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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.)

Osteopontin (OPN) is a phosphoglycoprotein that is expressed by various immune cells in a secreted and intracellular form. It has cytokine, chemotactic and cell signaling functions enhancing Th1 and Th17 immunity and protects against apoptosis. Recent studies found OPN to be modulatory in cell-mediated and immediate-type allergic diseases. In allergic asthma, OPN enhances sensitization but downmodulates Th2-driven IL-4-dominated inflammation. The finding that OPN expression is augmented during specific immunotherapy supports a Th2 suppressive effect of OPN. In Th1-driven delayed-type allergy, such as allergic contact dermatitis, OPN supports dendritic cell migration and IL-12 expression and is secreted by T effector cells and keratinocytes, augmenting Th1-mediated allergy and supporting disease chronification. There are numerous missing links as to how OPN variants modulate allergic inflammation through different OPN receptors. OPN research in allergy is an interesting, rapidly expanding field that has high potential for translational research.

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.

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 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.

Allergic rhinitis (AR) is the fifth most common chronic disease, and the association between allergic disorders and anxiety is well-documented. To investigate how anxiety and stressors modulate skin prick test (SPT) responses and associated inflammatory responses, 28 men and women with AR were selected by clinical history and skin test responses. The participants were admitted twice to a hospital research unit for 4h in a crossover trial. Changes in SPT wheals were assessed before and after a standardized laboratory speech stressor, as well as again the following morning; skin responses assessed twice during a lab session without a stressor and again the following morning served as the contrast condition. Anxiety heightened the magnitude of allergen-induced wheals following the stressor. As anxiety increased, SPT wheal diameters increased after the stressor, compared to a slight decrease following the control task. Anxiety also substantially enhanced the effects of stress on late phase responses: even skin tests performed the day after the stressor reflected the continuing impact of the speech stressor among the more anxious participants. Greater anxiety was associated with more IL-6 production by Con A-stimulated leukocytes following the stressor compared to the control visit. The data suggest that stress and anxiety can enhance and prolong AR symptoms.

Background: The increased production of nerve growth factor (NGF) has been associated with allergen-induced airway hyperresponsiveness and enhanced airway inflammation in experimental models of asthma. The aim of this study was to investigate whether a local application of anti-NGF to the lungs may affect the allergen-specific early (EAR) and late (LAR) airway responses to ovalbumin (Ova) of Ova-sensitized brown Norway rats., Methods: Rats were sensitized systemically with Ova and were boosted twice intratracheally with Ova aerosol using a microsprayer. Two hours before every boost, the animals were pretreated either with aerosolized anti-NGF or with a control antibody. On day 21, all animals were challenged with inhalational Ova aerosol and pulmonary resistance was recorded in anesthetized, orotracheally intubated animals during the early and late asthmatic responses. In addition, differential cell counts from bronchoalveolar lavage and serum immunoglobulin E (IgE) levels were determined 48 h post-Ova challenge., Results: Pretreatment with anti-NGF significantly attenuated the EAR but had no significant effect on the LAR. Serum IgE levels and inflammatory cell influx into the lungs were not affected by anti-NGF pretreatment., Conclusion: The data from this study suggest that NGF is directly involved in the development of the EAR without affecting the inflammatory airway response or LAR.

Allergic reactions are the most commonly reported adverse events after administration of antivenoms. Conventional horse serum-based crotalid antivenom used in the United States (Antivenin [Crotalidae] polyvalent) can lead to both immediate and delayed hypersensitivity reactions. Crotalidae polyvalent immune Fab (ovine) (CroFab; FabAV) has recently been approved for use in the United States. Experience from premarketing trials of this product and in the administration of other types of Fab, such as in digoxin poisoning, has demonstrated these fragments to be safe and effective, with a low incidence of sequella; however, allergic reactions can occur when any animal-protein derivatives are administered to human subjects. We report in detail the nature and course of allergic reactions that occurred in 4 patients treated with FabAV. Cases of anaphylaxis, acute urticaria, angioedema, and delayed serum sickness are described. All reactions were easily treated with some combination of antihistamines, epinephrine, and steroids, with prompt resolution of signs and symptoms enabling further dosing of antivenom as required. Several of these cases may have resulted from batches of antivenom contaminated with Fc fragments. The overall incidence of immediate and delayed allergic reactions to this product appears so far to be lower than that reported with conventional whole-immunoglobulin G (IgG) antivenom, but postmarketing surveillance is warranted.

The effects of Fujibitol, a remedy for the nasal symptoms of immediate and delayed type allergic reactions were studied. Fujibitol inhibited active systemic anaphylaxis in mice, heterologous passive cutaneous anaphylaxis (PCA) in rats, Masugi's nephritis in rats and delayed type hypersensitivity induced by picryl chloride in mice, but did not affect homologous PCA or immune complex-induced glomerulonephritis in rats. These results suggested that Fujibitol is effective for treatment of allergy-induced inflammation since IgG and type IV allergic reactions were inhibited.

