Drug Eruptions and Hypersensitivity Syndromes












CHAPTER 9
DRUG ERUPTIONS AND HYPERSENSITIVITY SYNDROMES

 


Exanthematous Drug Eruption







































Synonyms Morbilliform drug eruption, drug exanthem, maculopapular drug eruption, and symmetrical drug-related intertriginous and flexural exanthema (SDRIFE).
Inheritance n/a
Prenatal Diagnosis n/a
Incidence ~2% of prescriptions of new drugs cause a drug eruption, ~95% are morbilliform eruptions, including 5% to 10% of individuals treated with ampicillin.
Age at Presentation Any age.
Pathogenesis Idiosyncratic, T-cell-mediated, type IV/delayed hypersensitivity reaction to active drug, its metabolite or an associated protein; most commonly associated with β-lactam antibiotics (penicillins, cephalosporins), sulfonamides, allopurinol, anticonvulsants, nonsteroidal anti-inflammatory drugs (NSAIDs), as well as herbal and natural therapies; SDRIFE is rare but is associated with β-lactam antibiotics (most common), pseudoephedrine, codeine, allopurinol, cimetidine, and nystatin.
Key Features

Starts 5 to 14 days after starting a medication, possible mild fever, mild to severe pruritus.



  • Skin: Generalized erythematous macules, patches, papules, and plaques without blisters or pustules; often starts on the head and caudally spreads; usually spares mucous membranes, axillae, groin, hands, and feet; rare manifestation called SDRIFE that involves only the skin folds, such as buttocks, natal cleft, and proximal medial thighs.
Differential Diagnosis Viral exanthem (eg, measles, enterovirus, and adenovirus), drug hypersensitivity syndrome (DHS), Stevens-Johnson syndrome (SJS), Kawasaki disease/multisystem inflammatory syndrome in children, and ampicillin-induced eruption associated with Epstein-Barr virus (EBV)/mononucleosis.
Laboratory Data Skin biopsy, if necessary, shows mixed perivascular infiltrate, eosinophils, and an interface dermatitis; if patient appears toxic, check CBC, comprehensive metabolic panel (CMP), thyroid function tests, and urinalysis (UA), but these should be normal except eosinophilia; check serology for possible viral trigger.
Management Discontinue suspected drug(s), supportive care including fluids, emollients, wet wraps, oral antihistamines, or mild-to-moderate topical steroids; consider a tapering course of systemic corticosteroids if severe.
Prognosis Good. Resolves with scaling or desquamation within 7 to 14 days of discontinuing the drug; erythroderma is possible if causative medication is continued.

image PEARL/WHAT PARENTS ASK


Rechallenging the medication will most likely cause a similar (but not more severe such as SJS or toxic epidermal necrolysis [TEN]) rash; so if critical, a rechallenge can be considered.











Skin | Associated Findings
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Fixed Drug Eruption







































Synonym n/a
Inheritance n/a, genetic predisposition possible with HLA-B55.
Prenatal Diagnosis n/a
Incidence Unknown but second most common drug reaction after exanthematous reactions. More common in adults than children.
Age at Presentation Any age.
Pathogenesis Activation of epidermal, CD-8+ cytotoxic T cells by an antigen from the drug causes release of cytokines that lyse keratinocytes and melanocytes via CD-4 helper T cells and neutrophils. These primed epidermal, cytotoxic T cells remain within the dermis of lesional skin and, when reexposed to the antigen, are reactivated, leading to the “fixed” clinical pattern. Commonly associated with barbiturates, antibiotics (sulfonamides, tetracyclines more common), acetaminophen, aspirin (ASA)/NSAIDs, dapsone, quinine, azole-class antifungals, and supplements, such as Ginkgo biloba leaf extract and vinpocetine, also pseudoephedrine; many others reported.
Key Features

Symptoms develop 30 min to 24 hours after exposure; pruritus or burning is possible.



  • Skin: Commonly hands and feet, lips, eyelids, genitalia and perianal areas; well-circumscribed, round or oval patch or edematous plaque, red-brown or gray-blue with dusky center, progressing to red or violaceous plaques or targetoid lesions (similar to EM); may develop vesicles/bullae or purpura/ecchymoses; mucosal lesions may erode; resolves with scaling, crusting, then finally a dusky brown hyperpigmentation that may fade over months to years; with repeated exposure, existing lesions may become larger and/or new lesions develop, usually solitary but can be multiple and generalized; rare malaise and fever.
Differential Diagnosis Arthropod bite reaction, autoimmune blistering disease, erythema multiforme (EM), SJS, psoriasis, trauma, erythema dyschromicum perstans, and post-inflammatory hyperpigmentation.
Laboratory Data Skin biopsy, if necessary, shows an interface dermatitis with vacuolar change; dyskeratosis and necrotic keratinocytes may also be present, mimicking EM; patch testing at the site of a previous lesion with the drug may be helpful in confirming.
Management Discontinuation of suspected drug(s), supportive care, including fluids, antipyretics, wet wraps, and topical steroids.
Prognosis Excellent. Lesions last days to a few weeks after discontinuation of drug, but high risk of recurrence at the same location with reexposure; cross-sensitivity to related drugs may occur; rarely, lesions may flare after a refractory period.

image PEARL/WHAT PARENTS ASK


Hyperpigmentation may fade with avoidance; pseudoephedrine linked to nonpigmented FDE. If the offending drug has not been identified and the patient is taking a number of medications that are important for their health, challenging with careful monitoring may be undertaken, but there is some risk that the subsequent reaction may be more widespread and severe.











