Drug-induced Allergic Reactions Research Articles

Drug-Induced Allergies ??? An Increasing Problem In Current Pharmacotherapy

Drug-Induced Allergies ??? An Increasing Problem In Current Pharmacotherapy

Allergic reaction to topical eyedrops

Purpose of review To examine recently published papers dealing with drug-induced allergic reactions. As allergy is only one possible mechanism, this review was extended to all reports or studies describing allergic, inflammatory or toxic effects related to eyedrops since 2004. Recent findings These studies were first classified into clinical reports or surveys, experimental works and biological studies showing drug-induced effects on the ocular surface or eyelids. Studies aimed at determining the role of preservatives or comparing preservative-free and preserved eyedrops were further analysed separately. Summary Reports on allergic or toxic reactions of eyedrops are published repeatedly. The reports raising the most important issues are those concerning antiglaucoma drugs. They consistently describe inflammatory reactions at the conjunctival level, with strong evidence that preservative is a major source of toxicity for the ocular surface.

Allergic reaction to topical eyedrops

To examine recently published papers dealing with drug-induced allergic reactions. As allergy is only one possible mechanism, this review was extended to all reports or studies describing allergic, inflammatory or toxic effects related to eyedrops since 2004. These studies were first classified into clinical reports or surveys, experimental works and biological studies showing drug-induced effects on the ocular surface or eyelids. Studies aimed at determining the role of preservatives or comparing preservative-free and preserved eyedrops were further analysed separately. Reports on allergic or toxic reactions of eyedrops are published repeatedly. The reports raising the most important issues are those concerning antiglaucoma drugs. They consistently describe inflammatory reactions at the conjunctival level, with strong evidence that preservative is a major source of toxicity for the ocular surface.

Antigenicity of sulfanilamide and its metabolites using fluorescent-labelled compounds

In order to clarify the onset mechanisms of drug-induced allergies, three fluorescent-labelled compounds were synthesized by subjecting sulfanilamide (SA), a base compound for sulfonamides, and its active metabolites, i.e. sulfanilamide hydroxylamine and sulfanilamide nitroso, to dansylation using dansylchloride. In other words, 5-dimethylamino-N-(4-aminobenzyl)-naphthalenesulfonamide (DNS-4ABA), 5-dimethylamino-N-(4-hydroxylaminobenzyl)-1-naphthalenesulfonamide (DNS-4HABA) and 5-dimethylamino-N-(4-nitrosobenzyl)-1-naphthalenesulfonamide (DNS-4NSBA) were synthesized as model haptens. When analysed by HPLC, a conjugate of DNS-4HABA and glutathione (GSH) with nucleophilic amino acids had two peaks (P-1 and P-2). FAB-MS and 1H-NMR revealed that the DNS-4HABA-GSH conjugate consisted of sulphinamide and semimercaptal. The reactivity of GSH to DNS-4ABA, DNS-4HABA and DNS-4NSBA was quantified by HPLC using an oxidization system (horseradish peroxidase/H2O2). The results show that production of DNS-4NSBA-GSH-conjugate was four to eight times higher than that of DNS-4HABA-GSH conjugate, but that DNS-4ABA did not bind with GSH. Skin reactions were assessed using guinea pigs, and strong delayed erythema was seen with DNS-4NSBA, which bound most strongly with GSH, whereas weak delayed erythema was seen with DNS-4ABA, which did not bind with GSH. This suggests a correlation between GSH conjugate production and skin reactions. DNS-4HABA enzymatically bound with proteins in rat and guinea pig liver cytosol and microsomal fractions. The proteins that bound to DNS-4HABA were purified by HPLC and then subjected to N-terminal amino acid analysis. Ubiquitin (10 kDa) and fatty acid binding protein (30 kDa) were detected in the rat liver cytosol fraction; retinol-dehydrogenase (35 kDa) in the rat microsomal fraction; and glutathione-S-transferase B (mμ) (25 kDa) in the guinea pig liver cytosol fraction. When DNS-4HABA or DNS-4NSBA binds to proteins that play important roles in the body, unexpected adverse reactions may occur. Furthermore, by utilizing our technique using model compounds, it may be possible to identify the carrier proteins of various compounds, including pharmaceutical agents.

