Hypersensitivity reactions to iodinated contrast media

Adverse reactions after iodinate contrast media (ICM) administration have been observed, which can be classified as immediate (i.e., occurring within one hour after administration) and delayed or non-immediate (i.e., occurring more than one hour after administration). Even though the incidence of ICM adverse reactions has been significantly reduced by the introduction of non-ionic compounds, immediate reactions still occur in about 3% of administrations. Different pathogenic mechanisms have been suggested for ICM reactions, including immunologic ones. Basophils and mast cells participate in immediate reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most non-immediate reactions, particularly maculopapular rashes. Skin tests and specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while both delayed-reading intradermal tests and patch tests are usually performed to evaluate non-immediate reactions. However, in vitro specific IgE assays are not commercially available. As far as in vitro tests are concerned, a response involving ICM-related T-cell activity may be assessed by the lymphocyte transformation test. Allergologic evaluation appears to be indicated in hypersensitivity reactions to ICM, although the sensitivity, specificity, and predictive values of allergologic tests have not yet been established. This paper summarizes the current state of the art and addresses the research that is still needed on the pathogenic mechanisms, diagnosis, and prevention of ICM-induced hypersensitivity reactions.     

T cell assessment in allergic drug reactions during the acute phase according to the time of occurrence

Allergic drug reactions can be classified as immediate, accelerated or delayed. This classification usually correlates with the mechanism involved: immediate reactions are IgE mediated and delayed reactions are T cell dependent. We analyzed lymphocyte involvement in patients with these reactions by determining cell subpopulations, activation state and skin homing receptor expression (CLA) in blood and skin. Patients with immediate, accelerated and delayed reactions were evaluated during the acute phase and after resolution. Controls taking drugs were included. Phenotypic immunofluorescence analysis was done by flow cytometry in peripheral blood, and by immunohistochemistry in skin for delayed reactions. Forty-six patients were included, 17 with immediate reactions, 10 accelerated and 19 delayed. At the acute phase CLA was significantly increased in delayed reactions and HLA-DR in all three types of reaction. In the severest delayed reactions, Steven-Johnson/Lyell syndromes, the CD4 subsets were increased in peripheral blood and skin compared to maculopapular exanthemas and urticaria and HLA-DR when compared with urticaria. In maculopapular exanthemas CLA was significantly increased in peripheral blood and skin compared to urticaria and the severe reactions. We found that T-cells are implicated, besides delayed reactions, in immediate and accelerated reactions. In delayed reactions there is a parallelism between results found in skin and peripheral blood with a higher participation of CD4+ cells the more severe the reaction.     

IgE-mediated hypersensitivity to cephalosporins

Like penicillins, cephalosporins may cause IgE-mediated reactions such as urticaria, angioedema, and anaphylactic shock, which occur because of sensitization to determinants shared with penicillins or to unique cephalosporin haptens. In particular, side-chain structures may be responsible for selective sensitization or cross-reactivity. For this reason, individual free cephalosporins are usually employed in skin testing, in addition to the classic penicillin reagents. Cephalosporin skin tests are sensitive in diagnosing immediate hypersensitivity to these betalactams. As far as in vitro tests are concerned, IgE assays for cephalosporins, specifically sepharose-radioimmunoassays, are a potentially useful tool in evaluating immediate reactions and could be used as complementary tests. In selected cases displaying negative results in both skin tests and IgE assays, a graded challenge with the implicated cephalosporin can be performed. Cephalosporin IgE-mediated hypersensitivity may be a transient condition; therefore, allergologic exams should be repeated in patients with negative initial allergologic work-ups, including challenges. Performing allergologic tests with cephalosporins other than the culprit, as well as with penicillin reagents, allows the identification of cross-reactivity with penicillins, selective responses, or cross-reactivity among cephalosporins. In the latter group, cross-reactivity is more frequently related to R1 than to R2 side-chain recognition. In assessing the selectivity of the response, negative results in skin testing with cephalosporins other than the responsible one appear to be a reliable indicator of tolerability.     

