Approach to the Patient with a Drug Hypersensitivity Reaction – Clinical Perspectives

Drug hypersensitivity reactions are a common clinical problem which may affect a considerable number of the treated patient population. Between 10 and 15% of patients may suffer from an unwanted drug reaction, 2–5% of these have to be hospitalized, and in 1–3% of hospitalized patients mortality may result [1] .
Drug hypersensitivity reactions are systemic reactions which often involve the skin. Cutaneous manifestations may be the only clinically relevant presentation of a drug hypersensitivity, but the skin can also act to herald for example a systemic hypersensitivity reaction such as anaphylaxis or the severe drug hypersensitivity syndrome (drug rash with eosinophilia and systemic symptoms (DHS/DRESS) [2] . 

Particularly the hypersensitivity reactions of type B (bizarre) present with symptoms and signs which are typically not related to pharmacologic doses and effects of the eliciting drugs. Therefore, drug hypersensitivity reactions present a complex challenge for treating physicians and the diagnosing allergologist. To arrive at a useful final diagnosis, a structured stepwise approach is required.

In principle, two steps can be differentiated:
(1) handling the acute drug hypersensitivity reaction: it comprises the classification as well as the definition of the severity of the reaction, its documentation, the choice of an alternative drug, and the symptomatic  treatment, and (2) identification of the eliciting drug(s).

Acute Phase

Drug hypersensitivity reactions can occur during all types of medical treatments, including biologicals [3] , their additives [4, 5] , phytotherapeutic remedies [6] or their adulterated contents [7, 8] . It is of utmost importance that the initial diagnosis is done carefully including some laboratory analysis, in particular an involvement of blood cells, and the affection of internal organs, such as liver and kidneys, should be excluded by appropriate blood tests (differential blood count, liver enzyme analysis, etc.). 

Actually, it is advisable to consult a dermatologist or alternatively to take a photograph of the exanthem and of the particular cutaneous efflorescences, and to note all drugs taken during the last 2 weeks and particularly all newly introduced drugs taken within the last 4 weeks. A skin biopsy for histological examination may be helpful to further differentiate the exanthem. This documentation should give a clue to the severity of the reaction [2] , which is decisive for prognosis, treatment and future pharmacotherapy The morphological differential diagnosis should exclude other causes, the most probably eliciting drugs should be immediately stopped and symptomatic treatment should be started if necessary, particularly when danger signs such as severe anaphylactic symptoms, facial edema with drug treatments causing DHS/DRESS or bullous manifestation, vasculitis or important mucosal signs are present [2] . 

After the complete clearing of the clinical manifestations and normalization of laboratory values, an allergologic investigation is recommended. This should be best done between 3 weeks to 6 months after the incident.


The diagnosis of drug hypersensitivity aims, firstly, to define the disease as drug allergy, and, secondly, to identify the eliciting drug or drugs. History and experience (from various textbooks listing drugs and their side effects) are the most widely used and important pillars on which the identification of a potentially eliciting drug is based. Dose, the duration of treatment, the chronology of the appearance of symptoms, and the identification of cofactors such as underlying disorders, for example viral infections, hepatopathy or renal diseases help for the identification of the relevant drug.

The application of a standardized approach, for example with a drug questionnaire, is recommended [12] , in particular for persons less experienced in drug hypersensitivity.

The clinical characteristics of the more common and of some of the severe drug reactions are briefly presented. Some drug-induced syndromes have been proposed to differentiate them from other diseases.


Drugs and drug allergens may elicit a wide variety of clinical manifestations that are based on various pathogenetic mechanisms. However, there still remain many clinical reactions where the pathomechanism is not known and therefore, no validated diagnostic tools are available. The diagnosis of a drug hypersensitivity reaction is based on clinic, history and experience with the drug. In addition, skin [55] and in vitro tests are
available and some rules how to perform them have been published [21, 22, 56] . 

The preparation of drug allergens for skin tests, the performance of in vitro tests [57, 58] , correctly conducted provocation tests [23] and the required validation procedures are time-consuming and cost-intensive. Despite these limitations, an investigation into a drug hypersensitivity reaction is important and useful to prevent recurrences and it may help to select safe drug alternatives in future pharmacological therapies.

by Umaee
image: worldallergy
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