IgE-mediated immediate-type hypersensitivity to the pyrazolone drug propyphenazone

BACKGROUND: Propyphenazone (1,2-dihydro-1,5-dimethyl-4-(1-methylethyl)-2-phenyl-3H-pyrazol-3-one; PP) is a nonsteroidal anti-inflammatory drug frequently used as mild analgesic medicament. It belongs to the chemical group of pyrazolones. Severe adverse reactions to PP are frequent and have generally been regarded as pseudoallergic or intolerance reactions. Presently, there are no useful in vitro test systems available for the detection of antibodies directed against analgesic drugs. OBJECTIVE: The purpose of this study was to unequivocally demonstrate that IgE-mediated Type I allergy is the main mechanism leading to immediate-type adverse reactions to the analgesic drug PP. METHODS: We investigated 53 young adult patients with adverse reactions to PP. All patients developed symptoms suggestive of IgE-mediated anaphylaxis within 30 minutes after intake of a painkiller containing PP. Patients were subjected to skin tests (prick test and intracutaneous test). In addition, a novel ELISA system was developed to prove the existence of specific IgE antibodies in patients' sera. RESULTS: In 44 of 53 (83%) patients, skin tests showed typical wheal and flare reactions. Significant amounts of PP-specific serum IgE was detected in 31 of 53 (58%) of the serum samples. Moreover, in 7 of 9 patients with skin test negative results, PP-specific IgE could be detected. The assay was PP-specific because only PP, but no other pyrazolone derivative (antipyrine, aminophenazone, or metamizol), was able to inhibit IgE-binding in the system. CONCLUSION: Propyphenazone is a sensitizing agent in susceptible individuals and can elicit IgE-mediated anaphylaxis. By using skin tests and our ELISA system we were able to confirm Type I allergy in 51 of 53 (96%) patients in this study.     

Skin prick testing and peanut‐specific IgE can predict peanut challenge outcomes in preschoolchildren with peanut sensitization

Background The rise in peanut allergy is a source of considerable burden in the community. A growing number of preschoolchildren have been identified as peanut sensitized in the course of investigation of other allergic conditions. Although many have never knowingly ingested peanuts and their clinical reactivity is not known, it has been common practice to place these children on avoidance diets for many years. Objective To determine the utility of skin prick tests (SPT) and fluorescent‐enzyme immunoassays (FEIA) for identifying either peanut allergy or tolerance in preschoolchildren with peanut sensitization. Methods Forty‐nine preschoolchildren (<5 years of age) with peanut sensitization (SPT 2 mm or peanut‐specific IgE 0.35 kU/L) but unknown clinical reactivity had graded open peanut challenges reaching a total of 11 g. A positive challenge was defined as an objective IgE‐mediated reaction during challenge or the 2‐h observation. Results Forty‐nine percent (24/49) of children had positive challenges. An SPT of >7 mm on the day of challenge predicted a positive challenge with a sensitivity of 83% and a negative predictive value (NPV) of 84%. An FEIA of >2.0 kU/L showed a sensitivity of 79% and an NPV of 80%. Predicting challenge outcome from a combination of SPT and FEIA (SPT >7 and/or FEIA >2 is positive) increased sensitivity to 96% and NPV to 95%. Conclusion and Clinical Relevance At least half of preschoolchildren with peanut sensitization and no antecedent history of peanut ingestion can tolerate peanuts. A SPT<7 mm and FEIA<2 kU/L identify children most likely to tolerate peanut, with only a 5% likelihood of failing an oral challenge. This study assists clinicians considering challenges in very young peanut‐sensitized children. Cite this as: H. Johannsen, R. Nolan, E. M. Pascoe, P. Cuthbert, V. Noble, T. Corderoy, A. Franzmann, R. Loh and S. L. Prescott, Clinical & Experimental Allergy, 2011 (41) 994–1000.     

Skin testing and oral penicillin challenge in patients with a history of remote penicillin allergy.

BACKGROUND: Penicillin administration is usually contraindicated in penicillin-allergic patients with positive skin test results. OBJECTIVE: To examine whether penicillin oral challenge for patients with a history of remote non-life-threatening allergic reaction to penicillin can be well tolerated irrespective of skin test results. METHODS: In a prospective open-label trial, 8,702 individuals were screened between November 1998 and January 2000. Of 687 patients with a non-life-threatening allergic reaction to penicillin, occurring longer than 3 years earlier, 169 were enrolled. Regardless of the response to penicillin skin testing, patients received the usual 1-day dosage of penicillin and amoxicillin, on 2 separate occasions. Two to 6 years later, a follow-up was conducted to assess the outcomes of further penicillin administration. RESULTS: A total of 272 combined skin tests and oral challenges were performed on 169 patients. Among 137 challenges with a positive skin test result and 135 patients with a negative skin test result, 9 (6.6%) and 5 (3.7%) (P = .29), respectively, developed a mild rash to oral challenge. At follow-up, 2 to 6 years afterward, 3 of 55 patients (5.5%) who were given a full treatment course of penicillin developed a mild skin eruption. CONCLUSIONS: Positive penicillin skin test results for patients with a remote history of non-life-threatening allergic reaction to penicillin were not associated with a greater prevalence of adverse reactions to oral challenge with penicillin than negative results. Because skin testing is considered the gold standard and the safest method for predicting tolerance to penicillin administration, oral penicillin challenge may be used as a diagnostic method only in these specific patients when skin testing is not feasible.     

