Kathrin Scherer

Anaphylaxis to isosulfan blue and cross- reactivity to patent blue V: case report and review of the nomenclature of vital blue dyes

BACKGROUND Blue dyes used for lymphatic mapping in sentinel lymph node biopsy cause intraoperative anaphylactic reactions in up to 2.7% of patients. With increasing implementation of this technique, the incidence of anaphylaxis to these dyes can be expected to increase. In the literature, the chemically often unrelated and inconsistently designated dyes have been confused, adding to other inconsistencies in the nomenclature. OBJECTIVE To demonstrate the nomenclature, chemical and physiologic differences, and allergenicity of the various blue dyes used in a medical context. METHODS We describe a patient with an intraoperative grade IV anaphylactic reaction to isosulfan blue. Immediate-type hypersensitivity was proved by positive skin test reactions and CD63 expression to isosulfan blue and cross-reactivity to patent blue V. RESULTS A review of the literature clarified the exact nomenclature of the blue dyes and the possible pitfalls of confusing nomenclature in the context of structurally closely related dyes with different allergenic properties. For the detection of type I hypersensitivity, intracutaneous tests are valuable tools. An IgE-mediated mechanism has been shown recently. In most cases, sensitization exists without known previous exposure in a medical context. This may be due to the widespread use of such dyes in objects of everyday life. Preoperative antiallergic medication use does not prevent anaphylactic reactions but apparently reduces their severity. CONCLUSION For better comparison and precision, the Chemical Abstracts Service number of the respective dye should always be given.

Delayed Cutaneous Manifestations of Drug Hypersensitivity

Drugs may elicit a considerable variety of clinical signs, often affecting the skin and the mucous membranes. The most common are maculopapular exanthemas and urticaria, more rarely pustules, bullae vasculitic lesions, and lichenoid lesions may also be observed. Apart from the morphology, the chronology of the occurrence and the evolution of single skin lesions and exanthema are also paramount in the clinical diagnosis of cutaneous drug hypersensitivity. Often, the skin represents the only organ manifestation; however, it may be the herald for a systemic involvement of internal organs, such as in severe drug-induced hypersensitivity syndromes or anaphylaxis.

Allergic complications from orthopaedic joint implants: the role of delayed hypersensitivity to benzoyl peroxide in bone cement

Background. Orthopaedic implants and osteosynthesis materials are increasingly being used. Complications include mainly physical–mechanical problems and infections. Uncommonly, an allergic reaction towards an alloy metal or a bone cement component has been implicated. Potential bone cement allergens include acrylates, benzoyl peroxide, N,N‐dimethyl‐p‐toluidine, and gentamicin. Typical symptoms are pain, swelling, inflammatory skin reactions, implant loosening, and fistula formation.

Immediate Hypersensitivity to Rifampicin in 3 Patients: Diagnostic Procedures and Induction of Clinical Tolerance

Background: Desensitization with drugs may be indicated in some clinical situations. Apart from large experiences with β-lactam antibiotics and cotrimoxazole in HIV infection, experience with other drugs is limited. Rifampicin may elicit exanthema and urticaria, and their pathomechanisms are not known in detail. Since therapy with rifampicin may be indispensable in mycobacterial infections or against multiresistant Staphylococcusaureus, desensitization may be indicated in some patients. Objective: Report of immediate hypersensitivity to rifampicin and description of diagnostic and desensitization procedures. Methods: We report 3 patients with immediate urticarial reactions to rifampicin. Diagnostic procedures included skin and in vitro tests (specific IgE, lymphocyte transformation test, LTT, and CAST®). The non-irritant cutoff concentration was evaluated in 24 volunteers. A 7-day desensitization procedure was used. Results: Only intradermal tests at a dilution of at least 1:10,000 (concentration of rifampicin approximately 0.006 mg/ml) were true positive, whereas in vitro tests (IgE, LTT and CAST) did not correctly identify hypersensitive patients. Two patients had positive accidental reexposure. All patients were successfully desensitized with rifampicin according to a slow 7-day protocol. Conclusions: Rifampicin rarely elicits immediate hypersensitivity symptoms which may be diagnosed by intradermal skin tests. In vitro tests did not contribute to the diagnosis. Therefore, an IgE-mediated mechanism remains to be proven. Desensitization with rifampicin using different protocols has been reported. In our 3 cases, clinical tolerance to rifampicin was achieved using a 7-day protocol.

