaclor), and the most usual symptoms were exanthema in 43 cases, urticaria in 12, urticaria-angio-oedema in 1 and erythema in 1 case., Conclusion: After an allergological work-up, over 90% of the children evaluated were finally confirmed as tolerant to BLs. Most reactions were of the non-immediate type, and DPT was an essential tool for diagnosis., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Penicillins and cephalosporins are the most widely used antibiotics for the treatment of common infections, and they are the two main classes of β-lactams. On the basis of the time of appearance of the reaction after drug intake and for diagnostic purposes, hypersensitivity reactions to β-lactams have been classified as immediate or non-immediate. The diagnostic evaluation of allergic reactions to β-lactams has changed over the last decade, for several reasons. In many countries, major and minor determinants for skin testing are not available. In immediate allergic reactions, the sensitivity of skin testing is decreasing. For non-immediate reactions, skin testing appears to be less sensitive than previously reported. The drug provocation test is still necessary for diagnosis. In this education review series, we described three cases of β-lactam allergy: first, a child with an IgE-mediated allergy to benzyl-penicillin; second, a child with a non-allergic hypersensitivity to amoxicillin; and in the third patient, we will discuss about cross-reactivity between penicillins and cephalosporins. These cases are correlated with the practical management of evaluating β-lactam allergy., (© 2011 John Wiley & Sons A/S.)

Studies based on skin and challenge tests have shown that 12-60% of children with suspected betalactam hypersensitivity were allergic to betalactams. Responses in skin and challenge tests were studied in 1865 children with suspected betalactam allergy (i) to confirm or rule out the suspected diagnosis; (ii) to evaluate diagnostic value of immediate and non-immediate responses in skin and challenge tests; (iii) to determine frequency of betalactam allergy in those children, and (iv) to determine potential risk factors for betalactam allergy. The work-up was completed in 1431 children, of whom 227 (15.9%) were diagnosed allergic to betalactams. Betalactam hypersensitivity was diagnosed in 50 of the 162 (30.9%) children reporting immediate reactions and in 177 of the 1087 (16.7%) children reporting non-immediate reactions (p<0.001). The likelihood of betalactam hypersensitivity was also significantly higher in children reporting anaphylaxis, serum sickness-like reactions, and (potentially) severe skin reactions such as acute generalized exanthematic pustulosis, Stevens-Johnson syndrome, and drug reaction with systemic symptoms than in other children (p<0.001). Skin tests diagnosed 86% of immediate and 31.6% of non-immediate sensitizations. Cross-reactivity and/or cosensitization among betalactams was diagnosed in 76% and 14.7% of the children with immediate and non-immediate hypersensitivity, respectively. The number of children diagnosed allergic to betalactams decreased with time between the reaction and the work-up, probably because the majority of children with severe and worrying reactions were referred for allergological work-up more promptly than the other children. Sex, age, and atopy were not risk factors for betalactam hypersensitivity. In conclusion, we confirm in numerous children that (i) only a few children with suspected betalactam hypersensitivity are allergic to betalactams; (ii) the likelihood of betalactam allergy increases with earliness and/or severity of the reactions; (iii) although non-immediate-reading skin tests (intradermal and patch tests) may diagnose non-immediate sensitizations in children with non-immediate reactions to betalactams (maculopapular rashes and potentially severe skin reactions especially), the diagnostic value of non-immediate-reading skin tests is far lower than the diagnostic value of immediate-reading skin tests, most non-immediate sensitizations to betalactams being diagnosed by means of challenge tests; (iv) cross-reactivity and/or cosensitizations among betalactams are much more frequent in children reporting immediate and/or anaphylactic reactions than in the other children; (v) age, sex and personal atopy are not significant risk factors for betalactam hypersensitivity; and (vi) the number of children with diagnosed allergy to betalactams (of the immediate-type hypersensitivity especially) decreases with time between the reaction and allergological work-up. Finally, based on our experience, we also propose a practical diagnostic approach in children with suspected betalactam hypersensitivity., (© 2011 John Wiley & Sons A/S.)

