A drug hypersensitivity reaction is an adverse, allergic response to an ingested or parenterally administered drug characterized by a cutaneous eruption.
There are several different immune mechanisms thought to play a role:
Type I: IgE-dependent drug reactions characterized by urticaria, angioedema, and anaphylaxis.
Type II: Cytotoxic drug-induced reactions characterized by petechiae from drug-induced thrombocytopenia.
Type III: Immune complex-mediated drug reactions characterized by vasculitis, serum sickness, urticaria.
Type IV: Delayed-type, cell-mediated drug reactions characterized by exanthematous, fixed drug eruptions (FDEs), Stevens–Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN).
An exanthematous drug reaction is an adverse, allergic response to an ingested or parenterally administered drug characterized by a morbilliform cutaneous eruption that mimics a viral exanthem.
INSIGHT 
In the appropriate clinical setting, an exanthematous drug reaction, a viral exanthem, and acute graft-versus-host disease (GVHD) are all clinically and histologically indistinguishable.
SYNONYMS Morbilliform drug eruption, maculopapular drug eruption, drug rash.
AGE Children < adolescents < adults.
GENDER F > M.
INCIDENCE 1% of population on a systemic medication.
ETIOLOGY Numerous drugs have been associated with the development of exanthematous drug eruptions—see Table 15-1 for a partial list. Antibiotics are the most frequent class of medications associated with exanthematous drug eruptions.
Drugs with High Probability of Reaction | Penicillins, amoxicillin, ampicillin Cephalosporins Carbamazepine Allopurinol Gold salts Trimethoprim-sulfamethoxazole |
| Drugs with Medium Probability of Reaction | Sulfonamides (bacteriostatic, antidiabetic, diuretic) Nitrofurantoin Hydantoin derivatives Isoniazid Chloramphenicol Erythromycin Streptomycin |
| Drugs with Low Probability of Reaction | Barbiturates Benzodiazepines Phenothiazines Opioids (morphine, codeine) |
Exanthematous drug hypersensitivity reactions are likely type IV, cell-mediated immune responses. Viral infections may increase the incidence (e.g., aminopenicillins cause a morbilliform rash in nearly 100% of patients concurrently infected with EBV).
The exanthematous rash typically appears 7 to 14 days (peak incidence ninth day) after drug administration; however, skin lesions can appear anytime between day 1 and 21 after drug exposure. The rash starts on the trunk and typically spreads to the face and extremities. It can be quite pruritic and distressing. Fever and malaise are variably present.
TYPE OF LESION Macules, papules, plaques (Fig. 15-1A).
SIZE Individual lesions 1 mm to 1 cm with diffuse body surface area involvement possible.
COLOR Pink/red to dusky purple/brown, especially in darker skin types.
DISTRIBUTION OF LESIONS Trunk, spreads centrifugally to face (Fig. 15-1B) and extremities. Confluent in intertriginous areas (axilla, groin, inframammary area). Palms and soles may be involved.
MUCOUS MEMBRANES ± Exanthem on buccal mucosa.
± Fever, malaise
An exanthematous drug reaction can be confused with a viral exanthema, allergic contact dermatitis, pityriasis rosea, psoriasis, toxic shock syndrome, scarlet fever, acute GVHD, eczema, or secondary syphilis.
DERMATOPATHOLOGY Perivascular inflammation with scattered eosinophils.
Exanthematous drug reactions can occur 1 to 21 days after drug exposure. With discontinuation of the drug, the rash begins to fade (often after a 2- to 3-day lag time following drug discontinuation). The fiery red rash gradually fades to a dull purple and then desquamates. A rechallenge with the drug often elicits a faster, more severe response. Ten percent of patients sensitive to penicillins given cephalosporins will exhibit cross-drug sensitivity and develop an eruption. Similarly, patients sensitized to one sulfa-based drug (bacteriostatic, antidiabetic, diuretic) may cross-react with another category of that drug.
Correct identification and discontinuation of the offending drug is needed. Symptomatic relief for pruritic skin lesions can be obtained with systemic antihistamines (diphenhydramine, hydroxyzine HCl, cetirizine HCl), oatmeal baths, emollients (hydrated petrolatum, Vaseline, camphor-menthol creams, moisturizers), and topical steroids. Severe cases may benefit from a limited course of systemic steroids (prednisone or methylprednisolone). Steroid use may not speed ultimate resolution of the eruption but can offer symptomatic relief from pruritus.