Adverse drug reactions to biologics

The use of biologics has rapidly expanded since the introduction of the first diagnostic antibodies; they are now widely employed in oncology, autoimmune disorders, inflammatory diseases and transplantation medicine. Their widespread use has resulted in an increase in adverse drug reactions. Adverse effects result from both direct pharmacological actions and immunological actions, as well as through induction of a specific immune response. The nomenclature, particularly of the monoclonal antibodies, identifies the target structure and organ as well as the species of origin, which then helps predict their effects and antigenic properties. Depending on the extent of foreign protein, anti‐allotypic or anti‐idiotypic antibodies with or without neutralizing properties may be induced. Adverse drug reactions from biologics often depend on the target and may be explained by activation or inhibition of particular cytokine pathways. Adverse drug reactions are classified by their pathomechanism, which enhances understanding of the pathogenesis and facilitates both allergologic diagnostic measures and planning of premedication in future treatments. This review emphasizes immunostimulatory and hypersensitivity reactions.

Hypersensitivity Reactions to Anticoagulant Drugs

Drugs with anticoagulant activity, including heparins, hirudins, coumarins, and platelet aggregation inhibitors belong to the most widely used drugs. Hypersensitivity reactions from these agents are rare. However, due to their widespread use, they may have a considerable impact on patient safety and treatment. Accurate diagnosis of potentially life-threatening adverse events and identification of alternatives is mandatory. We review hypersensitivity reactions caused by the different groups of anticoagulant agents and discuss the pathophysiological mechanisms, diagnostic possibilities and management options. According to patients histories the most common hypersensitivity reaction is intolerance to acetylsalicylic acid (ASA). Also localized erythematous plaques, occurring to subcutaneous application of heparins are rather common. Other hypersensitivity reactions are rare but may be life-threatening, e.g. skin necrosis due to heparin-induced thrombocytopenia. Rarely anaphylactoid reactions have been observed to ASA, heparin, and hirudin. Skin and provocation tests with immediate and late readings are the most reliable diagnostic tools for heparin- or hirudin-induced urticaria/anaphylaxis or heparin-induced delayed plaques. Provocation tests may be used to identify safe alternatives. In cases of necrosis from heparins or coumarins, all in vivo tests are contraindicated. Most in vitro tests are not universally available, and with the exception of platelet aggregation tests, they have a low sensitivity. In some anticoagulant-associated hypersensitivity reactions detailed allergologic investigation may help to identify safe treatment alternatives. Typically, several tests are needed, and therefore the test procedures are time consuming.

Danger Signs in Drug Hypersensitivity

ADRs are frequently considered iatrogenic complications and, therefore, pose a specific challenge for the physician-patient relationship. Early recognition of a potential ADR is possible, especially on the skin, in addition to characteristic clinical danger signs. Cutaneous manifestations are variable, depending on the causative pathomechanism. It is impossible to conclude the causative agent from the morphology of the cutaneous lesions. The intake of several drugs in the time before the elicitation of the drug reaction usually poses a diagnostic challenge. It is crucial for the precision of any further allergological work-up to document the type of rash precisely as well as the time course of drug intake and appearance of the first symptoms. involvement of internal organs or circulating blood cells. Timely recognition of such cutaneous lesions and the correct differential diagnosis with prompt withdrawal of the putative culprit drug are essential to reducing morbidity and preventing mortality. This article discusses risk factors, early symptoms, and danger signs indicating a possibly severe course of an ADR and advises on early actions.

Blue dyes in medicine - a confusing terminology

Dear Sir, Lymphatic mapping and sentinel lymph node biopsy with blue dyes are routinely used for staging of patients with breast cancer and other malignant tumours. With increasing use of this technique, studies and reports of adverse effects have become more frequent, most commonly regarding anaphylactic reactions to the dyes used for lymphatic mapping. Although it is very important to raise awareness and collect data of adverse events, many recent publications, among them also the latest on this topic in this journal (1), suffer from some inaccuracies that are in part due to complicated systematics of the dyes and a misleading terminology even in the chemical literature (2). As the authors correctly state, there is a strong cross-reactivity between Patent Blue V (calciumchelated dimer: CAS number: 3536-49-0) and Isosulfan Blue (CAS number: 68238-36-8). Both belong to the group of triarylmethan dyes and basically share the same formula; however, Patent Blue V has an additional hydroxyl group at position 5. Isosulfan Blue is the structural isomer of Patent Blue VF (CAS number: 129-17-9, not Patent Blue V) (2) (Fig. 1). Patent Blue V, not Patent Blue VF, is also used as food colourant with the number E 131 and is still on the market as such, in contrast to several reports (1, 3) (Table 1). Methylene blue [CAS number: 61-73-4 (anhydrous methylene blue), CAS number: 7220-79-3 (methylene blue trihydrate)] is sometimes mentioned as another dye successfully used for lymphatic mapping (1, 4, 5). It is also approved for oral or intravenous administration for the treatment of methemoglobinaemia and haemolysis, but maximal doses should be respected because of its systemic toxicity. If used locally, it should be deeply injected, since it may cause severe necrosis upon intradermal administration (6). According to Tsopelas and Sutton (7), however, methylene blue does not bind to plasma proteins, having no sulfonic acid groups, and is therefore not taken up by lymph but diffuses directly into blood capillaries, which may limit its use as agent for lymphatic mapping. An immunoglobulin E (IgE)-mediated mechanism was recently demonstrated by Woehrl et al. (8) in patients with prior anaphylactic reactions to Isosulfan Blue, although previous publications suggested pseudoallergic mechanisms. Determination of specific IgE to both dyes may be attempted by the commercial ImmunoCAP method (Pharmacia Diagnostics, Uppsala, Sweden). Given the relatively small molecular weight of Isosulfan Blue and Patent Blue V, theses dyes are very likely to act as haptens. This may influence the sensitivity of in vitro tests, which are based on detection of complete antigens. It is important to publish reports on adverse events from a technique with widespread use. However, a strong emphasis should be put on the correct terminology to avoid misleading or even dangerous statements. Therefore, we strongly recommend the use of CAS or CI numbers (9) to unambiguously identify the dyes.

