Andreas J. Bircher

Guidelines for performing skin tests with drugs in the investigation of cutaneous adverse drug reactions

Skin testing with a suspected drug has been reported to be helpful in determining the cause of cutaneous adverse drug reactions (CADR). Many isolated reports of positive drug skin tests are published, but without detailed information concerning the clinical features of the CADR and the method used in performing drug skin tests, such data are not very informative. A working party of the European Society of Contact Dermatitis (ESCD) for the study of skin testing in investigating cutaneous adverse drug reactions, has proposed the herein‐reported guidelines for performing skin testing in CADR in order to standardize these procedures. In each reported case, the imputability of each drug taken at the onset of the CADR and a highly detailed description and characterization of the dermatitis need to be given. Drug skin tests are performed 6 weeks to 6 months after complete healing of the CADR. Drug patch tests are performed according to the methods used in patch testing in studying contact dermatitis. The commercialized form of the drug used by the patient is tested diluted at 30% pet. (pet.) and/or water (aq.). The pure drug is tested diluted at 10% in pet. or aq. In severe CADR, drug patch tests are performed at lower concentrations. It is also of value to test on the most affected site of the initial CADR. Drug prick tests are performed on the volar forearm skin with the commercialized form of the drug, but with sequential dilutions in cases of urticaria. Intradermal tests (IDT) are performed with sterile sequential dilutions (10–4, 10–3, 10–2, 10–1) of a pure sterile or an injectable form of the suspected drug with a small volume of 0.04 ml. Drug skin tests need to be read at 20 min and also later at D2 and D4 for patch tests, at D1 for prick tests and IDT. All these tests also need to be read at 1 week. The success of skin tests varies with the drug tested, with a high % of positive results, for example, with betalactam antibiotics, pristinamycin, carbamazepine and tetrazepam on patch testing, or with betalactam antibiotics and heparins on delayed readings of IDT. The results of drug skin tests also depend on the clinical features of the CADR. The use of appropriate control patients is necessary to avoid false‐positive results.

Skin test concentrations for systemically administered drugs – an ENDA/EAACI Drug Allergy Interest Group position paper

Skin tests are of paramount importance for the evaluation of drug hypersensitivity reactions. Drug skin tests are often not carried out because of lack of concise information on specific test concentrations. The diagnosis of drug allergy is often based on history alone, which is an unreliable indicator of true hypersensitivity.To promote and standardize reproducible skin testing with safe and nonirritant drug concentrations in the clinical practice, the European Network and European Academy of Allergy and Clinical Immunology (EAACI) Interest Group on Drug Allergy has performed a literature search on skin test drug concentration in MEDLINE and EMBASE, reviewed and evaluated the literature in five languages using the GRADE system for quality of evidence and strength of recommendation. Where the literature is poor, we have taken into consideration the collective experience of the group.We recommend drug concentration for skin testing aiming to achieve a specificity of at least 95%. It has been possible to recommend specific drug concentration for betalactam antibiotics, perioperative drugs, heparins, platinum salts and radiocontrast media. For many other drugs, there is insufficient evidence to recommend appropriate drug concentration. There is urgent need for multicentre studies designed to establish and validate drug skin test concentration using standard protocols. For most drugs, sensitivity of skin testing is higher in immediate hypersensitivity compared to nonimmediate hypersensitivity.

Guidelines for measurement of cutaneous blood flow by laser Doppler flowmetry : a report from the standardization group of the European Society of Contact Dermatitis

The report reviews individual‐related variables (age, sex. race, anatomical site), intra‐ and inter‐individual variation (temporal, physical and mental activity, food and drugs), and environment‐related variables (air convection, temperature). Technical variation, instrument validation including a standard reactive hyperemia experiment, and a standard operating procedure are discussed and included in the guidelines.

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.

The European baseline series in 10 European Countries, 2005/2006 : results of the European Surveillance System on Contact Allergies (ESSCA)

Background: Continual surveillance based on patch test results has proved useful for the identification of contact allergy.

Hypersensitivity reactions to anticoagulant drugs: diagnosis and management options

Anticoagulants, including heparins, coumarins, hirudins, and some of the previously used plasma volume expanders, belong to the most widely used drugs. Hypersensitivity reactions from these agents are uncommon. However, they may have a considerable impact on patient safety and treatment decisions. Therefore, early diagnosis of potentially life‐threatening adverse events and identification of alternatives is clinically important. This review contains an update on current knowledge about hypersensitivity reactions caused by the different anticoagulants. In addition, it discusses pathophysiologic mechanisms, diagnostic possibilities, and management options. The most common hypersensitivity reactions are erythematous plaques, occurring with a delay after subcutaneous application of heparins. Seldom they turn into maculopapular exanthema. Other hypersensitivity reactions are rare but may be life‐threatening, e.g. skin necrosis because of heparin‐induced thrombocytopenia. 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. If necrosis from heparins or coumarins is suspected, skin tests are contraindicated. In anaphylactic reactions caused by dextrans or hydroxyethyl starch skin tests are useless. Most in vitro tests have a low sensitivity and are not generally available. Therefore, in some anticoagulant‐associated hypersensitivity reactions detailed allergologic investigation may help to identify safe treatment alternatives. However, several tests may be needed, and the procedures are usually time‐consuming.