Immediate allergic reactions to beta-lactams: diagnosis and therapy

Beta-lactams are the antibiotics which most frequently provoke adverse reactions mediated by specific immunological mechanisms. These reactions, classifiable as immediate or non-immediate, can be produced by the four classes of beta-lactams (penicillins, cephalosporins, carbapenems and monobactams) currently available, which share a common beta-lactam ring structure. Immediate reactions occur within the first hour after drug administration and are characterized by urticaria, angioedema, rhinitis, bronchospasm, and anaphylactic shock. Immediate reading skin tests are the quickest and most reliable method for demonstrating the presence of beta-lactam specific IgE antibodies. It is crucial to use in diagnosis the suspected beta-lactams themselves, particularly cephalosporins, in addition to penicillin determinants. Serum specific IgE assays can be used as complementary tests. Negative test results should be interpreted in light of the time elapsed from the last exposure to the responsible beta-lactam. In fact, both in vivo and in vitro test sensitivity is known to decrease over time. In some diagnostic work-ups, patients with a positive history and negative skin and in vitro tests with classic reagents undergo a controlled administration of the suspected beta-lactam. The management of immediate allergic reactions should take into consideration their severity and type. Adrenaline is the drug of choice in the treatment of anaphylactic shock. In addition to adrenaline, corticosteroids and antihistamines should be administered. Histamine H(1) receptor antagonists are the mainstay of the treatment of immediate allergic reactions such as urticaria, rhinitis and conjunctivitis.     

Current understanding of contrast media reactions and implications for clinical management.

Iodinated contrast media (CM) are an integral part of modern diagnostic medicine. Although these agents are considered to be relatively safe, adverse effects in the form of allergy-like reactions occur in a significant number of exposed patients. These reactions may be divided into immediate and delayed responses. Immediate (within 1 hour of administration) anaphylactic reactions range from urticaria and angioedema to laryngeal oedema, hypotension and even death. Delayed reactions to CM occur from 1 hour to 1 week after administration and usually have mostly cutaneous manifestations. History of prior CM reactions and atopy predispose patients to CM reactions. Despite intense research into the pathogenesis of the immediate anaphylactoid responses, new evidence shows that true IgE type I hypersensitivity mediation occurs only in rare, severe cases. The aetiology appears to be multifactorial in most individuals. There is strong evidence to conclude that type IV hypersensitivity is responsible for the delayed reactions to CM. Although switching to non-ionic agents significantly reduces the incidence of immediate reactions to CM, there is little consensus regarding corticosteroid prophylaxis in high-risk individuals. Skin testing and provocative challenges also provide little security. Therefore, physicians must be better prepared to treat immediate anaphylactoid responses. Preventing delayed CM reactions is best performed with patch and delayed intradermal testing in those with a history of prior reactions, although false-negative results have been reported. Corticosteroids and antihistamines may be required for treatment. Until newer agents are developed that negate these issues, healthcare providers must strive to better understand the risk factors associated with CM reactions, as well as the available prophylactic and treatment options.     

Hypersensitivity reactions to ophthalmic products

Adverse reactions after administration of ophthalmic products have frequently been observed. These reactions can be provoked by both active principles and excipients. Different pathogenic mechanisms have been suggested for such reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly conjunctival ones and eyelid dermatitis. Prick tests and immediate-reading intradermal tests are carried out to diagnose immediate hypersensitivity reactions, while patch tests are usually performed to evaluate delayed reactions. Other diagnostic tests, such as serum-specific IgE assays in immediate reactions, as well as delayed-reading intradermal tests and/or lymphocyte transformation tests in delayed ones, are rarely performed. In this review, particular attention is addressed to the clinical and practical aspects of both cell-mediated and IgE-mediated hypersensitivity reactions to ophthalmic products.     

Tolerability of aztreonam in patients with IgE-mediated hypersensitivity to beta-lactams