Drug-induced nephropathy: an update

Medications cause renal disease by promoting various types of injury in the kidney. Several drugs reduce renal perfusion and cause prerenal azotemia. Vascular disease can develop following exposure to various medications through direct and indirect effects. A number of glomerular lesions have been described with therapeutic agents and illicit drugs. Acute interstitial nephritis occurs from a drug-induced allergic reaction, which promotes interstitial inflammation and tubular damage. Acute tubular necrosis is a dose-dependent process that occurs from direct drug toxicity on tubular epithelia. Other less common patterns of drug-induced tubular injury include osmotic nephropathy, crystal nephropathy and acute nephrocalcinosis. Finally, postrenal azotemia from structural or functional obstruction of the urinary tract also complicates therapy with a number of medications.

Cefuroxime-induced coronary artery spasm manifesting as Kounis syndrome

Allergic angina and allergic myocardial infarction (Kounis syndrome) occurring during the course of a drug-induced allergic reaction in the absence of angiographically stenosed coronary arteries, is rare in clinical practice.This paper reports the case of a 70-year-old woman with no significant risk factors for coronary artery disease who developed coronary artery spasm after intravenous injection of cefuroxime.A subsequent coronary angiogram revealed normal coronary arteries (type I variant of the syndrome). The allergic reaction following cefuroxime administration seems to have triggered the development of coronary artery spasm. Susceptible individuals expressing an amplified mast cell degranulation effect may be more vulnerable to coronary artery spasm. The clinical implications of this syndrome are also discussed.

Drug-Induced Type 1 and Type 2 Immune Responses are Characterized by Distinct Profiles of Cell Kinetics, Cytokine Production, and Expression of Co-Stimulatory Molecules in the Popliteal Lymph Node Assay

Some drugs have the undesired side effect of systemically stimulating the immune system, which may eventually lead to the development of drug-induced allergy or autoimmunity. Unfortunately, validated predictive screening tools to assess the immune stimulatory potential of compounds are presently unavailable. The popliteal lymph node assay (PLNA) with reporter antigens (RA) seems a valuable candidate for this purpose. The aims of the present study were 1) to provide additional mechanistic information on the very early induction phase of drug-induced type 1 (TH1-associated) and type 2 (TH2-associated) immune reactions in the PLNA and 2) to explore the use of these mechanism-based parameters to predict the immune stimulating potential of drugs. Streptozotocin (STZ), a chemotherapeutic drug, and D-Penicillamine (D-Pen, anti-rheumatic drug) were used as model compounds as they respectively induce clearly differentiated type 1 and type 2 immune responses in the PLNA. Type 1 responses were characterized by the production of high levels of IFNγ and IL-12 from day 2 after exposure. Expression of CD40 was absent, but CD54, CD80, and CD86 were present predominantly on non-B APC, presumably macrophages. Increased percentages of activated CD8+ T-cells and macrophages accompanied these phenomena. Type 2 responses were clearly different and were characterized by an early influx of dendritic cells (DC) and B-cells that expressed CD40, CD54, and CD86, but no CD80. First DC, but later B-cells, appeared to function as APC. In addition, the production of IL-4 was elevated. Apparently, reactivity of these type 1- and type 2-inducing drugs produce drug-specific patterns of immune stimulating factors that determine very different, time-dependent profiles of activated cells, cytokine production, and expression of co-stimulatory molecules very shortly after the initial exposure to drugs. As such, these parameters obtained with the PLNA may help to provide information about the immunological mechanisms in the early induction phase of drug-induced immune stimulation and may be useful in the development of an appropriate screening test to predict the immune stimulatory potential of drugs in a preclinical phase.