The patient should be made aware of the possible drug allergen and cross-reactants. His or her medical chart should be updated accordingly. For morbilliform eruptions, the drug can be readministered, though the eruption may recur upon reexposure. It is possible to “treat through” an exanthematous drug hypersensitivity rash in cases where the offending drug is critical or life-sustaining and there are no appropriate non–cross-reacting alternative medications.
Urticaria is a transient allergic response characterized by edematous plaques (wheals) and/or deep dermal swelling (angioedema). In some cases, urticaria is accompanied by respiratory symptoms, vascular collapse, and/or shock (anaphylaxis).
INSIGHT 
The hallmark of urticaria is its transience. An individual lesion should not persist for more than 24 hours.
SYNONYMS Wheals, hives, nettle rash.
AGE Any age.
GENDER F > M, 2:1.
INCIDENCE 5% of the population.
ETIOLOGY >50% of urticaria is idiopathic. Urticaria can result from immune (autoimmune, IgE-mediated, immune complex, or complement/kinin-dependent) or nonimmune (direct mast cell degranulators, vasoactive stimuli, ASA, NSAIDs, dietary pseudoallergens, ACE inhibitors) mechanisms.
The mast cell is the primary cell type responsible for urticaria. IgE, opiates, C5a anaphylatoxin, quinolones, vancomycin, and some neuropeptides can cross-link or bind receptors on the surface of mast cells leading to degranulation of its contents. Mast cells release histamine and other proinflammatory mediators which bind to receptors on the postcapillary venules in the skin. This leads to vasodilation and plasma leakage clinically seen as wheals and/or angioedema.
In urticaria, wheals are transient skin lesions that come and go in <24 hours. Skin symptoms can include pruritus, flushing, or burning. In angioedema, deeper swelling of the dermis, subcutaneous, or submucosal tissue occurs and may persist for 3 to 4 days. Systemic symptoms can include respiratory symptoms, arthralgias, fatigue, abdominal pain, fever, and diarrhea.
TYPE Wheal: edematous papule, plaque (Fig. 15-2).
SIZE 1 mm to 10 cm.
SHAPE Round, oval, annular, or polycyclic.
COLOR Pink to red, with surrounding or central pallor.
DISTRIBUTION Typically generalized (Fig. 15-3).
TYPE Diffuse swelling.
COLOR Pink-red.
SITES OF PREDILECTION Face (eyelids, lips, tongue).
Malaise, fever, arthralgias, respiratory symptoms, hypotension, and shock.
The transient edematous plaques are diagnostic for urticaria, although often parents can mistake blisters or insect bites for urticaria. Urticaria also needs to be differentiated from dermatographism (present in 5% of the normal population), eczema, contact dermatitis, mastocytosis, erythema multiforme (EM), and allergic vasculitis.
DERMATOPATHOLOGY Dermal or subcutaneous edema, vascular dilation, and mild perivascular infiltrate.
BLOOD TESTS In evaluating patients with urticaria or angioedema, a complete blood count with differential, chemistry panel, liver function tests, and complement levels should be obtained to evaluate for systemic causes. Complement levels, particularly C4, will be depressed in individuals with C1-inhibitor deficiencies. Serum tryptase—a marker of mast cell activation—may be elevated in episodes of angioedema associated with anaphylaxis.
Urticaria self-resolves in 1 year in 50% of cases. Up to 20% of cases can have a chronic relapsing course.
Identification and elimination of any causative agent is most helpful. Several drugs have been associated with urticaria, as listed in Table 15-2. Foods that can cause urticaria include milk, eggs, wheat, shellfish, and nuts. Other forms include physical urticaria (dermatographism, cold; Fig. 15-4); solar, cholinergic, pressure, vibratory, and hereditary angioedema (autosomal dominantly inherited disorder caused by a low level of, or dysfunctional, plasma protein C1 inhibitor). In up to 50% of cases, the etiology is undetermined. Urticaria can be precipitated by stress.
Antibiotics | Penicillins Sulfonamides |
Cardiac medications | Amiodarone Procainamide |
Immunotherapeutics | Serum-derived products |
Chemotherapies | L-asparagine Bleomycin Cisplatin Daunorubicin 5-fluorouracil Thiotepa |
ACE inhibitors | Captopril, Enalapril, Lisinopril |
Calcium channel blockers | Nifedipine, Diltiazem, Verapamil |
Direct histamine releasers | Morphine Radiocontrast dye Muscle relaxants Salicylates Sympathomimetics Various antimicrobials |
TREATMENT Treatment is primarily symptomatic with one or more antihistamines (chlorpheniramine, hydroxyzine, diphenhydramine, doxepin, acrivastine, cetirizine, loratadine, mizolastine, desloratadine, fexofenadine, levocetirizine, cimetidine, or ranitidine). Topical regimens include oatmeal baths, calamine or 1% menthol cream, and/or topical steroids.