Cross-reactivity between aztreonam and penicillins is poor, but clinical tolerance of aztreonam has been assessed, by means of tolerance challenge tests, only in a few groups of penicillin-allergic patients. The aim of this study is to evaluate the tolerability of aztreonam in a large group of beta-lactam-allergic patients. We studied all patients (greater than 14 years of age), with a clinical history of immediate reactions to any beta-lactam and with positive immediate-type skin tests and/or positive specific IgE to any of the studied beta-lactam; they were studied by means of: skin prick and intradermal tests with penicilloyl polylysine, minor determinant mixture, semisynthetic penicillins, cephalosporins, aztreonam and imipenem; detection of specific IgE to penicillin G, penicillin V, ampicillin, amoxicillin, cefaclor and ceftriaxone. Patients with negative immediate-type skin tests with aztreonam then underwent a graded intramuscular challenge. Forty-five patients (mean age 46.1 +/- 15.2 years), 27 females and 18 males, had positive skin tests and/or specific IgE to at least one of the studied beta-lactams. The most involved drugs were amoxicillin (23 cases), ampicillin (9 cases), penicillin G (8 cases) and other beta-lactams in the remaining cases. The most frequent reactions were anaphylaxis (27 cases) and urticaria (15 cases). All patients had negative intradermal tests with aztreonam and all patients tolerated the intramuscular graded challenge. Our data confirm the lack of cross-reactivity between beta-lactams and aztreonam. Immediate-type skin tests with aztreonam represent a simple and rapid diagnostic tool to establish tolerability in beta-lactam-allergic patients who urgently need this drug.     

Hypersensitivity reactions to complementary and alternative medicine products

Complementary and alternative medicine (CAM) is becoming increasingly popular, and is often used for treating hypersensitivity diseases. Virtually all alternative remedies can cause hypersensitivity reactions, but the most frequently involved ones are tea tree oil, members of the Compositae family, propolis, oils used in aromatherapy, substances responsible for photosensitization, and metal-containing compounds. The main target organ is skin, with manifestations ranging from contact dermatitis (the most common) to urticaria-angioedema, maculopapular eruptions, photosensitivity reactions, and the Stevens-Johnson syndrome. Other types of reactions are possible, including respiratory and anaphylactic ones. Different pathogenic mechanisms have been suggested for CAM product reactions, including immunologic ones. Basophils and mast cells participate in IgE-mediated reactions through the release of mediators like histamine and tryptase, whereas a T-cell-mediated pathogenic mechanism is involved in most delayed reactions, particularly contact dermatitis and maculopapular eruptions. Skin tests and serum specific IgE assays are carried out to diagnose immediate hypersensitivity reactions, while patch tests and lymphocyte transformation tests are usually performed to evaluate delayed hypersensitivity reactions. Thus clinicians should know about the potential of CAM products for causing adverse reactions. Our study is aimed at highlighting the risk of hypersensitive reactions to CAM remedies on the basis of the numerous cases reported in the literature. Because little is known about adverse reactions to CAM products, further systematic studies and an appropriate regulation by heath authorities are necessary.     

Skin tests in the diagnosis of drug hypersensitivity reactions

Adverse drug reactions (ADRs) are an area of concern for pharmaceutical drug development. Among these, drug hypersensitivity reactions are neither dose-dependent nor predictable, and affect only predisposed individuals. Clinical and immunological studies suggest that IgE-mediated (type I) and cell-mediated (type-IV) pathogenic mechanisms are involved in many immediate (i.e., occurring within 1 hour after the last drug administration) and non-immediate (i.e., occurring more than 1 hour after the last drug administration) hypersensitivity reactions, respectively. Skin prick, patch, and intradermal tests are the most readily available tools for the evaluation of hypersensitivity drug reactions. The diagnostic value of skin tests for many drugs still has not been fully established. Reliable skin test procedures for the diagnosis of drug hypersensitivity have been defined, and test concentrations have been validated for many drugs. Skin tests should be carried out according to the clinical features of ADRs. In immediate drug reactions, an IgE-mediated mechanism can be demonstrated by a positive skin prick and/or intradermal test after 20 minutes, whereas in non-immediate reactions, a T-cell involvement can be found by a positive patch test and/or a late-reading intradermal test. The predictive value of skin tests varies with the drug tested and is especially high with beta-lactams, muscle relaxants, insulins, platinum salts, streptokinase, and chymopapain. Further diagnostic tests are required in the assessment of drug hypersensitivity reactions. However, skin tests can provide information about the culprit drug and the mechanism involved in certain reactions. The present review addresses literature data regarding the diagnosis of drug hypersensitivity reactions by skin tests.     

