Is Drug Allergy Less Prevalent Than Previously Assumed?
Is Drug Allergy Less Prevalent Than Previously Assumed?
Background Rashes are a frequent conundrum in clinical practice as they may be reactive, drug induced or disease specific. Identification of the culprit drug is important as re-exposure may be harmful or even life-threatening and unnecessary avoidance of 'innocent' drugs leads to limitations of treatment options.
Objective To objectify the cause of suspected cutaneous drug reactions in a large patient population.
Method Over 5 years (2006–10), 612 patients with suspected cutaneous drug reactions were evaluated. Histology was assessed. About 200 patients were invited for complete work-up with skin tests (prick/intracutaneous testing and scratch/patch as indicated) and, if necessary, lymphocyte transformation tests (LTT). In special cases, drug provocation tests were conducted.
Results A total number of 141 cases with suspected drug reaction underwent full work-up (age 6–86 years; 75% female, 25% male). In 107 cases (76%) a drug was identified whereas 34 (24%) were reactive rashes or had other causes. Mostly, cutaneous drug reactions were maculopapular rashes, urticaria/angio-oedema; less frequently, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, systemic drug-related intertriginous and flexural exanthema, toxic epidermal necrolysis and fixed drug eruptions were present. Of all the cutaneous drug reactions investigated, 39·8% were caused by antibiotics, 21·2% by anti-inflammatories, 7·6% by contrast media and 31·4% by others (oral antidiabetics, antimycotics, antipsychotics, antiepileptics and others).
Conclusion Clinical assessment overestimates the role of drug allergies in cutaneous reactions. Assessment of suspected drug reactions can be greatly improved by thorough evaluation including dermatological and allergological work-up with skin testing and assays such as LTT.
Adverse reactions to drugs are frequent. Skin reactions are among the most common undesired effects of drugs, occurring in 2–3% of medical patients. Besides the immediate-type reactions (angio-oedema/urticaria or anaphylaxis), clinical pictures include maculopapular rash, bullous reactions, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), vasculitis, fixed drug eruption and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). The attribution of a cutaneous reaction to a particular drug frequently entails a difficult judgment; since the clinical picture often gives no clue to the offending drug, patients receive several drugs simultaneously and are ill, so that the skin reaction may also be reactive, e.g. induced by an infection [Epstein–Barr virus (EBV), cytomegalovirus, human herpes virus 6, parvovirus B19)], toxic or inflammatory (Still disease). Further differential diagnoses include graft-versus-host disease and Kawasaki syndrome.
All drug reactions can be classified into immediate and delayed reactions. If allergic, the former are IgE mediated whereas the latter are T-cell dependent. Nonallergic pathomechanisms also exist. Most cutaneous drug reactions are related to drug hypersensitivity, i.e. by a drug-specific activation of the immune response. The drug may act as a hapten/antigen as well as similarly to a superantigen, with a pharmacological interaction of parts of the drug with an immune receptor (p-i concept). These latter reactions do not need a sensitization phase – the drug reaction can occur upon the first encounter with the drug. The Coombs and Gell classification introduced four categories of immunological reactions with classes I–IV (IgE, cytotoxic, immunoglobulin complexes, T-cell dependent). Further, according to the classification of Pichler there are four distinct subtypes within class IV with Th1, Th2, cytotoxic T lymphocytes and other T cells being the immune reactants, and macrophages (IVa, contact dermatitis), eosinophils (IVb, maculopapular exanthema with eosinophilia), T cells (IVc, maculopapular and bullous exanthema) and neutrophils (IVd, AGEP) being the effector cells. These different pathomechanisms explain the large variety in clinical and histological pictures that can be seen.
There have been a number of epidemiological studies investigating drug-induced cutaneous reactions in hospital patients (reviewed in ref.). A large study was conducted in the U.S.A. (the Boston Collaborative Drug Surveillance) with a 7-year monitoring programme of 22 227 consecutive medical inpatients that identified 347 patients with suspected drug-induced cutaneous reactions (1·6%). Other studies investigated hospital inpatients in Spain, France, Malaysia, China, Singapore and India. A study from Switzerland gives results from a computerized drug-monitoring system between 1974 and 1993 reporting on 1317 cases with definite or probable drug-induced skin reactions out of a total of 48 005 inpatients (2·7%). Mostly, attribution of the reaction to a drug has been made by probability based on factors such as timing of drug intake.
Few studies have extensively tested patients to prove the diagnosis. This may be misleading as a wide range of skin lesions are not specific for an underlying cause. Allergological testing and re-exposure can help to underscore the drug as the trigger of the cutaneous reaction as opposed to other possible causes. In Denmark, a study with allergological work-up was conducted which evaluated a total of 194 patients with suspected cutaneous drug reactions but diagnosed a drug reaction in only 65 (33·5%) of these patients. Out of these patients, 18 were tested. Drug testing is essential as otherwise the diagnosis will be made mainly based on former reports, thus overestimating drugs that are known frequently to induce drug reactions and underestimating drugs that have not yet been described as inducers of drug reactions.
The study described here reports on a large number of patients with suspected drug reaction who have been fully evaluated. This is an important overview because the allergologist in clinical practice is often expected to give a first judgment of potential culprit drugs to stop. It sums up the experiences of a tertiary care hospital over 5 years.