More refractory cases may require systemic steroids (prednisone or methylprednisolone), but only short courses are recommended and rebound is possible. Chronic urticaria may require long-term management.
Epinephrine, intravenous fluid resuscitation, and airway protection are the treatments of choice for anaphylaxis, and it can be reassuring for patients with urticaria to carry an epinephrine pen for self-administration during severe episodes if necessary.
EM is a reactive syndrome characterized by “target” lesions of the skin and mucous membranes most commonly precipitated by an infection (usually HSV).
SYNONYM EM von Hebra.
EM MINOR Mild, sudden onset of papules, some of which evolve into target lesions. No prodrome or mucosal involvement. Recurrences common.
EM MAJOR EM associated with mucosal lesions and systemic symptoms. Historically erroneously synonymous with SJS, which is probably a separate disease with distinct pathophysiology.
AGE 50% of patients are older than 20 years of age. Rare under 2 years of age.
GENDER M > F.
INCIDENCE Uncommon, less than 1% of individuals affected.
ETIOLOGY Most common precipitant is HSV (>50%); reported association with other infections, drugs, or systemic disease.
GENETICS May see increased incidence in HLA-DQw3, HLA-DRw53, HLA-Aw33 populations, particularly with HSV-triggered EM.
Likely an aberrant immune response to select precipitants in certain predisposed individuals. Possible precipitants include infections (HSV >>> Mycoplasma pneumoniae, Histoplasma capsulatum, parapoxvirus, vaccinia, VZV, adenovirus, EBV, CMV, hepatitis viruses, Coxsackie virus, parvovirus B19, HIV, Chlamydophila psittaci, salmonella, Mycobacterium tuberculosis, dermatophytes), rarely drugs (NSAIDs, sulfonamides, antiepileptics, antibiotics), or systemic disease (IBD, SLE, Behçet’s).
Skin lesions appear abruptly 3 to 14 days after precipitant (HSV-induced herpes labialis in >50%) and new lesions can continue to appear for up to 10 days. Fever, malaise, and mucous membrane involvement may also be present in EM Major.
TYPE Macules, papules, scale, vesicles, bullae.
COLOR Red ring, dusky purple center (Fig. 15-5).
SIZE 5 mm to 3 cm.
SHAPE Target or iris lesions are typical. Classic target lesions contain a dusky or violaceous center, an edematous inflammatory zone, and an erythematous periphery, though atypical target or “targetoid” lesions may be seen.
DISTRIBUTION Upper body, extremities. Grouped on elbows, knees.
SITES OF PREDILECTION Upper extremities and face > palms, neck, trunk > legs. Lesions often start acrally and spread centripetally.
MUCOUS MEMBRANES Oral, ocular, and genital blistering and ulceration may be present.
EM can be confused with viral exanthems, bullous diseases, urticaria, secondary syphilis, psoriasis, FDE, subacute cutaneous lupus erythematosus, vasculitis, polymorphous light eruption, or pityriasis rosea. The “target lesions” are classic for EM, but may be confused with erythema annulare centrifugum (EAC), tinea corporis, or other annular eruptions.
DERMATOPATHOLOGY Interface dermatitis, spongiosis, exocytosis, vacuolar degeneration of the basal keratinocytes, dermal edema, perivascular mononuclear infiltrate.
INFECTIOUS DISEASE EVALUATION If lesions suggestive of primary HSV are present, direct fluorescence antibody, viral culture, or PCR may be used to confirm the etiology of the primary lesion. Serology for M. pneumoniae is generally positive in associated eruptions.
EM appears abruptly 3 to 14 days after insult (HSV, infection, drug, etc.); skin lesions fully evolve in 72 hours and persist for 1 to 2 weeks. Lesions can be pruritic or painful, systemic symptoms and mucosal involvement may be present. EM typically resolves after 2 weeks with no sequelae, but recurrences are common.
For EM management, if a precipitant can be identified, it should be treated or removed. In recurrent EM cases secondary to HSV, daily prophylactic acyclovir, valacyclovir, or famciclovir may be necessary.
In most cases of EM, the rash will self-resolve in 5 to 15 days without treatment. Symptomatic relief for pruritic skin lesions can be obtained with systemic antihistamines (diphenhydramine, hydroxyzine HCl, cetirizine HCl), oatmeal baths, emollients (hydrated petrolatum, Vaseline, moisturizers), and topical steroids.