Diagnosing and managing patients with drug hypersensitivity

Introduction: Diagnosing and managing drug hypersensitivity is challenging because there are no clear limits between different types of drug reactions. Distinguishing between type A (predictable) and type B (hypersensitivity) reactions when a drug is introduced on the market is not easy. When many people use a drug, adverse reactions can occur, conditioned by diverse genetic profiles, viral infections or concomitant therapy. Occasionally the only tool clinicians have on which to base the diagnosis is the clinical history. Skins tests or in vitro tests sometimes have low sensitivity or are unavailable, and drug provocation tests may be dangerous or strictly forbidden in case of severe cutaneous reactions.

Areas covered: This paper reviews the diagnosis and management of the two main types of immunological reactions: IgE-mediated immediate drug hypersensitivity reactions (IDHRs) and non-immediate drug hypersensitivity reactions (NIDHRs).

Expert commentary: Although Europe and the United States use different diagnostic methods, patients with history of drug hypersensitivity must avoid the suspicious drug, and clinicians must assess tolerance to safe alternatives under medical surveillance. Sometimes desensitization may be required. There is a consensus about the need to perform genetic testing for specific drugs and give patients proper documentation to prevent future exposure to culprit drugs.     

Skin testing in patients with hypersensitivity reactions to iodinated contrast media – a European multicenter study

Background:  Iodinated contrast media cause both immediate and nonimmediate hypersensitivity reactions. The aim of this prospective study was to determine the specificity and sensitivity of skin tests in patients who have experienced such reactions.
Methods:  Skin prick, intradermal and patch tests with a series of contrast media were conducted in 220 patients with either immediate or nonimmediate reaction. Positive skin tests were defined according to internationally accepted guidelines. Seventy-one never-exposed subjects and 11 subjects who had tolerated contrast medium exposure, served as negative controls.
Results:  Skin test specificity was 96–100%. For tests conducted within the time period from 2 to 6 months after the reaction, up to 50% of immediate reactors and up to 47% of nonimmediate reactors were skin test positive. For immediate reactors, the intradermal tests were the most sensitive, whereas delayed intradermal tests in combination with patch tests were needed for optimal sensitivity in nonimmediate reactors. Contrast medium cross-reactivity was more common in the nonimmediate than in the immediate group. Interestingly, 49% of immediate and 52% of nonimmediate symptoms occurred in previously unexposed patients. Many of these patients were skin test positive, indicating that they were already sensitized at the time of first contrast medium exposure.
Conclusions:  These data suggest that at least 50% of hypersensitivity reactions to contrast media are caused by an immunological mechanism. Skin testing appears to be a useful tool for diagnosis of contrast medium allergy and may play an important role in selection of a safe product in previous reactors.     

Banana allergy in patients with immediate-type hypersensitivity to natural rubber latex: Characterization of cross-reacting antibodies and allergens

Background: An association between allergy to latex and banana has been reported. Even though cross-reacting IgE antibodies have been demonstrated, in no study has the existence of structurally similar allergens been confirmed. In the present study banana allergy was studied in a large series of patients with latex allergy. Specific IgE antibodies were characterized for cross-reactivity and compared with pollen RAST results. Latex and banana extracts were investigated for common antigens and allergens. Methods: Latex-, banana-, and pollen-specific (birch, timothy, mugwort) IgE were measured in 47 sera from patients with latex allergy. Thirty-one patients were skin prick tested with banana and questioned for possible reactions after eating bananas. Several RAST inhibition and immunospot inhibition studies were used to characterize cross-reacting IgE antibodies. Structurally similar antigens and allergens were evaluated with crossed-line immunoelectrophoresis and crossed-line radioimmunoelectrophoresis, respectively. Results: Latex RAST results were positive in 31 (66%) and banana RAST results were positive in 26 (55%) of the 47 sera. Of the 31 latex RAST–positive sera, 25 (81%) were also banana RAST–positive. Results from latex RAST correlated significantly with results from banana RAST (p < 0.001), but not with those from pollen RAST (p > 0.05). Banana skin prick test results were positive in 11 (35%) of the 31 patients tested. Symptoms after eating bananas were reported by 16 (52%) of the 31 patients. In inhibition studies the binding of IgE antibodies to solid-phase banana and to several latex preparations was inhibited by latex and banana, respectively. In crossed-line immunoelectrophoresis at least one antigen from banana fused with an antigen from latex, which also bound IgE antibodies in autoradiography (crossed-line radioimmunoelectrophoresis). Conclusions: Patients with latex allergy have symptoms caused by banana and show positive skin test and specific IgE test results. Cross-reacting IgE antibodies were confirmed by several inhibition techniques. For the first time, a structurally similar antigen/allergen was demonstrated. (J ALLERGY CLIN IMMUNOL 1994;93:990-6.)     