Allergy to dexchlorpheniramine. Study of a case

IntroductionDexchlorpheniramine (DH) is a classical or first generation antihistamine belonging to the ethanolamine groupAdverse effects related to these antihistamines are frequent, but the hypersensitivity reactions described in the literature since 1940 are exceptionalWe report the case of a 32-year-old woman who experienced two episodes of acathisia secondary to intravenous (i.v.) dexchlorpheniramine administration for a possible hypersensitivity reaction to local anesthetics Material and methodsAllergological study consisted of the following tests: skin prick tests with routine allergens, with a negative result; skin prick and intradermal tests with local anesthetics and DH, with a positive result to DH in the intradermal skin test (+ +); serum specific IgE, which was within normal levels; histamine release test with DH with a negative result, and the basophil activation test (BAT) with local anesthetics and DH, which was positive for DH and weakly positive to Lidocaine? ConclusionBAT is proving to be a highly useful tool in the field of drug allergy, with a higher sensitivity and specificity than other in vitro tests. Because it avoids the need for provocation tests, this is especially important in drug-induced allergic reactions in which in vivo tests are repeatedly negative despite a clear clinical history

Antithrombotic drugs for the treatment of heparin-induced thrombocytopenia.

Heparin remains the anticoagulant of choice in the therapy of thromboembolic events. Heparin is effective in the prevention and treatment of venous thromboembolism (VTE), as a surgical anticoagulant, and in interventional cardiology (). Heparin is also used in the treatment of unstable angina and acute myocardial infarction (AMI), and in some patients with disseminated intravascular coagulation. Although the clinical effects of heparin are meritorious, side effects do occur. Bleeding is the primary undesirable effect of heparin. Heparin-induced thrombocytopenia (HIT), the most frequent of drug-induced allergies, necessitates the use of alternative agents to treat or prevent thrombus formation.

Contribution de la cytométrie de flux au diagnostic d’une allergie

For the laboratory investigation of allergic diseases, flow cytometric methods to detect leukocytes that have been activated by allergen in vitro have recently been developed. Cellular tests for the detection of in vitro-activated blood basophils are complementary to specific IgE determinations. After in vitro incubation with allergen, basophils are fixed and then labeled with anti-IgE antibodies, and activation is then identified with anti-CD63 or anti-CD203c monoclonal antibodies. Assays based on basophil activation complement the measurement of specific IgE. With some allergens, particularly in cases of drug-induced allergy, flow cytometry has greater sensitivity than specific IgE determination. However, high concentrations of drugs can induce cell toxicity, and this may be confused with basophil activation. Cytometry can also be used to explore allergies with a cell-mediated mechanism. The detection of cytokine synthesis in T cells and basophils incubated with allergen is now technically feasible, but the usefulness of this procedure in the diagnosis of allergy remains to be demonstrated. We believe that the application of flow cytometry to the investigation of allergy is likely to increase.

Tolerogenic role of Kupffer cells in allergic reactions.

Drug-induced allergic reactions (DIARs), including allergic hepatitis, cutaneous reactions, and blood dyscrasias, are unpredictable and can be life threatening. Although current studies suggest that DIARs are caused by immunogenic drug-protein adducts, it remains unclear what factors determine the susceptibility to DIARs. We hypothesized that most individuals may be resistant to DIARs in part because they become immunologically tolerant to drug-protein adducts in the liver, an organ with tolerogenic properties. Because animal models of DIARs are elusive, we tested this hypothesis using a murine model of 2,4-dinitrochlorobenzene (DNCB)-induced delayed type hypersensitivity reaction that is mediated by immunogenic 2,4-dinitrophenylated (DNP)-protein adducts. Intravenous pretreatment of mice with DNP-BSA led to its accumulation in hepatic Kupffer cells (KC) and induced immunological tolerance to subsequent DNCB sensitization. Tolerance could be abrogated by prior depletion of KC or induced in naïve mice by transferring a T cell-depleted, KC-enriched fraction of liver nonparenchymal cells from mice tolerized 1 month earlier by DNP-BSA pretreatment. These findings implicate KC as a primary and sustained inducer of tolerance against DNP-protein adducts and suggest a similar role in modulating allergic reactions against drug-protein adducts. Perhaps genetic and/or environmental factors affecting the activities of these cells may play a role in determining individual susceptibility to DIARs.