A humanized murine monoclonal antibody directed to the Fc epsilonR1-binding domain of human IgE (rhuMAb-E25) has been shown to inhibit the binding of IgE to mast cells without provoking mast cell activation. To examine the effects of neutralizing IgE on allergic airway responses, we assessed the effects of 9 wk of treatment with rhuMAb-E25 in a parallel group, randomized, double-blind, placebo-controlled study of 19 allergic asthmatic subjects. We found that treatment with rhuMAb-E25 reduced serum IgE, increased the dose of allergen needed to provoke an early asthmatic response, reduced the mean maximal fall in FEV1 during the early response (30 +/- 10% at baseline to 18.8 +/- 8%, versus 33 +/- 8% at baseline to 34 +/- 4% after placebo; p = 0.01), and reduced the mean maximal fall in FEV1 during the late response (24 +/- 20% at baseline to 9 +/- 10% versus 20 +/- 17% at baseline to 18 +/- 17% after placebo; p = 0.047). We conclude that an anti-IgE monoclonal antibody, which inhibits binding of IgE to its receptor, suppresses the early- and late-phase responses to inhaled allergen in allergic asthmatic subjects. Targeting IgE with rhuMAb-E25 might be a useful treatment for allergic asthma.

Physiological changes during late phase nasal responses after allergen challenge are difficult to establish and different criteria are used for the definition of a positive late phase nasal reaction. The objective of this study was to assess the value of whole body plethysmography in detecting changes in nasal airway resistance after allergen challenge and to suggest criteria for the definition of early and late phase nasal reactions. Nasal challenge with allergen was performed in 15 allergic patients. Nasal resistance was followed until 10 h after allergen challenge and on a control day using whole body plethysmography. The mean percentage changes in the inspiratory nasal resistance during the early phase period (0.25-2 h) and the late phase period (4-10 h) were significantly higher on the allergen challenge day than on the control day (p=0.001 and p=0.01, respectively). The mean percentage change in the inspiratory nasal resistance during the early and late phase period on the control day plus 2 times the standard deviation served as cut-off point for a positive reaction. Using this definition, all patients had early reactions and 7 of the 15 patients (47%) also had late reactions. We conclude that whole body plethysmography is a useful, noninvasive method for the measurement of the physiological changes in the nose following allergen challenge.

Adverse reactions to foods are classified into immediate and delayed reactions. Immediate reactions are caused by interactions between food antigen and antigen-specific IgE that lead to a pathological process mediated by mast cells and basophils. Delayed reactions are more diverse, both in the manifestations and in the biological mechanisms involved. Because the majority of food antigens are proteins or glycoproteins, the increased diversity of food sources and the application of modern molecular biology techniques that allows changes in the protein composition of traditional foods may intensify the public interest in reactions to foods.

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)

Complex study of the immunologic status of rats from the first days after the injection of nephrotoxic serum up to formation of chronic renal failure in comparison with functional and morphological characteristics of the disease confirmed the hypothesis on the phasic development and different pathogenetic role of the hypersensitivity reactions of the immediate and delayed types during nephritis. Signs of the immediate hypersensitivity predominated during the initial stages of the disease; realization of this hypersensitivity is indicated both by the liberation of the mediators of the pathochemical phase and by the change of the renal processes. The development of delayed hypersensitivity reactions plays the basic role in the pathogenesis of chronic nephritis.