Background: Cross-reactivity between aztreonam and β-lactams is poor, but tolerability of aztreonam has been assessed in a few groups of patients suffering from IgE-mediated allergy to β-lactams. The aim of this study was to assess the cross-reactivity of aztreonam with other β-lactams and its tolerability in patients with cell-mediated allergy to these drugs., Methods: We studied 78 patients with cell-mediated allergy to β-lactams who underwent skin prick, immediate and delayed-reading intradermal tests as well as patch tests with penicilloyl-polylysine, minor determinant mixture, semi-synthetic penicillins, cephalosporins, aztreonam and imipenem. Patients with negative allergy testing with aztreonam underwent an intramuscular test dosing and were observed for 3 h., Results: Our patients experienced 94 non-immediate reactions; delayed-onset urticaria (34 cases), maculopapular exanthema (13 cases), urticaria/angioedema (15 cases) and itching erythema (13 cases) were the most reported symptoms. Amoxicillin (35 cases), ampicillin (28 cases) and bacampicillin (18 cases) were the most involved drugs. All patients had a positive patch test and/or a positive delayed-reading intradermal test to at least 1 β-lactam antibiotic and none had a positive patch or delayed-reading intradermal test to aztreonam. Then, 65 patients underwent intramuscular test dosing with aztroenam, and none of them had a clinical reaction., Conclusions: Our data confirm the lack of cross-reactivity between β-lactams and aztreonam in patients with cell-mediated allergy to these drugs. Delayed-reading intradermal tests and patch tests with aztreonam represent a simple and rapid diagnostic tool to establish tolerability in β-lactam-allergic patients., (Copyright © 2010 S. Karger AG, Basel.)

Local anesthetics (LA) are common elicitors of adverse reactions and the clinical symptoms often correspond to anaphylaxis with tachycardia, hypotension and subjective feelings of weakness, heat or vertigo. The pathomechanism of immediate hypersensitivity reactions to LA is largely unknown -they are commonly regarded as 'pseudo-allergic' or 'non-immune type' anaphylaxis. Immunologically mediated reactions have rarely been observed with positive skin prick tests. Other ingredients in LA preparations have to be considered as elicitors, e.g. preservatives like benzoates or sulfites or latex contaminants in injection bottles. Practical management of patients with a history of LA reaction includes a careful allergy history, skin-prick and intradermal tests. Undiluted LA solutions may elicit false-positive intradermal test reactions. If prick and intradermal tests are negative, the procedure of subcutaneous provocation testing is applied in a placebo-controlled manner. When patients are constantly reacting to placebo, a regimen of 'reverse placebo provocation' with injection of a LA (verum) is applied while the patient is informed about receiving placebo in order to 'rule out psychosomatic involvement'. With this regimen it is possible to eliminate anxiousness and fear, and the patient has proof that he has tolerated the respective LA substance., (Copyright 2010 S. Karger AG, Basel.)

Purpose of Review: The purpose of the present review is to examine the hypersensitivity reactions to preservatives in topical ophthalmic therapies., Recent Findings: Ocular hypersensitivity reactions to different types of preservatives in different chemical classes of topical ophthalmic treatments reviewed in the literature include IgE-mast cell mediated, cell mediated and toxic. Quaternary ammoniums (benzalkonium chloride) are most commonly (8% reported cases in OVID and PubMED based searches) associated with irritant toxic reactions whereas the organomercurials (thimerosal) and the alcohols (chlorobutanol) have the highest association (19% of OVID and 14% of PubMED based searches and 20% of OVID and 11% of PubMED searches), respectively, with allergic responses although the term allergy for the 'alcohols' appears to be actually an irritant effect whereas the organomercurials appear to truly interact with the immune system as neoantigens., Summary: A large number of clinical and experimental studies reveal that preservatives in topical ophthalmic medications have been demonstrated to produce effects from inflammation/ hypersensitivity to permanent cytotoxic effects involving all structures of the eye.