Guideline for acute therapy and management of anaphylaxis

S2 Guideline of the German Society for Allergology and Clinical Immunology (DGAKI), the Association of German Allergologists (AeDA), the Society of Pediatric Allergy and Environmental Medicine (GPA), the German Academy of Allergology and Environmental Medicine (DAAU), the German Professional Association of Pediatricians (BVKJ), the Austrian Society for Allergology and Immunology (ÖGAI), the Swiss Society for Allergy and Immunology (SGAI), the German Society of Anaesthesiology and Intensive Care Medicine (DGAI), the German Society of Pharmacology (DGP), the German Society for Psychosomatic Medicine (DGPM), the German Working Group of Anaphylaxis Training and Education (AGATE) and the patient organization German Allergy and Asthma Association (DAAB)

Occupational Exposure to Dusts, Gases, and Fumes and Incidence of Chronic Obstructive Pulmonary Disease in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults

RATIONALE There is limited evidence from population-based studies demonstrating incidence of spirometric-defined chronic obstructive pulmonary disease (COPD) in association with occupational exposures. OBJECTIVES We evaluated the association between occupational exposures and incidence of COPD in the Swiss Cohort Study on Air Pollution and Lung and Heart Diseases in Adults (SAPALDIA). MEASUREMENTS AND MAIN RESULTS Prebronchodilator ratio of forced expiratory volume in 1 second over forced vital capacity (FEV(1)/FVC) was measured in 4,267 nonasthmatic SAPALDIA participants ages 18-62 at baseline in 1991 and at follow-up in 2001-2003. COPD was defined by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criterion (FEV(1)/FVC < 0.70) and Quanjer reference equation (FEV(1)/FVC < lower limit of normal [LLN]), and categorized by severity (≥ 80% and <80% predicted FEV(1) for stage I and stage II+, respectively). Using a job-exposure matrix, self-reported occupations at baseline were assigned exposures to biological dusts, mineral dusts, gases/fumes, and vapors, gases, dusts, or fumes (VGDF) (high, low, or unexposed as reference). Adjusted incident rate ratios (IRRs) of stage I and stage II+ COPD were estimated in mixed Poisson regression models. Statistically significant (P < 0.05) IRRs of stage II+ GOLD and LLN-COPD, indicating risks between two- and fivefold, were observed for all occupational exposures at high levels. Occupational exposure-associated risk of stage II+ COPD was observed mainly in males and ages ≥ 40 years, and remained elevated when restricted to nonsmokers. CONCLUSIONS In a Swiss working adult population, occupational exposures to biological dusts, mineral dusts, gases/fumes, and VGDF were associated with incidence of COPD of at least moderate severity.

Current patch test results with the European baseline series and extensions to it from the 'European Surveillance System on Contact Allergy' network, 2007-2008

Background. The pattern of contact sensitization to the supposedly most important allergens assembled in the baseline series differs between countries, presumably at least partly because of exposure differences.

Desensitization in delayed drug hypersensitivity reactions -- an EAACI position paper of the Drug Allergy Interest Group.

Drug hypersensitivity may deprive patients of drug therapy, and occasionally no effective alternative treatment is available. Successful desensitization has been well documented in delayed drug hypersensitivity reactions. In certain situations, such as sulfonamide hypersensitivity in HIV‐positive patients or hypersensitivity to antibiotics in patients with cystic fibrosis, published success rates reach 80%, and this procedure appears helpful for the patient management. A state of clinical tolerance may be achieved by the administration of increasing doses of the previously offending drug. However, in most cases, a pre‐existent sensitization has not been proven by positive skin tests. Successful re‐administration may have occurred in nonsensitized patients. A better understanding of the underlying mechanisms of desensitization is needed. Currently, desensitization in delayed hypersensitivity reactions is restricted to mild, uncomplicated exanthems and fixed drug eruptions. The published success rates vary depending on clinical manifestations, drugs, and applied protocols. Slower protocols tend to be more effective than rush protocols; however, underreporting of unsuccessful procedures is very probable. The decision to desensitize a patient must always be made on an individual basis, balancing risks and benefits. This paper reviews the literature and presents the expert experience of the Drug Hypersensitivity Interest Group of the European Academy of Allergy and Clinical Immunology.