Drug patch testing in systemic cutaneous drug allergy

Patch testing with the suspected compound has been reported to be helpful in determining the cause of a cutaneous adverse drug reaction (CADR) and in studying the pathophysiological mechanisms involved. The main advantages of drug patch tests are that they can be done with no hospital surveillance because they induce only rarely adverse reactions and that any commercialized form of a drug can be used. In contrast, intradermal tests can be performed only with injectable forms or with a pure and sterile form of the drug. It is advised to perform drug patch tests during the 6 months following the CADR as we do not know whether positive results will persist. Due to the possibility that a low concentration might yield false negative results, drug patch tests have to be performed with rather high concentrations of the commercialized form of the drug, mostly diluted at 30% in petrolatum and/or in water. For some drugs and severe CADR, it is necessary to tests with lower concentrations or in other vehicles. Drug patch tests are positive in ca. 32-50% of patients who have developed a CADR. The clinical relevance of drug patch tests depends on the clinical features of the CADR (valuable in testing generalized eczema, systemic contact dermatitis, maculopapular rash, acute generalized exanthematous pustulosis, fixed drug eruption) and on the involved drug. As false positive results can be observed, it is always necessary to consider the relevance of any positive drug patch test. Their specificity and their negative predictive value have not been yet determined.     

Immediate hypersensitivity reactions to penicillins and other betalactams

Immediate hypersensitivity reactions to betalactams are IgE mediated and constitute the most frequent allergic reactions mediated by specific immunological mechanisms. IgE responses to benzyl penicillin (BP), the first antibiotic producing the benzyl penicilloyl structure (BPO), are characterized by a quick release of inflammatory mediators, resulting in anaphylactic shock, urticaria and angioedema. With the progressive appearance of other structures, comprising cephalosporins, carbapenems, monobactams and clavulanic acid, IgE selective responses and cross-reactivity reactions were observed. The diagnosis of betalactam hypersensitivity, classically based on skin testing with major and minor determinants of benzyl penicillin or in vitro IgE antibodies to BP, has been modified by the inclusion of different determinants generated from these compounds, for which amoxicillin (AX) is the most relevant, followed by cephalosporins. Some subjects develop positive responses to several betalactams, mostly within the same family, but others develop a selective response. These are relevant for the appropriate selection of antimicrobial drugs in patients who have immediate hypersensitivity to betalactams.     

Delayed allergy to aminopenicillins: clinical and immunological findings

Aminopenicillins are the most used beta-lactam antibiotics. Morbilliform or maculopapular rashes are rather frequent during therapy with aminopenicillins. The pathogenesis of these reactions is often due to a cell-mediated allergy. The aim of this work is to characterize patients with cell-mediated allergy to aminopenicillins and to identify alternative beta-lactam drugs that can be safely administered to these patients. We studied 27 subjects affected by cell-mediated allergy to aminopenicillins. The diagnosis was made on the basis of positivity of patch tests with aminopenicillins. These patients then underwent an allergological evaluation (skin and patch tests, oral and/or intramuscular challenge tests) with a wide spectrum of beta-lactam antibiotics. Our work highlights the following main characteristics of cell-mediated allergy to aminopenicillins: time elapsing between drug administration and onset of symptoms of about 2 days; the maculopapular rash and delayed appearance of urticaria/angioedema were the most typical symptoms (82.8 percent of cases); a cross-reactivity with aminocephalosporins is usually absent, or it is limited to cephalexin (in our study, in fact, just 3 out of 20 patients challenged with cephalexin showed a positive oral challenge test); all the beta-lactams, other than aminopenicillins, are well tolerated. Patch tests represent a specific diagnostic tool with a good predictive value of identifying alternative drugs that can be safely administered to patients with beta-lactam allergy. Our patients could tolerate other beta-lactam drugs after a complete allergological evaluation. On the basis of our study, cell-mediated allergy to aminopenicillins should be considered a well-defined nosologic entity.     

