| Drug eruption | |
|---|---|
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| Examples of drug eruptions. (A)Bullous dermatitis caused bysulfathiazole (B)Fixed drug eruption caused byphenolphtalein (C) Bullouserythema multiforme (D) Diffusephotosensitivity reaction. | |
| Specialty | Dermatology  |
Inmedicine, adrug eruption is anadverse drug reaction of theskin. Most drug-induced cutaneous reactions are mild and disappear when the offending drug is withdrawn.[1] These are called "simple" drug eruptions. However, more serious drug eruptions may be associated with organ injury such as liver or kidney damage and are categorized as "complex".[2] Drugs can also causehair andnail changes, affect themucous membranes, or causeitching without outward skin changes.[3]
The use of synthetic pharmaceuticals andbiopharmaceuticals in medicine has revolutionized human health, allowing us to live longer lives. Consequently, the average human adult is exposed to many drugs over longer treatment periods throughout a lifetime.[4] This unprecedented rise in pharmaceutical use has led to an increasing number of observed adverse drug reactions.[4]
There are two broad categories of adverse drug reactions.Type A reactions are known side effects of a drug that are largely predictable and are called,pharmatoxicologic.[5] WhereasType B orhypersensitivity reactions, are often immune-mediated and reproducible with repeated exposure to normal dosages of a given drug.[5] Unlike type A reactions, the mechanism of type B or hypersensitivity drug reactions is not fully elucidated. However, there is a complex interplay between a patient's inherited genetics, the pharmacotoxicology of the drug and the immune response that ultimately give rise to the manifestation of a drug eruption.[5]
Because the manifestation of a drug eruption is complex and highly individual, there are many subfields in medicine that are studying this phenomenon. For example, the field ofpharmacogenomics aims to prevent the occurrence of severe adverse drug reactions by analyzing a person's inherited genetic risk.[6] As such, there are clinical examples of inherited geneticalleles that are known to predict drug hypersensitivities and for which diagnostic testing is available.[6]
Some of the most severe and life-threatening examples of drug eruptions areerythema multiforme,Stevens–Johnson syndrome (SJS),toxic epidermal necrolysis (TEN),hypersensitivity vasculitis,drug induced hypersensitivity syndrome (DIHS),erythroderma andacute generalized exanthematous pustulosis (AGEP).[4] These severe cutaneous drug eruptions are categorized as hypersensitivity reactions and are immune-mediated. There are four types of hypersensitivity reactions and many drugs can induce one or more hypersensitivity reactions.[4]
| Reaction | Description | Mediator | Mechanism | Clinical phenotype |
|---|---|---|---|---|
| Type I | Immediate | IgE | antigen binds to mast cell/ basophil surface receptors | Urticarial (hives),anaphylaxis, |
| TypeII | Antibody-mediated | IgM, IgG | antibody binds antigen leading to complement-driven cell lysis | drug-inducedthrombocytopenia, hemolytic anemia, Goodpasture's,ANCA vasculitis |
| Type III | Immune complex | IgM, IgG, IgA | antigen-antibody complex deposits in tissues-triggers recruitment ofleukocytes | Serum sickness, Henoch-Schonlein Purpura |
| Type IV | Delayed-type | T-lymphocytes | Activated T-cells produce cytokines causing inflammation leading to tissue destruction | Drug reaction with eosinophilia and systemic symptoms (i.e. DRESS syndrome or DIHS),Stevens–Johnson syndrome,toxic epidermal necrolysis,acute generalized exanthematous pustulosis |
The most common type of eruption is amorbilliform (resemblingmeasles) orerythematous rash (approximately 90% of cases).[7] Less commonly, the appearance may also beurticarial,papulosquamous,pustular,purpuric,bullous (with blisters) orlichenoid.[3]Angioedema can also be drug-induced (most notably, byangiotensin converting enzyme inhibitors).
The underlying mechanism can be immunological (such as indrug allergies) or non-immunological (for example, inphotodermatitis or as a side effect ofanticoagulants). Afixed drug eruption is the term for a drug eruption that occurs in the same skin area every time the person is exposed to the drug. Eruptions can occur frequently with a certain drug (for example, withphenytoin[8]), or be very rare (for example,Sweet's syndrome following the administration ofcolony-stimulating factors[9]).