Purpose of Review: A number of studies over recent years have shown the relevance of nonimmediate immunological reactions to drugs and emphasized the need for these reactions to be studied in greater depth, including both in-vivo and in-vitro tests and provocation studies., Recent Findings: Several clinical entities are involved, ranging from mild to severe reactions. Nonimmediate reactions have a special tropism for the skin, although other organspecific or systemic reactions may also occur. In the affected organ, the drug acts as a hapten or protohapten, originating an immunological stimulus that is followed by recruitment of T lymphocytes and other types of cells, depending on the reaction. This involves a trafficking phenomenon in which these cells use different receptors that interplay with their corresponding ligands in the tissue. In addition, a number of activation and cytotoxic markers are also expressed, which are related with disease severity., Summary: Current studies provide overwhelming evidence of the interaction between the organ involved, very often the skin, and immunocompetent cells. This is of relevance for diagnostic and therapeutic approaches.

Itching erythematous or eczematous plaques around injection sites are quite frequent side effects of heparin treatment and clinical symptoms of delayed-type non-IgE-mediated allergic hypersensitivity (DTH) to heparin. For diagnosis, intradermal, patch, and subcutaneous challenge tests with heparins are suitable. In most cases, changing the subcutaneous therapy from unfractionated to low molecular weight heparin or treatment with heparinoids does not provide improvement because of extensive cross-reactivity. Hirudin polypeptides, which exhibit a different chemical structure, are a safe therapeutic alternative for subcutaneous application, however. Importantly, despite DTH to subcutaneously injected heparins, most patients tolerate heparin intravenously. Moreover, in case of therapeutic necessity and DTH to heparins, the simple shift from subcutaneous to intravenous heparin administration without prior testing may be justified.

Drug allergies are adverse drug reactions mediated by the specific immune system. Despite characteristic signs (eg, skin rash) that raise awareness for possible drug allergies, they are great imitators of disease and may hide behind unexpected symptoms. No single standardized diagnostic test can confirm the immune-mediated mechanism or identify the causative drug; therefore, immune-mediated drug hypersensitivity reactions and their causative drugs must be recognized by the constellation of exposure, timing, and clinical features including the pattern of organ manifestation. Additional allergologic investigations (skin tests, in vitro tests, provocation tests) may provide help in identifying the possible eliciting drug.

Purpose of Review: This review presents the current knowledge of the role of T cells in drug allergy manifesting as exanthematous, pustular and bullous skin diseases, collectively referred to as nonimmediate allergic drug reactions., Recent Findings: Both CD4+ and CD8+ T cells producing type 1 and type 2 cytokines and endowed with cytotoxic properties are involved in nonimmediate allergic drug reactions. Recent studies have confirmed that CD8+ T cells play a major role in the pathophysiology of nonimmediate allergic drug reactions, and have characterized new cytotoxic molecular pathways responsible for the severity of the bullous forms of nonimmediate allergic drug reactions., Summary: Nonimmediate allergic drug reactions are mediated by T cells and mostly affect the skin. Nonimmediate allergic drug reactions comprise several diseases ranging from the frequent and benign maculo-papular exanthema to the severe and rare toxic epidermal necrolysis. Progress in the knowledge of the pathophysiology of nonimmediate allergic drug reactions comes from a better understanding of the mechanisms of drug recognition by T cells and from a careful analysis of the phenotype and functions of CD4+ and CD8+ T cells infiltrating the skin lesions. Recent studies have confirmed that the different clinical forms of nonimmediate allergic drug reactions are associated with distinct types of T cell-mediated skin inflammation. However, CD8+ T cells appear as major effector T cells in most of the nonimmediate allergic drug reactions. Future studies to analyze the early cellular and molecular events leading to the development of the allergic skin reaction will be helpful in order to define diagnostic and therapeutic targets.