10. Drug allergy

Adverse drug reactions are common, but only 6% to 10% are immunologically mediated. Unlike most adverse drug reactions, allergic drug reactions are unpredictable. Whereas some drug-induced allergic reactions may be easily classified into one of the four Gell and Coombs hypersensitivity categories, many others that appear to have an immunologic component cannot be classified because of our lack of mechanistic information. Theoretically, any drug can induce an immune response. However, some drugs are more likely to elicit clinically relevant immune responses than are others. Drugs in this category include antimicrobial drugs, anticonvulsants, chemotherapeutic agents, heparin, insulin, protamine, and biologic response modifiers. After a drug-disease connection is established, it must be determined whether the reaction was immunologically mediated. Subsequently, confirmatory tests, if available, should be used to determine the allergic status of the patient. If these tests are not available, a graded challenge or desensitization may be considered, depending on the type of clinical reaction previously demonstrated and the need for drug readministration. Education of the patient and primary care physician is an important component of patient management. (J Allergy Clin Immunol 2003;111:S548-59.)

MRNA Expression of Multiple Cytochrome P450 Isozymes in Four Types of Cultured Skin Cells

Background: Many drugs are known to induce allergic reactions in the skin. The metabolic activation of drugs resulting in the formation of protein adducts is thought to be a first step in the induction of these allergic reactions. We postulated that dermal tissue might be a site of drug activation by cytochrome P450 (CYP) isozymes. Methods: Messenger RNA was extracted from cultured Langerhans cells, keratinocytes, fibroblasts and melanocytes from 6 individuals, and CYP mRNA expression was analyzed by RT-PCR. Results: CYP1A1, 1B1 and 2E1 were found in all four cell types. CYP2A6, 2C, 2D6, 3A5, 3A7 and 4B1 mRNA was expressed in a cell-type- and/or individual-specific manner. CYP1A2, 2A7, 2B6 and 3A4 mRNA was not detectable. Conclusions: The mRNA for a variety of CYP isozymes was expressed in all four types of skin cells examined. These CYP enzymes may be involved in the pathogenesis of drug-induced allergic reactions in the skin.

Cellular and molecular pathophysiology of cutaneous drug reactions.

Hypersensitivity reactions to drugs can cause a variety of skin diseases like maculopapular, bullous and pustular eruptions. In recent years increasing evidence indicates the important role of T cells in these drug-induced skin diseases. Analysis of such drug-specific T cell clones has revealed that drugs can be recognized by alpha beta-T cell receptors, not only if bound covalently to peptides, but also if the drug binds in a rather labile way to the presenting major histocompatibility complex (MHC)-peptide. This presentation is sufficient to stimulate T cells. In maculopapular exanthema (MPE), histopathological analysis typically shows a dominant T cell infiltration together with a vacuolar interface dermatitis. Immunohistochemical studies demonstrate the presence of cytotoxic CD4+ and to a lesser degree of CD8+ T cells, which contain perforin and granzyme B. They are close to keratinocytes that show signs of cell destruction. Expression of Fas ligand is barely detectable, suggesting that cytotoxic granule exocytosis may be the dominant pathway leading to keratinocyte cell damage. While in MPE, the killing of cells seems to be predominantly mediated by CD4+ T cells, patients with bullous skin disease show a strong CD8+ T cell migration to the epidermis. This is probably due to a preferential presentation of the drug by MHC class I molecules, and a more extensive killing of cells that present drugs on MHC class I molecules. This might lead to bullous skin diseases. In addition to the presence of cytotoxic T cells, drug-specific T cells also orchestrate the inflammatory skin reaction through the release and induction of various cytokines [i.e. interleukin (IL)-5, IL-6, tumor necrosis factor-alpha and interferon-gamma] and chemokines (RANTES, eotaxin or IL-8). The increased expression of these mediators seems to contribute to the generation of tissue and blood eosinophilia, a hallmark of many drug-induced allergic reactions. However, in acute generalized exanthematous pustulosis (a peculiar form of drug allergy), neutrophils represent the predominant cell type within pustules, probably due to their recruitment by IL-8 secreting drug specific T cells and keratinocytes.

Immunohistochemical detection of protein adducts of 2,4-dinitrochlorobenzene in antigen presenting cells and lymphocytes after oral administration to mice: lack of a role of Kupffer cells in oral tolerance.

