Elsevier

Toxicology

Volume 209, Issue 2, 15 April 2005, Pages 123-129
Toxicology

Clinical heterogeneity of drug hypersensitivity

https://doi.org/10.1016/j.tox.2004.12.022Get rights and content

Abstract

Skin is the most frequent target of drug reactions that are reported, may be because they are easily detected. Most (probably more than 90%) are related to drug hypersensitivity, i.e. an individually tailored, unexpected effect mediated by a drug specific activation of the immune response.

The clinical presentation of “drug eruptions” is highly variable, from the most common transient and benign erythema that occurs 6–9 days after the introduction of a new drug in 1 to 3 % of users to the most severe forms, that fortunately affect less than 1/10,000 users.

Even though there are some overlapping or unclassifiable cases, it is important for clinicians to recognize and categorize severe cutaneous adverse reactions/SCAR (bullous fixed drug eruptions/bFDE, acute generalized exanthematous pustulosis/AGEP, drug reaction with eosinophilia and systemic symptoms/DRESS, Stevens-Johnson syndrome/SJS, toxic epidermal necrolysis/TEN). First they must suspect rapidly that an unusual eruption with high fever and severe constitutional symptoms is caused by a medication and not by an infection. Second they have to look for involvement of organs that differ according to the type of reaction. Third they can determine a prognosis, the mortality rate being virtually 0 for bFDE, 5% for AGEP, 10% for “hypersensitivity syndrome”/DRESS and 25% for SJS or TEN. In addition if some medications are “usual suspects” for all types (e.g. anticonvulsants), some other are more specific of a given pattern (pristinamycine, hydroxychloroquine, diltiazem for AGEP, minocycline for DRESS, anti-infectious sulfonamides, allopurinol for epidermal necrolysis).

The “phenotypic” diversity of the final expression drug reactions can be explained by the engagement of a variety of cytokines and inflammatory cells and by regulatory mechanisms. For example, memory cytotoxic T-Cells are key effectors in both localized blisters of bFDE and in extensive blisters of epidermal necrolysis.

Section snippets

Common “drug rashes”

Exanthematous or maculo-papular eruptions, often reported as “drug rashes” or “drug eruptions” are the most common adverse drug reactions affecting the skin. Prospective cohort studies have shown that these benign rash account for more than 90% of all cutaneous ADRs (Hunziker et al., 1997). The eruption usually occurs between 4 and 14 days after the beginning of a new medication, and even 1 or 2 days after it has ceased (“eruption of the ninth day”). However, it can develop sooner, especially

Heterogeneity of skin pathology

In the common “drug rashes” cutaneous pathological slides show normal or nearly normal skin in the majority of cases. They may exhibit a mild lymphocytic infiltrate around vessels of the dermis, and a few necrotic keratinocytes within the epidermis. This pattern is not specific and cannot help to distinguish a drug eruption from an eruption of another cause.

The histopathology of AGEP is characteristic by showing spongiform pustules located under the stratum corneum, the most superficial layer

Heterogeneity of biological alterations

There are few biological alterations in “common” drug rashes. Mild eosinophilia is present in 20–40% of cases.

AGEP is characterized by hyperleukocytosis with elevated neutrophil count, transient functional renal failure.

In addition to biological alterations related to the involvement of each specific organ, patients with DRESS usually have blood counts alteration suggestive of “lymphocyte activation” with lymphocytosis and atypical basophil lymphocytes. Eosinophilia above 1500 mm−3 is present in

Heterogeneity of complications, prognosis and sequels

At first glance, similar organs e.g. liver, kidney or lung may be involved in all types of severe cutaneous ADRs. Looking more closely there are anyhow important differences in the frequency, severity and more importantly type of involvement.

Mild elevation of liver enzymes is frequent in SJS or TEN but definite hepatitis is present in only 10% of cases versus 50% in DRESS.

Interstitial nephritis is frequent in DRESS, with proteinuria, abnormal urinary sediment with occasionally eosinophils.

Heterogeneity of drug causes

Many medications are associated with “high risk” of inducing nearly all types of cutaneous ADRs. This is the case for anti-infective sulfonamides and antiepileptic drugs. But there are also many examples pointing to some specificity. Minocycline a frequent cause of DRESS, is not a “high risk” drug for AGEP, SJS or TEN. Other cyclines, frequently found in series of FDE, are not associated to a substantial risk of DRESS. Allopurinol and oxicam-NSAIDs are major causes of SJS or TEN, frequent

Why so many clinical presentations?

Most reactions being related to delayed hypersensitivity to a medication, the variety of clinical presentation needs additional explanations. It has been suggested that it could result from distinct T-lymphocyte recruitment. CD8 cytotoxic cells largely predominate in the lesions of blistering reactions (FDE, SJS, TEN) when CD4 cells predominate in “common” rashes (Barbaud et al., 1997), AGEP and DRESS. Different cytokine production may also contribute to different clinical features:

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