Drug desensitization is the induction of temporary clinical unresponsiveness to drug antigens to which patients have presented severe hypersensitivity reactions. It is typically achieved by gradual reintroduction of small doses of drug antigens at fixed time intervals, and it is aimed at providing increased safety and protection from side effects, including anaphylaxis. Delivery of full therapeutic doses is achieved during desensitization, allowing patients to receive firstline chemotherapy, antibiotics, or monoclonal antibodies, as well as other drugs such as insulin, aspirin, and iron. Desensitizations are high-risk interventions. Inhibition of cellular activation mechanisms occurs during drug desensitization, allowing for the protective clinical outcomes and lack of side effects in the majority of cases, but the cellular and molecular inhibitory mechanisms are incompletely understood. The indication for desensitization protocols can only be done by trained allergists and immunologists and should be implemented as standard of care because of their high success rates and outcomes-demonstrated safety profile.

Background: beta-Lactam (BL) antibiotics can induce non-immediate skin reactions, frequently manifested as exanthema or urticaria. The time between drug intake and the reaction appearance is generally 24-48 h. Because the mechanisms involved are not completely understood, diagnostic tests for these reactions have still to be fully validated., Objective: To evaluate the role of skin and drug provocation tests (DPTs) in the diagnosis of patients with non-immediate reactions to BL., Methods: We evaluated a group of 22 patients who developed maculopapular exanthema or urticarial exanthema after BL intake. Diagnosis was confirmed by DPT with BL. Intradermal/patch testing was performed with benzylpenicilloyl, minor determinant mixture, amoxicillin (AX), ampicillin (AMP) and the culprit drug in patients and in 22 negative controls. Immunohistochemical studies were done in the affected skin at the acute phase of the reaction and after a delayed positive skin test/DPT. IFN-gamma and IL-4 were quantified in peripheral mononuclear cells, obtained during the positive response to DPT and after resolution of the symptoms., Results: From the total number of cases, 12 patients developed urticarial exanthema and 10 maculopapular exanthema after DPT. Only two of the 22 patients (9%) had a positive delayed intradermal skin test: one to AX/AMP and the other to cloxacillin. Biopsies showed a mononuclear CD4, CD8 infiltrate and activated and memory cells. The cytokine expression showed a Th1 pattern in patients, in contrast with the Th0 pattern in controls., Conclusion: In patients with non-immediate reactions to BLs (maculopapular exathema or urticarial exanthema), the sensitivity of skin testing is low and DPT may be required to establish the diagnosis. The reproducibility of the reactions and the cytokine pattern expressed during the acute episode support a T cell-induced non-immediate response.

Allergy-like reactions may occur following administration of iodinated contrast media (CM), mostly in at-risk patients (patients with history of previous reaction, history of allergy, co-treated with interleukin-2 or beta-blockers, etc.) but remain generally unpredictable. Severe and fatal reactions are very rare events. All categories of CM may induce such reactions, although first generation (high osmolar CM) have been found to induce a higher rate of adverse events than low osmolar CM. However, no differences were found between the two categories of CM with respect to mortality. Delayed reactions can also occur. There are no differences between the various categories of CM except for non-ionic dimers, which are more likely to induce such effect. Numerous clinical studies have evaluated the prophylactic value of drugs (mostly antihistamines and corticosteroids). Results are unclear and highly variable. Any prevention depends upon the mechanism involved. However, the mechanism of CM-induced allergy-like reaction remains disputed. Relatively recent data revived the hypothesis of a type-I hypersensitivity mechanism. Positive skin tests to CM have been reported. However, the affinity of IgE towards CM has been found to be very low in the only study which actually evaluated it. Other pathophysiological mechanisms (involving direct secretory effects on mast cells or basophils, or activation of the complement system associated or not with the plasma contact system) are also much debated. Anaphylaxis and anaphylactoid reactions are, in the end, clinically undistinguishable.

Aim: To explore the pathophysiological significance of delayed type hypersensitivity (DTH) reaction in mouse gastrointestinal tract induced by an allergen 2,4-dinitrochlorobenzene (DNCB)., Methods: BALB/c mice were randomly divided into control and DTH(1-6) groups. After sensitized by DNCB smeared on the abdominal skin, the mice were challenged with DNCB by gavage or enema. The weight, stool viscosity and hematochezia were observed and accumulated as disease active index (DAI) score; the gastrointestinal motility was represented by active charcoal propulsion rate; the colon pathological score was achieved by macropathology and HE staining of section prepared for microscopy; and the leukocyte migration inhibitory factor (LMIF) activity was determined by indirect capillary assay of the absorbance (A) of migrated leukocytes., Results: Active charcoal propulsion rates of small intestine in the DNCB gavages groups were significantly higher than that in the control group (P<0.01). The DAI scores and pathological score in DNCB enema groups were also higher than that in the control group (P<0.05), and there were significant rises in LMIF activity in DNCB enema groups as compared with control groups (P<0.01)., Conclusion: Mouse gastrointestinal DTH reaction could be induced by DNCB, which might facilitate the mechanism underlying the ulcerative colitis.

