Antonino Romano

General considerations for skin test procedures in the diagnosis of drug hypersensitivity.

K. Brockow, A. Romano, M. Blanca, J. Ring, W. Pichler, P. Demoly Klinik und Poliklinik fur Dermatologie und Allergologie, Muenchen, Germany; Department of Internal Medicine and Geriatrics, UCSC, Allergy Unit, CI Columbus, Rome and IRCS Oasi Maria SS, Troina, Italy; Research Unit for Allergic Diseases, Carlos Haya Hospital, Malaga, Spain; Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, Bern, Switzerland; Maladies Respiratoires, Hopital Arnaud de Villeneuve, Montpellier, France

Drug provocation testing in the diagnosis of drug hypersensitivity reactions: general considerations.

A drug provocation test (DPT) is the controlled administration of a drug in order to diagnose drug hypersensitivity reactions. DPTs are performed under medical surveillance, whether this drug is an alternative compound, or structurally/pharmacologically related, or the suspected drug itself. DPT is sometimes termed controlled challenge or reexposure (1), drug challenge (2), graded (2) or incremental challenge (3), test dosing (2), W. Aberer, A. Bircher, A. Romano, M. Blanca, P. Campi, J. Fernandez, K. Brockow, W. J. Pichler, P. Demoly for ENDA, and the EAACI interest group on drug hypersensitivity Department of Environmental Dermatology, University of Graz, Graz, Austria; Department of Dermatology, Basle, Switzerland; Allergy Service, Catholic University of Rome, Italy; Allergy Service, University La Paz, Madrid, Spain; Clinic for Allergy and Immunology, Florence, Italy; Allergy Section, Dept. Clin. Med., UMH, Elche, Spain; Klinik und Poliklinik f1r Dermatologie und Allergologie, Muenchen, Germany; Clinic for Rheumatology and Clinical Immunology/Allergology, Inselspital, Bern, Switzerland; Maladies Respiratoires-INSERM U454, H7pital Arnaud de Villeneuve, Montpellier, France

Diagnosis of immediate allergic reactions to beta-lactam antibiotics

Allergic reactions to betalactams are the most common cause of adverse drug reactions mediated by specific immunological mechanisms. Reactions may be induced by all betalactams currently available, ranging from benzylpenicillin (BP) to other more recently introduced betalactams, such as aztreonam or the related betalactamase-inhibitor clavulanic acid (Fig. 1) (1–5). Although the production process of betalactams has improved over the years, the number of reactions has not decreased, M. J. Torres, M. Blanca, J. Fernandez, A. Romano, A. de Weck, W. Aberer, K. Brockow, W. J. Pichler, P. Demoly for ENDA, and the EAACI interest group on drug hypersensitivity Allergy Service, Carlos Haya Hospital, Malaga, Spain; Allergy Service, University La Paz, Madrid, Spain; Allergy Section, Dept. Clin. Med., UMH, Elche, Spain; Allergy Service, Catholic University of Rome, Italy; Fondation Gerimmun, Beaumont 18, CH1700, Fribourg, Switzerland; Department of Environmental Dermatology, Graz, Austria; Klinik und Poliklinik f5r Dermatologie und Allergologie, Muenchen, Germany; Clinic for Rheumatology and Clinical Immunology/Allergy, Inselspital, Bern, Switzerland; Maladies Respiratoires-INSERM U454, Hopital Arnaud de Villeneuve, Montpellier, France

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.

Update on the evaluation of hypersensitivity reactions to betalactams

Hypersensitivity reactions to betalactams (BLs) are classified as immediate or nonimmediate. The former usually appear within 1 h of drug‐intake and are mediated by specific IgE‐antibodies. Nonimmediate reactions are those occurring more than 1 h after drug‐intake, and they can be T‐cell mediated. The diagnostic evaluation of allergic reactions to BLs has changed over the last 5 years, for several reasons. Major and minor determinants are no longer commercially available for skin testing in many countries. In immediate allergic reactions, the sensitivity of skin testing and immunoassays is decreasing and new in vitro methods, such as the basophil activation test, are gaining importance for diagnosis. For nonimmediate reactions, skin testing appears to be less sensitive than previous results, although more studies need to be carried out in this direction. Nevertheless, the drug provocation test is still necessary for diagnosis.

Diagnosis of nonimmediate reactions to beta-lactam antibiotics.

Nonimmediate manifestations (i.e. occurring more than 1 h after drug administration), particularly maculopapular and urticarial eruptions, are common during β‐lactam treatment. The mechanisms involved in most nonimmediate reactions seem to be heterogeneous and are not yet completely understood. However, clinical and immunohistological studies, as well as analysis of drug‐specific T‐cell clones obtained from the circulating blood and the skin, suggest that a type‐IV (cell‐mediated) pathogenic mechanism may be involved in some nonimmediate reactions such as maculopapular or bullous rashes and acute generalized exanthematous pustulosis. In the diagnostic work‐up, the patients history is fundamental; patch testing is useful, together with delayed‐reading intradermal testing. The latter appears to be somewhat more sensitive than patch testing, but also less specific. In case of negative allergologic tests, consideration should be given to provocation tests, and the careful administration of the suspect agents. With regard to in vitro tests, the lymphocyte transformation test may contribute to the identification of the responsible drug.