依巴斯汀联合雷尼替丁在慢性荨麻疹中的综合疗效

目的：探讨依巴斯汀联合雷尼替丁在慢性荨麻疹中的综合疗效。方法：选取2008年6月～2010年11月于本院进行治疗的86例慢性荨麻疹患者为研究对象,将其随机分为对照组（西替利嗪联合雷尼替丁组）43例和观察组（依巴斯汀联合雷尼替丁组）43例,后将两组患者的治疗总有效率、不良反应发生率及治疗前后的血清总IgE、HA、ECP、5-HT、LT水平进行统计及比较。结果：观察组的治疗总有效率高于对照组,不良反应发生率低于对照组,血清总IgE、HA、ECP、LT水平低于对照组,血清5-HT高于对照组,P〈0.05或P〈0.01,差异有统计学意义或显著统计学意义。结论：依巴斯汀联合雷尼替丁在慢性荨麻疹中的综合疗效较佳,可影响血清总IgE、HA、ECP、5-HT、LT水平,可以作为治疗慢性荨麻疹的方案。     

Immediate reactions to contrast media: mediator release and value of diagnostic testing

Immediate reactions to iodinated contrast media (ICM) resembles anaphylaxis. The recent literature demonstrates that histamine is released in vivo, with a peak concentration correlating within the severity grade of the reaction. Mast cells participate in severe reactions, as shown by several authors through the release of tryptase. In patients with severe reactions, intradermal testing with immediate reading appear positive to the culprit ICM, confirming an immune mechanism. For further procedures, a strict avoidance of the culprit ICM must be observed. The injection of another ICM giving negative skin tests has proved safe in a few patients.     

Parenteral benzyl alcohol-induced hypersensitivity reaction

An uncommon hypersensitivity reaction due to parenteral benzyl alcohol administration is reported. One patient treated with benzyl alcohol-preserved cytarabine, vincristine, and heparin solutions developed a systemic hypersensitivity reaction on three separate occasions. Hypersensitivity to benzyl alcohol was confirmed by skin testing. Clinically, the patient presented with a fever and a maculopapular rash on the chest and arms. None of the reactions were life-threatening or required hospitalization of the patient.     

Pathophysiological characterization of drug hypersensitivity to tribenoside

Background

Tribenoside is a semisynthetic sugar derivative that is mainly indicated for treatment of chronic venous insufficiency. Up to 10% of patients treated by tribenoside can suffer from skin side effects. The adverse effects usually present as angioedema, urticaria, or maculopapular exanthema. The pathophysiology of the reaction has not as yet been elucidated.

Methods

In this study, we examined 22 patients with drug eruptions caused by tribenoside. Patch tests were performed to investigate in vivo cellular reactions. Laboratory investigations were carried out by lymphocyte transformation tests and basophil activation tests.

Results

We found a positive patch test reaction to tribenoside in one patient. The lymphocyte transformation test elicited a borderline positive reaction in one patient, and the basophil activation test gave a clearly positive reaction in another patient.

Conclusion

The diagnosis of drug hypersensitivity reactions is a challenge. Both delayed and immediate immunologic response may play a role in the etiology of tribenoside-induced exanthemas. Our investigation and results indicate that benzoic acid could be the antigenic determinant in drug hypersensitivity to tribenoside.     

Latex allergy in the workplace.