Although current studies suggest that most drug-induced allergic reactions (DIARS) are caused by immunogenic conjugates formed from the reaction of a reactive metabolite of a drug with cellular proteins, it is not clear why these reactions are relatively rare. One possible pathway that may explain the low incidence of DIARS in many cases is oral tolerance, an antigen-specific immunological hyporesponsiveness induced by oral administration of antigens. The mechanism of oral tolerance, however, is not clearly understood and is difficult to study directly with drugs, because animal models of DIARS have been elusive. We chose 2,4-dinitrochlorobenzene (DNCB) as a model compound to circumvent this problem because animal models of allergic reactions have been established for this compound. DNCB forms immunogenic 2,4-dinitrophenylated (DNP) protein conjugates that can induce immune reactions and it causes oral tolerance when it is fed to animals prior to sensitization. We hypothesized that DNP-protein conjugates may have a role in oral tolerance. To test this idea, we have begun to identify cells bearing these conjugates after the oral administration of DNCB. Female C57BL/6J mice were fed DNCB and tissues were examined after 6 and 24 h. Immunohistochemical analysis indicated the presence of DNP-protein conjugates in enterocytes of the small intestine, in macrophages and lymphocytes of the mesenteric lymph nodes, in dendritic cells and lymphocytes of the spleen, and in Kupffer cells and other sinusoidal cells of the liver. It was found that Kupffer cell depletion did not affect oral tolerance to DNCB. The findings suggest that the cells bearing DNP-protein conjugates, other than Kupffer cells, in the liver and other tissues may be important in the induction of oral tolerance against DNCB. Protein adducts of drugs administered orally may also be present in these cells, and they may have a role in the downregulation of DIARS in many individuals.

Transient, Profound Thrombocytopenia in a Premature Infant: Is this a Ranitidine-Induced Immune Reaction?

Case Report: A female infant was delivered at 31-weeks gestation for suspected chorioamnionitis. Maternal antenatal dexamethasone had been given one hour prior to delivery to hasten foetal lung maturation. From day 11 to 19, the infant received ranitidine for gastric hyperacidity (pH > 4). On day 16, her blood culture was positive for Staphylococcus epidermidis and her C-reactive protein (CRP) was slightly elevated. She was treated with vancomycin and cefotaxime. On day 19, when she had become clinically well, profound thrombocytopenia (8 x 109 IL), eosinophilia (3 x 109 /L) and borderline neutropenia (1 x 109/L) occurred in the presence of highly elevated CRP (132 mg/L). For this she received multiple platelet transfusions. Ranitidine was ceased on day 19. On day 20, leukopenia and neutropenia had resolved when the last dose of cefotaxime was given. Eosinophil count normalised by day 21 and platelet count by day 25. Discussion: This phenomenon was similar to that reported in ranitidine-treated adults during acute illness. Although premature infants are generally thought to be incapable of druginduced allergic reactions, the foetal immune system can be activated by intrauterine infections. Glucocorticoid therapy during mid to late gestation could heighten the immune sensitivity in premature infants. This infant's antenatal history and postnatal events could possibly have predisposed her to hypersensitivity to antigenic stimulation.

Involvement of T cells in drug-induced allergies.

The current understanding of drug-induced allergy is mainly based on the hapten model. This model may be relevant for the initiation of various severe forms of drug-induced allergy, but does not explain other features of drug-induced allergy. Our model of direct metabolism-independent drug recognition by activated T cells supplements the hapten model and appears to be relevant in various clinical situations, in particular in transient exanthematous skin reactions.

Immunochemical Detection and Identification of Protein Adducts of Diclofenac in the Small Intestine of Rats: Possible Role in Allergic Reactions