The culprit can be both aprescription drug or anover-the-counter medication.
Examples of common drugs causing drug eruptions areantibiotics and otherantimicrobial drugs,sulfa drugs,nonsteroidal anti-inflammatory drugs (NSAIDs),biopharmaceuticals,chemotherapy agents,anticonvulsants andpsychotropic drugs. Common examples include photodermatitis due to local NSAIDs (such aspiroxicam) or due to antibiotics (such asminocycline), fixed drug eruption due to acetaminophen or NSAIDs (Ibuprofen), and the rash followingampicillin in cases ofmononucleosis.[2]
Certain drugs are less likely to cause drug eruptions (rates estimated to be ≤3 per 1000 patients exposed). These include: digoxin, aluminum hydroxide, multivitamins, acetaminophen, bisacodyl, aspirin, thiamine, prednisone, atropine, codeine, hydrochlorothiazide, morphine, insulin, warfarin and spironolactone.[2]
Drug eruptions are diagnosed mainly from themedical history andclinical examination. However, they can mimic various other conditions, thus delaying diagnosis (for example, indrug-induced lupus erythematosus, or theacne-like rash caused byerlotinib). Askin biopsy,blood tests orimmunological tests can also be useful.
Drug reactions have characteristic timing. The typical amount of time it takes for a rash to appear after exposure to a drug can help categorize the type of reaction. For example,Acute generalized exanthematous pustulosis usually occurs within 4 days of starting the culprit drug.Drug Reaction with Eosinophilia and Systemic Symptoms usually occurs between 15 and 40 days after exposure.Toxic epidermal necrolysis andStevens–Johnson syndrome typically occur 7–21 days after exposure. Anaphylaxis occurs within minutes. Simple exanthematous eruptions occur between 4 and 14 days after exposure.[2]
TEN and SJS are severe cutaneous drug reactions that involve the skin andmucous membranes. To accurately diagnose this condition, a detailed drug history is crucial.[4] Often, several drugs may be causative and allergy testing may be helpful.[4] Sulfa drugs are well known to induce TEN or SJS in certain people. For example, HIV patients have an increased incidence of SJS or TEN compared to the general population and have been found to express low levels of the drug metabolizing enzyme responsible for detoxifying sulfa drugs.[5] Genetics plays an important role in predisposing certain populations to TEN and SJS. As such, there are someFDA recommended genetic screening tests available for certain drugs and ethnic populations to prevent the occurrence of a drug eruption.[5] The most well known example is carbamezepine (an anti-convulsant used to treat seizures) hypersensitivity associated with the presence of HLA-B*5801 genetic allele in Asian populations.[6]
| Drug | Allele | Population | Clinical syndrome | FDA recommended Pharmacogenetic testing |
|---|---|---|---|---|
| Abacavir | HLA-B*5701 | US European US African Australian | DIHS | Yes |
| Allopurinol | HLA-B*5801 | Han, Korean, Thai, European | SJS, TEN, DIHS | No |
| Carbamezepine | HLA-B*1502 | Han, Thai, Malaysian, Korean | SJS, TEN | Yes |
| Dapsone | HLA-B*1301 | Chinese | DIHS | No |
| Lamotrigine | HLA-B*38 HLA-B*1502 | European, Han | SJS, TEN | no recommendation available |
| Methazolamide | HLA-B*5901 | Korean | SJS, TEN | No |
| Phenytoin | HLA-B*1502 | Thai, Han | SJS, TEN | Warning |
DIHS is a delayed onset drug eruption, often occurring a few weeks to 3 months after initiation of a drug.[2] Worsening of systemic symptoms occurs 3–4 days after cessation of the offending drug.[5] There are genetic risk alleles that are predictive of the development of DIHS for particular drugs and ethnic populations.[5] The most important of which is abacavir (an anti-viral used in the treatment of HIV) hypersensitivity associated with the presence of the HLA-B*5701 allele in European and African population in the United States and Australians.[5]
AGEP is often caused by antimicrobial, anti-fungal or antimalarial drugs.[4] Diagnosis is often carried out bypatch testing. This testing should be performed within one month after resolution of the rash and patch test results are interpreted at different time points: 48 hours, 72hours and even later at 96 hours and 120 hours in order to improve the sensitivity.[4]
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