Diagnosis of stinging insect allergy: utility of cellular in-vitro tests.

Purpose of reviewDiagnosis of stinging insect allergy is based on a detailed history, venom skin tests, and detection of venom-specific IgE. As an additional diagnostic tool, basophil responsiveness to venom allergens has been shown to be helpful in selected patients. This review summarizes the current diagnostic procedures for stinging insect allergy and discusses the latest developments in cellular in-vitro tests. Recent findingsCellular assays have been evaluated in patients with Hymenoptera venom allergy. The diagnostic performance of the cellular mediator release test is similar to that of the flow cytometric basophil activation test (BAT), but the BAT has been the most intensively studied. BAT offers the possibility to assess basophil reactivity to allergens in their natural environment and to simultaneously analyze surface marker expression and intracellular signaling. It has been demonstrated that BAT represents a valuable additional diagnostic tool in selected patients when used in combination with other well established tests. A major limitation is the current lack of unified, standardized protocols. Flow cytometry offers huge possibilities to enhance knowledge of basophil functions. SummaryThe BAT may be used as an additional test to confirm the diagnosis of stinging insect allergy in selected patients, provided that it is performed by an experienced laboratory using a validated assay. Test results have to be interpreted by clinicians familiar with the methodological aspects. The utility of the BAT to confirm allergy diagnosis and to predict the risk of subsequent systemic reactions may be improved by combined analysis of multiple surface markers and intracellular signaling pathways.

Allergic rhinitis in patients with asthma: the Swiss LARA (Link Allergic Rhinitis in Asthma) survey

ABSTRACT Objective: To determine the characteristics of asthma (A) and allergic rhinitis (AR) among asthma patients in primary care practice. Research design and methods: Primary care physicians, pulmonologists, and allergologists were asked to recruit consecutive asthma patients with or without allergic rhinitis from their daily practice. Cross-sectional data on symptoms, severity, treatment and impact on quality of life of A and AR were recorded and examined using descriptive statistics. Patients with and without AR were then compared. Results: 1244 asthma patients were included by 211 physicians. Asthma was controlled in 19%, partially controlled in 27% and not controlled in 54%. Asthma treatment was generally based on inhaled corticosteroids (ICS) with or without long acting beta 2 agonists (78%). A leukotriene receptor antagonist (LTRA) was used by 46% of the patients. Overall, 950 (76%) asthma patients had AR (A + AR) and 294 (24%) did not (A − AR). Compared to patients with A − AR, A + AR patients were generally younger (mean age ± standard deviation: 42 ± 16 vs. 50 ± 19 years, p < 0.001) and fewer used ICS (75% vs. 88%, p < 0.001). LTRA usage was similar in both groups (46% vs. 48%). Asthma was uncontrolled in 53% of A + AR and 57% of A − AR patients. Allergic rhinitis was treated with a mean of 1.9 specific AR medications: antihistamines (77%), nasal steroids (66%) and/or vasoconstrictors (38%), and/or LTRA (42%). Rhinorrhoea, nasal obstruction, or nasal itching were the most frequently reported AR symptoms and the greatest reported degree of impairment was in daily activities/sports (55%). Conclusions: Allergic rhinitis was more common among younger asthma patients, increased the burden of symptoms and the need for additional medication but was associated with improved asthma control. However, most asthma patients remained suboptimally controlled regardl-ess of concomitant AR.