An in vitro model of canine immediate-type hypersensitivity reactions.

Fragmented lung prepared from dogs cutaneously sensitive to ascaris antigen released histamine and a slow-reacting substance of anaphylaxis-like (SRS-A) material upon antigen challenge. Passive sensitization of fragments with serum obtained from ascaris-sensitive donor dogs enhanced the release of both substances; heating (56 degrees C for 4 h) destroyed the ability of the serum to enhance release. In passively sensitized tissues isoproterenol and papaverine inhibited the release of histamine and SRS-A; propranolol antagonized the effect of isoproterenol. Carbachol enhanced the release of both substances from passively sensitized lung wheras disodium cromoglycate and aminoguanidine were without effect. It is concluded that fragmented canine lung is a useful model for study of immediate-type hypersensitivity reactions.     

Skin testing as a biomarker in drug allergy

Despite the significant negative impact drug allergies can have on patient care, the diagnosis is largely based on clinical history, and there are limited diagnostic tests that can be done at the time of a reaction. Biomarkers are needed to improve the diagnosis and the identification of the culprit medication. Skin testing is the most useful biomarker for immediate- and delayed-type reactions available, but it is limited by its low sensitivity. To improve its accuracy and reproducibility, a standardized procedure must be used. For immediate-type reactions, penicillin skin testing is the most widely studied, and it can be used in patients with history of anaphylaxis or recent immunoglobulin E-mediated reaction or for whom there is a significant risk if a reaction were to occur, such as pregnancy. Skin testing is also important in allergy to platinum agents allowing for continued first-line therapy. For delayed-type reactions, patch testing and delayed intradermal testing, used in conjunction with clinical history, can help to improve identification of the culprit medication depending on the type of reaction. Other biomarkers including in vitro testing for specific immunoglobulin E, basophil activation test, lymphocyte transformation test, ELISpot, and genetic factors that increase the likelihood of reaction are under investigation, and they may be most helpful when used in combination with the clinical history and skin testing results.     

Effect of Schizonepeta tenuifolia extract on mast cell-mediated immediate-type hypersensitivity in rats

We investigated the effect of an aqueous extract of Schizonepeta tenuifolia (STAE) on mast cell-mediated immediate-type hypersensitivity. STAE inhibited systemic allergic reaction induced by compound 48/80 in rats dose-dependently. STAE also inhibited plasma histamine levels induced by compound 48/80. STAE inhibited local allergic reaction activated by anti-dinitrophenyl (DNP) IgE. In addition, STAE does-dependently inhibited histamine release from rat peritoneal mast cells (RPMC) activated by compound 48/80 or anti-DNP IgE. However, STAE had a significant enhancing effect on anti-DNP IgE-induced tumor necrosis factor-alpha (TNF-alpha) production from RPMC. These results indicate that STAE inhibits immediate-type hypersensitivity and suggest that STAE can selectively activate the TNF-alpha production from RPMC.     

Histamine release in immediate-type hypersensitivity reactions in intact human skin measured by microdialysis

The purpose of this study was to evaluate the application of a microdialysis technique for measurement of interstitial histamine levels in intact human skin. Three allergic subjects were investigated. Single dialysis fibers were glued to nylon tubings and inserted in forearm skin by means of a fine cannula. Dialysis fibers were inserted in triplicate and perfused with isotonic saline at a rate of 3 microliters/min. After a period of 2 h a 60-microliters base-line period was established. Then the patients were skin prick tested (SPT) with allergen in duplicate and a single saline control. Dialysate was collected in consecutive 30 microliters fractions. Histamine concentration in the dialysate was analyzed with a glass fiber fluorescence assay. Median base-line histamine level was 4 (range 4-7) ng/ml. Following allergen SPT, dialysate histamine concentration increased to 81 ng/ml (74-128), with maximum values 10-20 min after SPT. Intraindividual coefficient of variation on peak histamine levels was 18.9%. No histamine increase was seen following saline SPT. We consider microdialysis to be a valuable method for assessment of allergic mechanisms in intact human skin.     