Abstract and Introduction
Abstract
Background Rashes are a frequent conundrum in clinical practice as they may be reactive, drug induced or disease specific. Identification of the culprit drug is important as re-exposure may be harmful or even life-threatening and unnecessary avoidance of 'innocent' drugs leads to limitations of treatment options.
Objective To objectify the cause of suspected cutaneous drug reactions in a large patient population.
Method Over 5 years (2006–10), 612 patients with suspected cutaneous drug reactions were evaluated. Histology was assessed. About 200 patients were invited for complete work-up with skin tests (prick/intracutaneous testing and scratch/patch as indicated) and, if necessary, lymphocyte transformation tests (LTT). In special cases, drug provocation tests were conducted.
Results A total number of 141 cases with suspected drug reaction underwent full work-up (age 6–86 years; 75% female, 25% male). In 107 cases (76%) a drug was identified whereas 34 (24%) were reactive rashes or had other causes. Mostly, cutaneous drug reactions were maculopapular rashes, urticaria/angio-oedema; less frequently, acute generalized exanthematous pustulosis, drug reaction with eosinophilia and systemic symptoms, systemic drug-related intertriginous and flexural exanthema, toxic epidermal necrolysis and fixed drug eruptions were present. Of all the cutaneous drug reactions investigated, 39·8% were caused by antibiotics, 21·2% by anti-inflammatories, 7·6% by contrast media and 31·4% by others (oral antidiabetics, antimycotics, antipsychotics, antiepileptics and others).
Conclusion Clinical assessment overestimates the role of drug allergies in cutaneous reactions. Assessment of suspected drug reactions can be greatly improved by thorough evaluation including dermatological and allergological work-up with skin testing and assays such as LTT.
Introduction
Adverse reactions to drugs are frequent. Skin reactions are among the most common undesired effects of drugs, occurring in 2–3% of medical patients. Besides the immediate-type reactions (angio-oedema/urticaria or anaphylaxis), clinical pictures include maculopapular rash, bullous reactions, acute generalized exanthematous pustulosis (AGEP), drug reaction with eosinophilia and systemic symptoms (DRESS), vasculitis, fixed drug eruption and Stevens–Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN). The attribution of a cutaneous reaction to a particular drug frequently entails a difficult judgment; since the clinical picture often gives no clue to the offending drug, patients receive several drugs simultaneously and are ill, so that the skin reaction may also be reactive, e.g. induced by an infection [Epstein–Barr virus (EBV), cytomegalovirus, human herpes virus 6, parvovirus B19)], toxic or inflammatory (Still disease). Further differential diagnoses include graft-versus-host disease and Kawasaki syndrome.
All drug reactions can be classified into immediate and delayed reactions. If allergic, the former are IgE mediated whereas the latter are T-cell dependent. Nonallergic pathomechanisms also exist. Most cutaneous drug reactions are related to drug hypersensitivity, i.e. by a drug-specific activation of the immune response. The drug may act as a hapten/antigen as well as similarly to a superantigen, with a pharmacological interaction of parts of the drug with an immune receptor (p-i concept). These latter reactions do not need a sensitization phase – the drug reaction can occur upon the first encounter with the drug. The Coombs and Gell classification introduced four categories of immunological reactions with classes I–IV (IgE, cytotoxic, immunoglobulin complexes, T-cell dependent). Further, according to the classification of Pichler there are four distinct subtypes within class IV with Th1, Th2, cytotoxic T lymphocytes and other T cells being the immune reactants, and macrophages (IVa, contact dermatitis), eosinophils (IVb, maculopapular exanthema with eosinophilia), T cells (IVc, maculopapular and bullous exanthema) and neutrophils (IVd, AGEP) being the effector cells. These different pathomechanisms explain the large variety in clinical and histological pictures that can be seen.
There have been a number of epidemiological studies investigating drug-induced cutaneous reactions in hospital patients (reviewed in ref.). A large study was conducted in the U.S.A. (the Boston Collaborative Drug Surveillance) with a 7-year monitoring programme of 22 227 consecutive medical inpatients that identified 347 patients with suspected drug-induced cutaneous reactions (1·6%). Other studies investigated hospital inpatients in Spain, France, Malaysia, China, Singapore and India. A study from Switzerland gives results from a computerized drug-monitoring system between 1974 and 1993 reporting on 1317 cases with definite or probable drug-induced skin reactions out of a total of 48 005 inpatients (2·7%). Mostly, attribution of the reaction to a drug has been made by probability based on factors such as timing of drug intake.
Few studies have extensively tested patients to prove the diagnosis. This may be misleading as a wide range of skin lesions are not specific for an underlying cause. Allergological testing and re-exposure can help to underscore the drug as the trigger of the cutaneous reaction as opposed to other possible causes. In Denmark, a study with allergological work-up was conducted which evaluated a total of 194 patients with suspected cutaneous drug reactions but diagnosed a drug reaction in only 65 (33·5%) of these patients. Out of these patients, 18 were tested. Drug testing is essential as otherwise the diagnosis will be made mainly based on former reports, thus overestimating drugs that are known frequently to induce drug reactions and underestimating drugs that have not yet been described as inducers of drug reactions.
The study described here reports on a large number of patients with suspected drug reaction who have been fully evaluated. This is an important overview because the allergologist in clinical practice is often expected to give a first judgment of potential culprit drugs to stop. It sums up the experiences of a tertiary care hospital over 5 years.
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