In severe EM, systemic steroids (prednisone, methylprednisolone) can be added. Open skin lesions can be treated with topical antibiotics and topical petrolatum-impregnated gauze if needed for prevention of secondary bacterial infection. Oral lesions can benefit from anesthetic rinses. Ocular lesions need topical treatment in conjunction with an ophthalmologist.
In severe refractory or recurrent EM cases, azathioprine, thalidomide, dapsone, cyclosporine, mycophenolate mofetil, or PUVA have had reported successes.
SJS and TEN are rare, severe cutaneous drug reactions characterized by tenderness of the skin/mucosa, followed by extensive exfoliation that is potentially life-threatening.
SYNONYM Lyell’s syndrome.
SJS and TEN are considered as two clinical ends along a spectrum of adverse drug reaction severity with:
SJS <10% body surface area skin sloughing.
SJS/TEN OVERLAP 10% to 30% body surface area skin sloughing.
TEN >30% body surface area skin sloughing.
AGE Older children. More common in adults older than 40 years.
GENDER SJS: M = F. TEN: F > M.
INCIDENCE SJS: 6 per million, TEN: 1 per million. Markedly increased incidence in individuals with HIV.
GENETICS Genetic susceptibility in HLA-B12 (particularly with NSAIDs), HLA-B*5801 (particularly with allopurinol), HLA-B*1502 (particularly with anticonvulsants).
ETIOLOGY SJS: Drugs (≥50%); TEN: Drugs (>95%); NSAIDs, antibiotics, and anticonvulsants are most common triggers. Antiretroviral agents may trigger SJS/TEN in individuals with HIV.
SJS/TEN develops because of a host’s impaired capacity to metabolize reactive drug metabolites. The metabolites then trigger an interaction between the cell-death receptor Fas and its ligand (FasL) causing extensive keratinocyte death (apoptosis), loss of cohesion, necrosis resulting in full-thickness epidermal necrolysis. Drugs implicated include NSAIDs (phenylbutazone, piroxicam), antibiotics (amithiozone, aminopenicillins) sulfa drugs (sulfadoxine, sulfadiazine, sulfasalazine, trimethoprim-sulfamethoxazole), allopurinol, antiretrovirals, and antiepileptics (barbiturates, carbamazepine, phenytoin, and lamotrigine).
One to three weeks after drug exposure, SJS/TEN begins with fever, pain with swallowing, and stinging eyes. Dysuria may be present. Up to 3 days later, the skin lesions appear on the trunk spreading to the upper extremities and face. The skin turns dusky purple-red before dermal–epidermal detachment with sheets of skin falling off leaving raw, red denuded areas. Systemic symptoms include fever, malaise, myalgia, arthralgias, dysuria, nausea and vomiting, diarrhea, and conjunctival burning.
TYPE Macules, papules, plaques, blisters, desquamation (Fig. 15-6).
COLOR Red/purple to gray.
PALPATION Nikolsky sign: lateral mechanical pressure causes epidermal detachment manifesting as blister extension.
DISTRIBUTION Often truncal initially, spreading to upper extremities and face. Palms/soles can be involved.
MUCOUS MEMBRANES (≥90%, especially in SJS) Erosions on buccal (Fig. 15-7A), ocular (Fig. 15-7B), genital mucosae.
Fever, Lymphadenopathy (LAD)
OCULAR (85%) Conjunctival hyperemia, keratitis, pseudomembrane formation, erosions.
RESPIRATORY (25%) Epithelial damage, erosions.
GASTROINTESTINAL Diarrhea, esophagitis.
RENAL Tubular necrosis, renal failure.
OTHER Hepatitis, cytopenia.
SJS/TEN can be confused with EM, staphylococcal scalded skin syndrome (SSSS), severe acute GVHD, DRESS, Kawasaki disease (KD), thermal burns, phototoxic eruptions, generalized FDE, LE, or generalized erythroderma (from severe psoriasis, atopic dermatitis, mycosis fungoides, etc.).
DERMATOPATHOLOGY Early: necrosis of the basal cell layer with subepidermal bullae formation. Late: full-thickness epidermal necrosis, sparse perivascular infiltrate. Analysis of frozen cryostat sections on “jelly roll” skin samples demonstrating full-thickness necrosis can expedite SJS/TEN diagnosis for more rapid clinical intervention.
Course is similar to that of severe widespread thermal burns. Outcome is worse in patients who are older, or have more extensive skin involvement. Mortality rate is 5% for SJS and 35% for TEN as is typically caused by sepsis (Staphylococcus aureus, Pseudomonas aeruginosa) or fluid and electrolyte imbalances.
