Drug Reactions and Hypersensitivity

Grouped by mechanism

• IgE-mediated (Type I): beta-lactams are the archetype; also neuromuscular blockers and platinum chemotherapeutics. Requires prior sensitization, so the first exposure is usually uneventful and the second course produces urticaria/anaphylaxis.
• Direct mast-cell degranulation (pseudoallergy, non-IgE): vancomycin (vancomycin infusion reaction, formerly "red man syndrome"), opioids, and radiocontrast trigger mediator release without IgE — rate-dependent, so slowing the infusion prevents recurrence. This is not a true allergy and does not preclude future use.
• Bradykinin accumulation: ACE inhibitors cause angioedema without urticaria or pruritus, often months to years after starting the drug; kininase II inhibition blocks bradykinin degradation.
• COX-1 inhibition with leukotriene shunting: aspirin/NSAIDs producing urticaria, angioedema, or aspirin-exacerbated respiratory disease (nasal polyps, asthma).
• T-cell mediated (Type IV) severe cutaneous adverse reactions: aromatic anticonvulsants (carbamazepine, phenytoin, lamotrigine), allopurinol, sulfonamide antibiotics, nevirapine, and oxicam NSAIDs dominate SJS/TEN and DRESS. AGEP skews toward aminopenicillins and macrolides.

Non-modifiable risk factors

• HLA associations: *HLA-B\*57:01* with abacavir hypersensitivity, *HLA-B\*15:02* with carbamazepine-induced SJS/TEN in patients of Han Chinese and Southeast Asian ancestry, *HLA-B\*58:01* with allopurinol severe reactions, and *HLA-A\*31:01* with carbamazepine DRESS. The FDA recommends *HLA-B\*57:01* testing before abacavir and *HLA-B\*15:02* testing before carbamazepine in at-risk ancestries; the 2020 ACR gout guideline conditionally recommends *HLA-B\*58:01* testing before allopurinol in Southeast Asian and African American patients.
• Immunosuppression and viral state: HIV markedly increases TMP-SMX reactions; aminopenicillins given during acute EBV infection commonly precipitate a non-allergic morbilliform exanthem (classically taught as near-universal, though modern series report substantially lower rates), and this does not establish a durable penicillin allergy. HHV-6/EBV/CMV reactivation is characteristic of DRESS.
• Female sex, prior drug reaction, and slow acetylator phenotype (sulfonamides, hydralazine).

Modifiable risk factors

• Rapid lamotrigine dose escalation, particularly with concurrent valproate, which raises lamotrigine levels.
• High allopurinol starting dose in CKD; guidelines favor low-dose initiation with titration.
• Polypharmacy, unnecessary antibiotics, and UV exposure with photosensitizers (doxycycline, thiazides, voriconazole).

• Type I Hypersensitivity (IgE-mediated): Immediate reaction occurring within minutes to 2 hours; involves cross-linking of IgE on mast cells and basophils, triggering release of histamine, tryptase, and other mediators causing urticaria, angioedema, and anaphylaxis

• Type II Hypersensitivity (Cytotoxic): IgG or IgM antibodies bind to drug-hapten complexes on cell surfaces, activating complement and antibody-dependent cellular cytotoxicity; results in fixed drug eruption and some bullous reactions

• Type III Hypersensitivity (Immune Complex): Circulating immune complexes deposit in small vessels, activating complement and causing serum sickness-like reactions; typically occurs 1-3 weeks after exposure with constitutional symptoms

• Type IV Hypersensitivity (Cell-mediated/Delayed): T-cell mediated response occurring 48-72 hours or later; involves CD8+ cytotoxic T cells and CD4+ helper T cells; responsible for exanthems, contact dermatitis, and severe reactions (SJS/TEN); mechanism in SJS/TEN involves keratinocyte apoptosis via Fas-FasL and perforin/granzyme pathways

• Phototoxic and Photoallergic Reactions: Phototoxic reactions are dose-dependent chemical reactions requiring light activation (no prior sensitization needed); photoallergic reactions are Type IV hypersensitivity requiring prior sensitization and occur with lower drug doses

• Non-immunologic Direct Toxicity: Some reactions (e.g., irritant contact dermatitis, certain toxic epidermal necrosis patterns) result from direct cytotoxic effects rather than immune mechanisms

• Maculopapular Exanthem: Most common drug reaction (75-95% of cutaneous drug reactions); typically symmetric, pruritic rash starting on trunk and extremities 4-14 days after drug initiation; may have associated fever and lymphadenopathy; classic appearance is fine, blanching erythematous papules