The role played by leukotriene B4 (LTB4) in human allergic reactions has been the subject of recent interest and speculation. To characterize further the role of this mediator, we quantitated LTB4 levels in nasal washing by radioimmunoassay in 13 atopic subjects during immediate and late reactions after nasal antigen challenge while the subjects were taking placebo or prednisone (20 mg every 8 hours for 48 hours) in a double-blind, placebo-controlled, crossover protocol and compared these levels with levels of seven nonatopic subjects undergoing similar nasal antigen challenge. Nasal antigen challenge of atopic subjects resulted in an increase in LTB4 levels during the immediate reaction in 10 of 13 subjects (9/13 with a greater than 50% increase over baseline) with no similar increase observed in nonatopic subjects (p less than 0.05). An increase in LTB4 levels was observed in 12/13 atopic subjects (6/13 with greater than 50% increase over a second baseline) during late time periods (p less than 0.05), which was associated with an influx of neutrophils (from 65,000 +/- 43,000 to 1,246,000 +/- 829,000; p less than 0.05). However, nonatopic subjects appeared to demonstrate a similar late increase in LTB4 levels. High-performance liquid chromatography analysis of immunoreactive LTB4 demonstrated that 84% of immunoreactive LTB4 coeluted with the biologically isomer during the immediate reaction, whereas 44% to 61% coeluted with the biologically active isomer during late reactions. Steroid pretreatment had no effect on either the early or late increase in LTB4 levels or on the neutrophil influx observed during the late reaction.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute and delayed hypersensitivity reactions were compared in mice fed diets low in copper (less than 20 mumol copper kg-1) or adequate (more than 300 mumol copper kg-1) for seven to nine weeks after weaning. In the copper depleted animals there was a significant enhancement (P less than 0.01) of histamine-induced paw oedema measured 15 minutes after challenge. The variance of responses within the two dietary groups was similar. Delayed contact hypersensitivity reactions to oxozalone were also significantly increased (P less than 0.01) in the deficient mice. In this study there were some signs of differences in variance heterogeneity but they were statistically insignificant. Delayed-type hypersensitivity to sheep erythrocytes was similarly but less markedly (P less than 0.05) affected. Group differences just failed to reach statistical significance after logarithmic transformation (P less than 0.07) or non-parametric analysis (P less than 0.06). At challenge, the copper deficient mice had a significant (P less than 0.05) plasma hypercholesterolaemia. A few individuals also showed signs of spleen enlargement and mild haemoglobinaemia but otherwise the animals appeared clinically normal and were similar in weight to the controls. Plasma (P less than 0.001), erythrocyte (P less than 0.01) and liver (P less than 0.01) copper concentrations were significantly reduced in the copper-depressed mice, although the concentrations of copper and zinc in the spleen were increased (P less than 0.05) in the same group. Whole blood superoxide dismutase activity was also significantly decreased (P less than 0.01) but erythrocyte glutathione peroxidase activities were similar in both groups, as were blood and liver zinc concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Although late bronchospastic reactions after exposure to antigenic and sensitizing agents usually significantly alter bronchial responsiveness to histamine or methacholine, presumably by causing bronchial inflammation, isolated immediate bronchospastic reactions do not induce such changes. We studied three subjects who demonstrated different patterns of reaction. The first individual was diagnosed as having occupational asthma to red cedar. This was confirmed by specific inhalation challenges that resulted in late bronchospastic reaction. No significant changes in the provocative concentration of histamine causing a 20% fall in FEV1 (PC20) were found 1 day after this reaction. Two weeks later, serial assessments (five and six, respectively) of PC20 histamine were recorded on control days and up to 48 hours after exposure to plicatic acid, which caused a late bronchospastic reaction with a maximum fall of 37% in FEV1. No significant changes in PC20 were found; the maximum variations on control days were 0.36 to 0.74 mg/ml, and on active days, from 0.37 to 0.59 mg/ml. By contrast, two other subjects, who demonstrated isolated immediate reactions after exposure to diphenylmethane diisocyanate, had significant changes in PC20 histamine and methacholine, in one subject from 3.1 mg/ml to 0.6 mg/ml 8 hours after exposure, and in the other subject, from 61.0 to 7.4 mg/ml 7 hours after exposure, with recovery during the next few days. These examples demonstrate that the pattern of nonspecific bronchial responsiveness after immediate and late bronchospastic reactions can be different from what has previously been described. Immediate bronchospastic reactions may lead to bronchial hyperresponsiveness, whereas late asthmatic reactions do not always induce changes in bronchial responsiveness.(ABSTRACT TRUNCATED AT 250 WORDS)

A wide variety of industrial materials is known to cause allergic pulmonary reactions. Respiratory symptoms may occur either immediately upon exposure to the agent (immediate-onset response), or several hours later (delayed-onset reaction). In order to determine both the mechanism of response, and a safe exposure level which would prevent development of pulmonary sensitization, animal models are currently being developed for both types of sensitivity responses. In the models, emphasis is placed on simulating conditions present in the industrial environment. For example, (1) exposure to agents is via the inhalation route, (2) animals are unrestrained and unanesthetized both during exposure and during elicitation of response, and (3) reactive chemicals, as opposed to hapten-protein conjugates, are used for exposure. In the model for immediate-onset sensitivity, concentration-response relationships have been observed between the concentration of agent inhaled and the percentage of animals becoming sensitized. Agents employed were bacterial subtilisin and toluene diisocyanate. Identification of "no observable effect" threshold concentrations implies that exposure levels can be proposed for industrial chemicals which will not result in sensitization of workers. Further development of the animal models, followed by calibration of the models to humans, should allow immunotoxicologic evaluation of chemicals for their respiratory sensitizing ability and recommendation of threshold-limit values (TLVs) which would prevent sensitization.

Studies have been made of movement of various macromolecules into and out of the pleural space of guinea pigs during the course of a delayed hypersensitivity reaction to purified protein derivative (PPD), and a passively transferred immediate hypersensitivity reaction to ovalbumin. While the immediate hypersensitivity reaction transiently alters vascular permeability as shown by increased movement of macromolecules into the chest, the delayed hypersensitivity reaction is marked by a decreased capacity to resorb macromolecules from the pleural space. The data suggest that the two hypersensitivity reactions may be distinguished by these physiologic differences. Additional data from studies of a chemically induced pleural effusion in these animals suggest that some type of outflow obstruction is necessary for the development of effusion, but that the outflow defect caused by the irritating chemical is based on a different mechanism than that seen during the delayed hypersensitivity reaction.