This report describes the frequency and characteristics of serious or life-threatening hypersensitivity reactions to the tuberculin skin test over an 11-year period through November 2000. There were 24 reports and no deaths, indicating that such reactions are rare (0.08 reported reactions per million doses of tuberculin).

The Gell and Coombs's classification divides drug allergies into four pathophysiological types, namely anaphylaxis (type I), antibody-mediated cytotoxic reactions (type II), immune complex-mediated reactions (type III), and delayed type hypersensitivity (type IV). Although this classification was proposed more than 30 years ago, it is still widely used. As only a limited number of drug allergies fit into this classification which does not include our current understanding of the immune response, its use is not recommended, particularly in the context of the preclinical safety evaluation of new therapeutic agents. In fact, three different situations can be identified, namely pseudo-allergic reactions, primarily antibody-mediated reactions and cell-mediated reactions, which could serve as a basis for modern and more adequate classifications

The use of vancomycin has increased dramatically in recent years with the emergence of methicillin-resistant Staphylococcus aureus and coagulase-negative staphylococci as important hospital pathogens. A patient receiving vancomycin 1.75 g intravenously as a single daily dose developed a syndrome characterized by high fever, erythema multiforme, eosinophilia, and presumed interstitial nephritis. This delayed hypersensitivity reaction resolved with discontinuation of the drug and treatment with methylprednisolone.

The ovalbumin (OA)-sensitized Brown Norway rat (BN) demonstrates early-response (ER) and late-response (LR) allergic bronchoconstriction. To determine whether these responses could be replicated in vitro, we studied lung explants from 8-wk-old male BN rats (wt: 239 +/- 28 g), of which 19 were sensitized to OA (test) and 16 served as controls. Two weeks after sensitization, the animals' lungs were removed, filled with a 1% (wt/vol) agarose-containing solution at 37 degrees C, and cooled to 4 degrees C. Transverse slices (0.5 to 1.0 mm thick) were cut and cultured overnight. Airways were visualized with an inverted microscope and baseline images were obtained with a video camera. To study the ER, 40 airways from 15 test rats and 29 airways from 10 control rats were challenged with 2 micrograms OA and imaged each minute for 10 min. To study the LR, 40 airways from 12 test rats and 44 airways from 12 control rats were challenged with 2 micrograms OA and imaged each hour for 8 h. The maximal response (MR) for each airway was defined as the percent of airway closure. The ER and LR were both defined as an MR > or = mean + 2 SD of the controls. An ER occurred in 38 of 40 test and 2 of 29 control airways (mean MR: 42 +/- 24% versus 4 +/- 3%, p < 0.001), and was completely blocked by methysergide pretreatment in 13 airways.(ABSTRACT TRUNCATED AT 250 WORDS)

The potency of cytostatic and anti-inflammatory drugs was tested on the oxazolone-induced cutaneous basophil hypersensitivity (CBH) in mice. The challenge reaction was performed early after sensitization in order to minimize B-cell expression; exudative and cellular infiltration was estimated 6 h, 24 h and 48 h after challenge. The potency of drugs was tested at three different periods of immunization: 2 days before or after sensitization or before challenge. Cytostatics act mainly when cells are being committed, a corticoid acts on inflammation linked to committed cells, NSAIDs show inconstant anti-inflammatory effects on this test. D-Penicillamine and levamisole act in the same depressive profile in normal animals. Thus the CBH model appears to be relevant in studying drug activities on inflammation linked to T-cell expression.