Hypersensitivity to tetracyclines: Skin testing,graded challenge,and desensitization regimens

BackgroundHypersensitivity reactions (HSRs) to tetracyclines and the related compound, tigecycline, can limit the use of these medications and compromise optimal patient care. Despite this, there is little discussion in the literature describing the presentation of these reactions or guiding clinicians on the management of these reactions in adult and pediatric patients.ObjectiveTo describe the clinical features, optimal diagnostic approach, and management of HSRs to tetracyclines.MethodsPatients with reactions to tetracyclines at our institution from 2011 to 2019 were identified by retrospective chart review. Skin testing protocols were designed for each antibiotic. Graded challenge and desensitization procedures were devised based on medical history, skin testing results when available, and need for readministration.ResultsThe HSRs to tetracyclines, their workup, and management are described for 10 patients, aged 7 to 68 years. Our skin testing protocols for doxycycline, minocycline, and tigecycline described herein had good negative predictive value. When skin testing was negative and the initial reaction was not severe, graded challenge to the culprit drug was performed. Using the included procedures, 3 patients were desensitized to oral doxycycline, 3 to oral minocycline, and 2 to intravenous tigecycline. All the desensitizations were successful.ConclusionOnce identified, HSRs to tetracyclines can be further evaluated with skin testing and graded challenge and managed in appropriate cases with desensitization. These procedures can facilitate first-line therapy for patients who require tetracyclines but developed hypersensitivity reactions.     

Skin testing for immediate hypersensitivity to betalactams: comparison between two commercial kits

INTRODUCTION: Skin testing with major and minor determinants of benzylpenicillin is the recommended standard practice to evaluate subjects with immediate hypersensitivity to betalactams. The withdrawal of these products from the market has set us back to the early days, before the introduction of reagents for in vivo testing. OBJECTIVES: To compare a recently released kit of benzylpenicillin conjugated to poly-l-lysine (PPL) and minor determinants mixture (MDM) with the previously existing kit in a positive control group of subjects sensitized to major and/or minor determinants of benzylpenicillin. METHODS: Skin tests with both kits were made in a group of positive subjects previously diagnosed with immediate hypersensitivity to penicillins and with positive results to PPL and/or MDM and in a negative control group. Radioallergosorbent test (RAST) inhibition assays with a pool of sera and individual samples were carried out to compare the inhibition capacity of PPL and MDM of both kits. RESULTS: Of 22 cases selected from our historical group, 14 were positive: eight to PPL, three to MDM and three to both. These results were equivalent for both kits. RAST inhibition studies showed similar potencies in the inhibition of PPL and MDM. CONCLUSIONS: Both tests show similar results in terms of RAST inhibition assays and skin tests sensitivity and specificity in the groups selected. The new assay can be used for the same purpose and indications as the previous test.     

Immunohistological assessment of cutaneous drug hypersensitivity in patients with HIV infection.

The pathogenesis of drug hypersensitivity in patients with HIV infection is unknown. To study further the nature of hypersensitivity, the histopathological features of morbilliform drug hypersensitivity reactions were examined in a group of HIV-infected patients. Skin sections from 23 HIV-infected subjects with morbilliform drug hypersensitivity reactions were examined by light microscopy, direct immunofluorescence and immunohistochemistry, to determine the nature of the inflammatory infiltrate and the role of immunoglobulin, complement and cytokines. The principal light microscopic findings were spongiosis, hydropic generation of the basal layer, civatte bodies, an epidermal lymphocytic infiltrate (48%), and a perivascular dermal infiltrate of lymphocytes (87%) and macrophages (52%). Two patients had findings consistent with toxic epidermal necrolysis. Immunohistochemistry demonstrated that the lymphocytic infiltrate consisted of CD8+, HLA-DR+ T lymphocytes (some of which also stained for CD38), a marked depletion of epidermal Langerhans cells (90%), and strong cytoplasmic staining of keratinocytes for IL-6 (60%), IL-1 beta (50%), tumour necrosis factor-alpha (TNF-alpha) (45%) and to a lesser degree, interferon-gamma (IFN-gamma) (35%). Immunofluorescence did not demonstrate any significant deposition of immunoglobulin or complement. The histological findings were independent of the responsible drug, the duration of either therapy or the rash, and of peripheral blood CD4+ and CD8+ cell counts. These findings suggest that activated CD8+ lymphocytes and perhaps epidermal production of cytokines are involved in the pathogenesis of cutaneous drug hypersensitivity in HIV-infected patients. The common histological features, regardless of the causative drug, suggest a common pathogenesis.