Skin | Associated Findings
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9.1. Fixed drug eruption to trimethoprim/sulfamethoxazole.


Erythema Multiforme







































Synonyms EM minor and bullous EM.
Inheritance n/a
Prenatal Diagnosis n/a
Incidence Unknown, less common in childhood (20% of cases).
Age at Presentation Any age.
Pathogenesis Immune response, partially understood; initiated by immune reaction to antigens resulting in keratinocyte death; most often precipitated by infections (90%), Herpes simplex virus is most common, Mycoplasma pneumoniae, Coxsackie virus, and EBV may cause EM; rarely drugs have been described including allopurinol, anticonvulsants (eg, phenobarbital, phenytoin, and valproic acid) antibiotics (eg, sulfonamides, penicillins, erythromycin, nitrofurantoin, and tetracyclines), ASA, statins, biologics (eg, adalimumab, infliximab, and etanercept), vaccination, and imiquimod.
Key Features

Possible prodrome of low-grade fever, cough, and anorexia.



  • Mucocutaneous: Crops of targetoid lesions, often asymptomatic but may be itchy and/or painful; central area can evolve into tense, clear, or hemorrhagic bulla or crusted erosions; atypical presentations include lichenoid or granulomatous lesions; painful, erythematous vesicles/bullae and erosions can also involve oral, ocular, perianal, or genital mucosa; lip involvement includes the vermillion border; develops over days on extremities and, occasionally, on face particularly during the spring and summer months.
Differential Diagnosis Urticaria, lupus erythematosus, vasculitis, generalized FDE, Kawasaki disease, drug eruption, SJS, Mycoplasma-induced rash and mucositis syndrome (MIRMS), autoimmune bullous dermatoses, polymorphous light eruption, and early TEN.
Laboratory Data Skin biopsy shows apoptotic keratinocytes and/or subepidermal blister; no specific laboratory features.
Management Immediate discontinuation of suspected drugs; supportive care, including fluids, nutritional supplements, antipyretics, antihistamines, topical steroids, topical anesthetics, and wound care; consider hospitalization if severe oral involvement restricts drinking; if severe, consider pulse methylprednisolone 4 mg/kg/day for at least 2 days; alternatively 1 mg/kg/day tapered over 7 to 10 days; recurrent EM with severe oral involvement may respond to early oral steroids tapered over 7 to 10 days; recurrent symptomatic cutaneous lesions may be treated with high potency topical steroids.
Prognosis Good, lesions resolve without treatment in 2 to 6 weeks; chronic complications include pigmentary changes, ocular scarring; does not progress to SJS/TEN; may overlap with MIRMS and fixed drug reaction.

image PEARL/WHAT PARENTS ASK


When EM recurs, how do we stop it? Early identification and treatment of rash before it becomes symptomatic.











Skin | Associated Findings
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9.2. Erythema multiforme.


Drug Reaction With Eosinophilia and Systemic Symptoms



























Synonyms Drug reaction with eosinophilia and systemic symptoms (DRESS) and drug-induced hypersensitivity syndrome (DHS).
Inheritance Possible autosomal recessive association with aromatic anticonvulsants. Proposed HLA-B*57:01 link to abacavir-induced DHS.
Prenatal Diagnosis n/a
Incidence 1:3,000 to 10,000 exposures to aromatic anticonvulsants (most common).
Age at Presentation Any age.
Pathogenesis T-cell-mediated, type IV/delayed hypersensitivity reaction. Often occurs with the first exposure to the drug; sulfonamide antibiotics, lamotrigine, and dapsone. Possible immune interactions between reactivation of a virus, such as human herpes virus 6 (HHV-6), and a medication.
Key Features

Starts 1 to 8 weeks after exposure.



  • Constitutional: High fever, malaise.
  • Skin: Facial edema (30%); generalized cutaneous erythematous macules, patches, papule, and plaques, sometimes annular, vesicular, or pustular (80%); may involve oral and genitalia (25%), erythroderma (10%), and lymphadenopathy (>70%).
  • Gastrointestinal: Hepatomegaly, hepatitis, and liver failure (rare); gastroenteritis and pancreatitis.
  • Cardiac: Myocarditis and pericarditis.
  • Pulmonary: Interstitial pneumonitis and acute respiratory distress syndrome.
  • Renal: Mild interstitial nephritis (10%); renal failure (rare).
  • CNS:

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    Aug 17, 2025 | Posted by in PEDIATRICS | Comments Off on Drug Eruptions and Hypersensitivity Syndromes

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