While less than 1% of the general population is sensitized to latex, the U.S. Occupational Safety and Health Administration estimates that 8-12% of health-care workers are sensitized. The major source of workplace exposure is powdered natural rubber latex (NRL) gloves. NRL is harvested from HEVEA: brasiliensis trees and ammoniated to prevent coagulation resulting in the hydrolysis of the latex proteins. Prior to use in manufacturing, the latex is formulated by the addition of multiple chemicals. Thus, human exposure is to a mixture of residual chemicals and hydrolyzed latex peptides. Clinical manifestations include irritant contact dermatitis, allergic contact dermatitis (type IV), and type I immediate hypersensitivity response. Type I (IgE-mediated) NRL allergy includes contact urticaria, systemic urticaria, angioedema, rhinitis, conjunctivitis, bronchospasm, and anaphylaxis. Taking an accurate history, including questions on atopic status, food allergy, and possible reactions to latex devices makes diagnosis of type-I latex allergy possible. To confirm a diagnosis, either in vivo skin prick testing (SPT) or in vitro assays for latex-specific IgE are performed. While the SPT is regarded as a primary confirmatory test for IgE-mediated disease, the absence of a U.S. Food and Drug Administration-licensed HEVEA: brasiliensis latex extract has restricted its use in diagnosis. Serological tests have, therefore, become critically important as alternative diagnostic tests. Three manufacturers currently have FDA clearance for in vitro tests, to detect NRL-specific IgE. The commercially available assays may disagree on the antibody status of an individual serum, which may be due to the assay's detecting anti-NRL IgEs to different allergenic NRL proteins. Sensitized individuals produce specific IgE antibody to at least 10 potent HEVEA: allergens, Hev b 1-Hev b 10, each of which differs in its structure, size, and net charge. The relative content and ratios of Hevs in the final allergen preparation most probably could effect diagnostic accuracy. The Hev proteins have been cloned and expressed as recombinant proteins. Sequencing demonstrates both unique epitopes and sequences commonly found in other plant proteins. Sequence homology helps to explain the cross reactivity to a variety of foods experienced by latex allergic individuals. The development of recombinant allergens provides reagents that should improve the diagnostic accuracy of tests for latex allergy. Although clinical and exposure data have been gathered on the factors affecting response in latex-allergic individuals, less is known regarding the development of sensitization. Coupled with in vitro dermal penetration studies, murine models have been established to investigate the route of exposure in the development of latex sensitization. Time-course and dose-response studies have shown subcutaneous, intratracheal, or topical administrations of non-ammoniated latex proteins to induce IgE production. Both in vitro penetration and in vivo studies highlight the importance of skin condition in the development of latex allergy, with enhanced penetration and earlier onset of IgE production seen with experimentally abraded skin. The diagnosis of latex allergy is complicated by these variables, which in turn hinder the development of intervention strategies. Further epidemiological assessment is needed to more explicitly define the scope, trends, and demographics of latex allergy. Diagnostic accuracy can be improved through greater knowledge of proteins involved in the development of latex allergy, and better documentation of the presently available diagnostic tests. In vivo and in vitro models can elucidate mechanisms of sensitization and provide an understanding of the role of the exposure route in latex allergy-associated diseases. Together, these efforts can lead to intervention strategies for reducing latex allergy in the workplace.     

小牛血清去蛋白注射液致广泛斑丘疹1例

1例48岁男性患者,静脉滴注小牛血清去蛋白注射液后出现广泛斑丘疹,予以报道,提醒临床使用该药时注意该种不良反应的发生。     

Cutaneous allergic drug reactions: update on pathophysiology,diagnostic procedures and differential diagnosic

Important changes in the understanding and management of drug hypersensitivity reactions during the last years result from the increasing importance of biologics in medical practice, which differ in their spectrum of adverse drug reactions (ADRs) from the classical covalent drugs. With regard to covalent drugs, ampicillin and amoxicillin as well as clavulanic acid play an increasing role among ADRs to betalactam antibiotics. Fluoroquinolones are mainly the cause of anaphylactic and photosensitivity reactions. Especially in allergic reactions to NSAIDs, pseudoallergic reactions should be considered in the differential diagnosis. In opposite to the main cutaneous allergic drug reactions such as urticaria or maculopapular skin rash, in which antibiotics are the main culprits, in severe drug allergic reactions such as SJS (Stevens-Johnson Syndrome), TEN (Toxic Epidermal Necrolysis), or DRESS (Drug Reaction with Eosinophilia and Systemic Symptoms) Syndrome, compounds like allopurinol and anticonvulsants are the main causes. Similar mutations in the IL36R gene, which were found in both patients with an AGEP (Acute Generalized Exanthematous Pustulosis) and pustular psoriasis, make the differential diagnosis more difficult and raise the question whether there is a difference between these diseases or whether AGEP is not just a drug induced pustular psoriasis. Finally, some special aspects of side effects of biologics and targeted therapies respectively are discussed.     

136例静脉滴注抗菌药物不良反应分析

目的:调查门急诊病人静脉滴注使用抗菌药物不良反应(ADR)的发生率、临床表现及相关因素,探讨抗菌药物的合理给药方案。方法:统计2004年1~12月期间上海市吴泾医院所有门急诊静脉滴注病人使用抗菌药物及发生ADR的情况。结果:总体ADR发生率为0.50%。女性ADR的发生率高于男性,ADR累及的系统-器官主要是皮肤及附件,占48·53%。临床表现为红斑疹、斑丘疹、荨麻疹、水疱疹。结论:合理使用抗菌药物,控制剂量和滴速,减少和避免ADR发生。