• Urticaria and Angioedema: Type I reaction presenting with transient, pruritic wheals lasting <24 hours at any given site; angioedema involves deeper dermal and subcutaneous layers causing swelling of face, lips, and airways; onset within minutes to 2 hours of exposure

• Fixed Drug Eruption (FDE): Recurrent lesion(s) appearing at same location with each drug exposure; classically appears as a solitary dusky red to violaceous plaque (often on lips, genitals, or acral areas); may blister and crust, then leave post-inflammatory hyperpigmentation; NSAIDs and antibiotics are common triggers

• Stevens-Johnson Syndrome (SJS): Severe mucocutaneous reaction with <10% body surface area (BSA) involvement; prodrome of fever, malaise, arthralgias followed by painful oral ulcers and hemorrhagic crusting lips; targetoid lesions with three zones (central necrosis, pale edema, erythematous rim) on palms/soles; systemic involvement common

• Toxic Epidermal Necrolysis (TEN): Most severe form with >30% BSA involvement; rapid onset of erythema progressing to widespread blistering and full-thickness epidermal sloughing; high mortality (30-40%) from sepsis and multi-organ failure; high-risk drugs include anticonvulsants (phenytoin, carbamazepine, lamotrigine), allopurinol, sulfonamides, and NSAIDs

• SJS/TEN Overlap (SJS/TEN): Intermediate form with 10-30% BSA involvement; shares features of both SJS and TEN with variable severity

• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): Hypersensitivity reaction occurring 2-8 weeks after drug exposure; features fever, lymphadenopathy, hepatosplenomegaly, and atypical lymphocytes; cutaneous findings include polymorphous exanthem, facial edema, and sometimes pustules; notable triggers include anticonvulsants, sulfonamides, and NSAIDs

• Erythema Multiforme (EM): Targetoid lesions (true 3-zone targets) predominantly on acral areas and extensor surfaces; typically mild with minimal mucosal involvement; often triggered by NSAIDs and sulfonamides (though infections more common overall)

• Acute Generalized Exanthematous Pustulosis (AGEP): Sudden onset of widespread sterile pustules on background erythema occurring 1-2 weeks after drug initiation; beta-lactam antibiotics and macrolides are common culprits; self-limited but requires drug discontinuation

• Serum Sickness-like Reaction: Occurs 1-3 weeks after exposure with fever, rash, and arthralgia/arthritis; differs from true serum sickness (which occurs with exogenous serum); beta-lactam antibiotics and sulfonamides are classic triggers

• Clinical History and Timeline: Establish drug exposure timeline (onset typically 4-14 days after initiation for delayed reactions, minutes to hours for IgE-mediated); identify temporal relationship between drug start and rash; assess naïve vs. re-exposure; obtain detailed medication list including OTC medications, supplements, and herbal products

• Morphology and Distribution: Classify reaction type by morphology (maculopapular, urticarial, vesiculobullous, targetoid); assess distribution pattern (symmetric vs. asymmetric, sun-exposed vs. unexposed); examine for mucous membrane involvement and systemic signs

• Severity Assessment: Calculate %BSA involvement using Rule of Nines; assess for mucosal involvement, fever, and systemic symptoms; use RegiSCAR scoring system (Reaction with Eosinophilia and Systemic Symptoms) for DRESS diagnosis (score ≥2 indicates possible DRESS)

• Laboratory Studies:
• CBC with differential: eosinophilia >1500/μL suggests DRESS; atypical lymphocytes supportive
• Comprehensive metabolic panel: hepatic and renal involvement common in severe reactions
• Skin biopsy with H&E histology: shows degree of epidermal necrosis, inflammatory infiltrate pattern (interface dermatitis in SJS/TEN, subcorneal pustules in AGEP)
• Frozen section or rapid immunofluorescence if pemphigus/pemphigoid suspected
• Prick testing or intradermal testing: may identify IgE-mediated reactions (perform cautiously after resolution)

• Diagnostic Criteria for SJS/TEN: Based on %BSA involvement with involvement of at least two mucous membranes; confirmed by histology showing full-thickness epidermal necrosis; Empiric Risk Stratification Tool (EsCAR) helps predict risk

• Patch Testing: Performed 2-4 weeks after reaction resolution to identify causative drug in delayed hypersensitivity; not useful for acute reactions or immunologic verification

• Immediate Management for All Reactions: Discontinue the offending drug immediately (most important intervention); document drug reaction in medical record and communicate to patient; cross-reactivity risk varies by drug class (high within beta-lactams, moderate with sulfonamides)

• First-line for Mild Maculopapular Exanthem: Discontinue drug; supportive care with cool comp

