Drug eruptions

Diagnosis

Diagnosis of the adverse event is based on three key clinical elements:

• 1.

  Appearance: the morphology of the drug eruption based on four main categories of the primary lesion: maculopapular (exanthem, enanthem), urticarial, bullous, and pustular.

• 2.

  Systemic signs that differentiate between a simple reaction involving only the skin and a complex reaction that comprises systemic involvement in addition to the skin. Systemic involvement is evaluated by assessing the patient’s symptoms such as fever, facial edema, malaise, chills, dyspnea, cough, palpitations, nausea, vomiting, diarrhea, sore throat, and arthralgia, and a basic laboratory screen, which includes a full blood count, liver and renal function tests, and urine analysis.

• 3.

  Histology: histopathology and, if relevant, direct immunofluorescence studies of skin biopsies to confirm the clinical impression and to distinguish between a drug eruption and other skin diseases.

In addition, it is valuable to use validated diagnostic criteria of specific types of drug eruptions, if available. Currently, only acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms (DRESS) have published validated diagnostic criteria.

Differential Diagnosis

Establishing a differential diagnosis, which considers all possible diagnoses, is essential.

Drug Exposure (Timing)

All medications, regardless of route of administration, must be considered, particularly new drugs taken in the 8 weeks before the drug eruption. Assessment of the lag period, the time between initiation of the drug and onset of the cutaneous reaction, is essential in view of the different lag times for different drug eruptions. A recommended method for drug exposure analysis is to chart a timeline to visualize the chronology and facilitate comprehension of the event.

Determine Probabilities

An important step in assessing a drug eruption is to establish whether there is a causal relationship between the suspected drug and the clinical event. The following methods are helpful:

• 1.

  Patient history: the patient should be questioned about previous drug eruptions and whether dechallenging with the drug improved the eruption.

• 2.

  Analysis of the literature: PubMed ( http://www.ncbi.nlm.nih.gov/pubmed/ ) and Litt’s DERM ( Drug Eruptions and Reactions Manual ) and database ( http://www.drugeruptiondata.com/ ).

• 3.

  In vitro and in vivo diagnostic assessments, including human leukocyte antigen (HLA) genetic tests.

An important progress in understanding the underlying mechanisms of several types of drug eruptions has been achieved by the discovery of an association between a specific HLA allele, a drug, an ethnic background, and a drug eruption. These tests are best utilized as genetic screening before drug prescription. However, they may serve as a simple, safe, and reliable method for establishing causality in specific cases of drug eruptions such as toxic epidermal necrolysis and DRESS induced by specific drugs, such as carbamazepine and allopurinol. In some countries in Asia, genetic tests are performed prior to prescription of high-risk drugs, and this strategy was proven to reduce the incidence of severe drug eruptions caused by these drugs. Unfortunately, although available in other places, these tests are not yet incorporated as a genetic screening tool to assess the risk of developing a severe drug eruption. In vitro tests, such as the lymphocyte transformation test and basophil activation test, exhibit varying sensitivity depending on the drug involved and clinical phenotype. In vivo tests, such as patch test and delayed intradermal testing, may also be used in assessment of a drug eruption. Caution should always be exercised regarding false-positive and false-negative results of these in vitro and in vivo tests.

After the diagnosis of a drug eruption, the physician must provide the patient with clear information on the drug eruption, the name of the offending drug, potential cross-reacting drugs, and drugs that can be safely taken as an alternative to the offending drug. In cases of complex reactions, it is also necessary to explain to the patient the need for long-term medical follow-up, to provide information on support groups, and to conduct family counseling because the predisposition may be genetic. The physician must also report the event to the patient’s healthcare provider, the manufacturer, and regulatory agencies.