Idiosyncratic adverse drug reactions are unpredictable, target multiple organ systems, and often become life-threatening events. Although the causes of idiosyncratic adverse drug reactions are not known in most cases, evidence suggests that they may be mediated through immunological mechanisms. It is generally thought that for a drug to lead to an immune response, it must first become covalently bound to a carrier protein. Since most drugs are unreactive, it is usually a reactive metabolite that is expected to form covalent adducts. However, it is not clear why more people do not develop immune reactions against drug-protein adducts. One possible explanation is that orally administered drugs may lead to oral tolerance in most individuals through mechanisms similar to that found with orally administered antigens. However, very little is known regarding the interaction of drugs with gut-associated lymphoid tissue of the small intestine, where oral tolerance can develop. As an initial step to test this hypothesis, we have investigated whether diclofenac, a commonly used nonsteroidal antiinflammatory drug, can lead to protein adducts in rat small intestine. Diclofenac was administered to rats by gastric gavage. Immunoblot analysis of small intestine homogenates and isolated enterocyte subcellular fractions with drug-specific antiserum revealed 142-, 130-, 110-, and 55-kDa protein adducts of diclofenac. The 142- and 130-kDa adducts of diclofenac were identified as aminopeptidase N (CD13) and sucrase-isomaltase, respectively, by amino acid sequence analyses and by their reactions with protein-specific antibodies. The adducts were localized by immunohistochemistry and found primarily in the mid-villus and villus-tip enterocytes and also in the dome overlying Peyer's patches. Similar adducts were detected immunochemically in villus-tip enterocytes of animals treated with halothane or acetaminophen. These results show that intestinal protein adducts of drugs can be formed in gut-associated lymphoid tissue where they may lead to the down-regulation of drug-induced allergic reactions in many individuals.

Carrier-independent hapten recognition and promiscuous MHC restriction by CD4 T cells induced by trinitrophenylated peptides.

The elucidation of mechanisms underlying the recognition of haptens by class II MHC-restricted T cells is instrumental for the understanding of chemical- and drug-induced allergies. We have previously demonstrated that trinitrophenyl (TNP) peptides represent dominant antigenic epitopes for CD8+ and CD4+ mouse T cells triggered by chemically TNP-modified APC. Here, we report the characterization of TNP-specific, CD4+ mouse T cell lines and hybridomas that were induced in vivo and in vitro by defined hapten-conjugated peptides. These peptides, which we had previously shown to induce contact sensitivity to picryl chloride in vivo regardless of sequence homologies to mouse proteins, were found to activate carrier-independent TNP-specific T cells in vitro. We interpret these findings to support our view that carrier-independent T cells, reactive to particularly repetitive hapten epitopes, may play a crucial role in allergies to chemicals and drugs. In addition to carrier independence, one of our hybridomas (IT-H6/A11) exhibited a striking promiscuity of MHC restriction. Although absolutely dependent in its TNP reactivity on the presence of MHC class II molecules, the IT H6/A11 hybridoma completely ignored class II polymorphism and even reacted to TNP peptides presented on human DR molecules. Regarding hapten allergies in humans with a heterozygous situation for three types of class II molecules (DR, DP, and DQ), such promiscuous MHC restriction should lead to the presentation of even higher epitope densities to the respective T cell clones. Hybridoma IT-H6/A11, reacting to TNP independent of carrier peptide and of MHC haplotype, also allowed for an unusually systematic study of the minimal requirements for TNP recognition. Despite an almost complete ignorance of amino acid side chains on the carrier peptide, our data indicate a clearly position-specific interaction of hapten and TCR.

T cell recognition of penicillin G: structural features determining antigenic specificity.

Penicillin G (Pen G) and other beta-lactam antibiotics frequently induce allergic reactions constituting typical examples of human immune responses to haptens. In fact, penicillins represent a unique set of haptens with outstanding structural variability on the basis of an identical protein-reactive beta-lactam containing backbone. Although both cellular and humoral responses are involved in drug-induced allergies, little is known about the T cell reactivity to penicillins. To understand which structural features determine antigenic specificity, we isolated a panel of MHC-restricted, Pen G-reactive T cell clones from different penicillin-allergic patients and tested them for their capacity to proliferate in the presence of other penicillin derivatives. We found that the antigenic epitope consists of both the amide-linked side chain, which is different in every member of the penicillin family, as well as the thiazolidine ring common to all penicillin derivatives. We also demonstrated the presence of two different types of penicillin-specific T cells, one dependent, and the other independent of antigen processing by autologous antigen-presenting cells. Our data strongly suggest that penicillins form part of the epitopes contacting the antigen receptors of T cells.