Disease complications — emergencies flagged

• Sepsis and bacteremia (EMERGENCY): loss of the epidermal barrier in TEN permits Staphylococcus aureus and Pseudomonas invasion; sepsis, not the skin disease itself, is the leading cause of death. Signals: hypothermia or new fever after defervescence, altered mentation, rising pressor need. Prophylactic systemic antibiotics are not standard; surveillance cultures are.
• Hypovolemia, hypernatremia, and acute kidney injury (EMERGENCY): transepidermal water loss mirrors burn physiology. Signals: oliguria, rising creatinine, hemoconcentration. Burn-unit-level fluid resuscitation is why transfer is recommended.
• Respiratory failure from tracheobronchial epithelial sloughing (EMERGENCY): dyspnea, hypoxemia, or bronchial casts early in TEN predicts intubation and ARDS.
• Ocular scarring: conjunctival pseudomembranes progressing to symblepharon, entropion, corneal neovascularization and blindness. Ophthalmology consultation within the first 24 hours is essential and is the key determinant of long-term ocular outcome (drug withdrawal remains the single most important overall intervention).
• Genitourinary and GI mucosal involvement: vaginal synechiae, urethral stricture, esophageal stricture, odynophagia and dysphagia.
• DRESS visceral injury: hepatitis is the most common organ involvement and the usual cause of death; eosinophilic myocarditis is an emergency signaled by chest pain, hypotension, new heart failure, or troponin elevation. Interstitial nephritis and pneumonitis also occur.
• Delayed autoimmune sequelae of DRESS: autoimmune thyroiditis (and less often type 1 diabetes) appearing months after recovery — check thyroid function on follow-up.
• Chronic skin sequelae: dyspigmentation, nail dystrophy, scarring alopecia; post-inflammatory hyperpigmentation is the expected endpoint of fixed drug eruption.

Treatment-related complications

• Systemic corticosteroids: infection masking, hyperglycemia, and delayed re-epithelialization — the reason their role in SJS/TEN remains contested.
• IVIG: volume overload, thrombosis, aseptic meningitis, and osmotic renal injury with sucrose-containing preparations; screen for IgA deficiency.
• Cyclosporine: nephrotoxicity, hypertension, and tremor.
• TNF-alpha inhibitors (etanercept): reactivation of latent tuberculosis and hepatitis B.
• Epinephrine for anaphylaxis: tachyarrhythmia and hypertension, acceptable given the alternative.

• **Mucosal involvement plus a positive Nikolsky sign means SJS/TEN until proven otherwise.** The single best next step is stopping every non-essential drug and transferring to a burn or ICU setting; ophthalmology consultation within the first 24 hours prevents symblepharon and blindness.
• The commonest distractor for TEN is staphylococcal scalded skin syndrome. SSSS spares mucous membranes, occurs in young children, and splits the epidermis at the granular layer (exfoliative toxin cleaving desmoglein-1); TEN causes full-thickness necrosis at the dermoepidermal junction and hits the mouth, eyes, and genitals.
• Latency is the discriminator. Minutes to hours = IgE urticaria/anaphylaxis; under 48 hours to a few days = AGEP, especially with beta-lactams (non-antibiotic triggers such as hydroxychloroquine or diltiazem can have considerably longer latency); 4-14 days, occasionally up to about 4 weeks = maculopapular exanthem and SJS/TEN; 2-8 weeks = DRESS. A rash appearing 4 weeks after starting allopurinol with facial edema and eosinophilia is DRESS, not a simple exanthem.
• **The association examiners love: *HLA-B\*15:02* and carbamazepine SJS/TEN in Han Chinese and Southeast Asian patients** — FDA-recommended pre-prescription testing. Its cousins are *HLA-B\*57:01*/abacavir and *HLA-B\*58:01*/allopurinol (ACR gout guideline).
• Erythema multiforme is usually infectious, not pharmacologic. HSV is the leading trigger; recurrent EM is treated with suppressive antivirals, and EM is a separate entity from SJS/TEN.
• Fixed drug eruption recurs at the identical site with each exposure and heals with slate-gray hyperpigmentation — classically lips or genitals after an NSAID, sulfonamide, or tetracycline.
• Not every reaction is allergy. Vancomycin infusion flushing is direct mast-cell degranulation (slow the infusion, pretreat with an H1 antihistamine); ACE-inhibitor angioedema is bradykinin-mediated with no urticaria and warrants switching classes rather than rechallenge.
• Anaphylaxis is treated with intramuscular epinephrine 0.3 mg in the anterolateral thigh first — antihistamines and corticosteroids are adjuncts, never the initial step.
• Penicillin-allergy label caveat: cephalosporin cross-reactivity is roughly 1-3% and tracks with shared R1 side chains, not the beta-lactam ring; the historical 10% figure is obsolete.