Practical guide to skin prick tests in allergy to aeroallergens

To cite this article: Bousquet J, Heinzerling L, Bachert C, Papadopoulos NG, Bousquet PJ, Burney PG, Canonica GW, Carlsen KH, Cox L, Haahtela T, Lodrup Carlsen KC, Price D, Samolinski B, Simons FER, Wickman M, Annesi‐Maesano I, Baena‐Cagnani CE, Bergmann KC, Bindslev‐Jensen C, Casale TB, Chiriac A, Cruz AA, Dubakiene R, Durham SR, Fokkens WJ, Gerth‐van‐Wijk R, Kalayci O, Kowalski ML, Mari A, Mullol J, Nazamova‐Baranova L, O’Hehir RE, Ohta K, Panzner P, Passalacqua G, Ring J, Rogala B, Romano A, Ryan D, Schmid‐Grendelmeier P, Todo‐Bom A, Valenta R, Woehrl S, Yusuf OM, Zuberbier T, Demoly P. Practical guide to skin prick tests in allergy to aeroallergens. Allergy 2012; 67: 18–24.

Natural evolution of skin test sensitivity in patients allergic to β-lactam antibiotics

BACKGROUND Subjects with immediate reactions to penicillins and positive skin test responses may lose sensitivity if penicillin is avoided. The longer the interval between the reaction and the skin test, the greater the likelihood of having a negative result. OBJECTIVE We sought to study prospectively the evolution of skin test sensitivity in a group of subjects allergic to penicillin with positive skin test responses to different penicillin determinants. METHODS Skin tests were performed with major and minor determinants of benzylpenicillin (BPO/MDM), amoxicillin (AX), and ampicillin at the initial evaluation and repeated 1, 3, and 5 years later if the responses were still positive. Subjects were divided into 2 groups. Group A consisted of patients with a positive skin test response to benzylpenicilloyl or minor determinant mixture, and group B consisted of those with a selective response to amoxicillin and good tolerance to benzylpenicillin. RESULTS In group A (n = 31) after 1 year, 25 patients continued to have positive responses and 6 began to have negative responses; after 3 years, 18 continued to have positive responses, 5 began to have negative responses, and 2 were lost to follow-up; and after 5 years, 12 continued to have positive responses, 5 began to have negative responses, and 1 was lost to follow-up. In group B (n = 24) 12 had positive responses, and 12 had negative responses after 1 year; 6 had positive responses, 5 had negative responses, and 1 was lost to follow-up after 3 years; and no patients had positive responses, 5 had negative responses, and 1 was lost to follow-up after 5 years. Survival analysis showed significant differences between groups (log-rank test = 12.8; P <. 0003). CONCLUSION Patients with a selective response to amoxicillin tended to lose sensitivity faster than those who responded to several penicillin determinants, supporting the existence of at least 2 distinct types of IgE response in patients allergic to beta-lactam.

Management of hypersensitivity reactions to iodinated contrast media.

All iodinated contrast media (CM) are known to cause both immediate (≤1 h) and nonimmediate (>1 h) hypersensitivity reactions. Although for most immediate reactions an allergic hypersensitivity cannot be demonstrated, recent studies indicate that the severe immediate reactions may be IgE‐mediated, while most of the nonimmediate exanthematous skin reactions, appear to be T‐cell mediated. Patients who experience such hypersensitivity reactions are therefore advised to undergo an allergologic evaluation. Several investigators have found skin testing to be useful in confirming a CM allergy, especially in patients with nonimmediate skin eruptions. If a patient with confirmed allergy to a CM needs a new CM exposure, a skin test negative CM should be chosen and premedication may be tried. However, none of these precautional measures is a guarantee against a repeat reaction. More research focusing on pathomechanisms, diagnostic testing and premedication is therefore clearly needed in order to prevent CM‐induced hypersensitivity reactions in the future.

Classification and practical approach to the diagnosis and management of hypersensitivity to nonsteroidal anti-inflammatory drugs.

Hypersensitivity reactions to aspirin (acetylsalicylic acid) and other nonsteroidal anti‐inflammatory drugs (NSAIDs) constitute only a subset of all adverse reactions to these drugs, but due to their severity pose a significant burden to patients and are a challenge to the allergist. In susceptible individuals, NSAIDs induce a wide spectrum of hypersensitivity reactions with various timing, organ manifestations, and severity, involving either immunological (allergic) or nonimmunological mechanisms. Proper classification of reactions based on clinical manifestations and suspected mechanism is a prerequisite for the implementation of rational diagnostic procedures and adequate patient management. This document, prepared by a panel of experts from the European Academy of Allergy and Clinical Immunology Task Force on NSAIDs Hypersensitivity, aims at reviewing the current knowledge in the field and proposes uniform definitions and clinically useful classification of hypersensitivity reactions to NSAIDs. The document proposes also practical algorithms for the diagnosis of specific types of NSAIDs hypersensitivity (which include drug provocations, skin testing and in vitro testing) and provides, when data are available, evidence‐based recommendations for the management of hypersensitive patients, including drug avoidance and drug desensitization.