SJS/TEN management consists of rapid diagnosis and elimination of the causative agent. Patients should be monitored closely and those with extensive skin involvement are best cared for in a burn or intensive care unit with IV fluid and electrolyte replenishment, temperature control, and vigilant wound care. Careful daily wound care (wash with isotonic sterile sodium chloride, mupirocin on orifices, Vaseline-impregnated gauze or silicone dressings, antibiotic eye drops to cornea) with minimal manipulation can lead to regrowth of epidermis in 1 to 3 weeks. Pressure points and perioral areas heal more slowly.
The use of systemic steroids for SJS/TEN management is controversial as large randomized controlled trials demonstrating efficacy are lacking. High-dose IV immunoglobulins may be of some benefit if administered early. Cyclosporine, cyclophosphamide, plasmapheresis, N-acetyl-cysteine have had anecdotal successes.
Those who do recover from TEN need to be aware of their drug sensitivity and possible cross-reactants. Reexposure to the offending agent or structurally similar drugs can lead to a faster, more severe TEN episode, thus drugs should not be readministered. The patient’s medical chart should clearly document the severe drug reaction and the patient should wear a medical alert bracelet.
AGE Any age.
GENDER M = F.
INCIDENCE Uncommon.
ETIOLOGY The drugs most commonly implicated are phenolphthalein, antimicrobial agents (tetracycline, minocycline, sulfonamides, trimethoprim-sulfamethoxazole, metronidazole), nystatin, anti-inflammatory agents (salicylates, NSAIDs, naproxen, acetaminophen, dipyrone, dimenhydrinate, phenylbutazone, phenacetin), psychoactive agents (barbiturates, carbamazepine), quinine and quinidine. The foods most commonly implicated are peas, beans, and lentils.
An FDE will first present as an erythematous plaque that occurs 1 to 2 weeks after exposure to the offending agent. With subsequent exposures, the violaceous plaque recurs within minutes to 24 hours and recurs at the same site. The patient typically reports seeing the lesion at seemingly random intervals. Careful history will usually elicit the sporadic use of an over-the-counter or PRN medication that is causing the recurrent rash (i.e., ibuprofen, aspirin, eye drops, laxatives, etc.).
TYPE Macule, plaque, bullae, erosion.
SHAPE Round to oval (Fig. 15-8).
COLOR Red, purple, brown.
SIZE 0.5 to 20 cm in diameter.
NUMBER Solitary lesion. With repeated attacks, multiple lesions may occur. Occasionally generalized FDEs with disseminated multiple lesions may occur.
SITES OF PREDILECTION Lips, hands, face, feet, genitalia.
FDE can be confused with recurrent herpetic lesions, arthropod bite, other drug reactions such as EM, a contact dermatitis, or other eczematous processes.
DERMATOPATHOLOGY Perivascular and interstitial dermal lymphohistiocytic infiltrate, at times with eosinophils and/or subepidermal vesicles and bullae with overlying epidermal necrosis. Between outbreaks, the site shows marked pigmentary incontinence with melanin in macrophages in the upper dermis.
The cutaneous lesions of FDE resolve within a few weeks of withdrawing the offending agent. The lesions often heal with hyperpigmentation given the pigmentary incontinence that occurs during the inflammatory phase of the lesions. A notable exception is pseudoephedrine, which classically causes a non-pigmented FDE. The rash recurs within hours following ingestion of a single dose of the drug.
The management for an FDE is to identify and withhold the offending drug. The hyperpigmented postinflammatory changes will slowly resolve with time.
Serum sickness is an allergic reaction characterized by urticaria, malaise, fever, LAD, splenomegaly, and arthralgias. It originally was seen most in treatment with horse or rabbit antiserum; it is now seen with drugs or vaccinations.
AGE Any age.
GENDER M = F.
INCIDENCE Uncommon.
ETIOLOGY Type-III (immune-complex mediated) hypersensitivity reaction.
Serum sickness is mediated by circulating antigen–antibody complexes (type III Arthus reaction), in which IgG is the predominant immunoglobulin.
Urticarial rash and low-grade fever, usually 7 to 21 days following administration of offending agent, or earlier in individuals previously sensitized to the agent. Agents derived from nonhuman animals (such as horse or rabbit antithymocyte globulin or mouse-based monoclonal antibodies) are common triggering drugs.
TYPE Wheals, edema (Fig. 15-9).
COLOR Pink, red, or violaceous.
SHAPE Round, oval, and polycyclic.
ARRANGEMENT Scattered, discrete lesions or dense, confluent areas.
DISTRIBUTION Trunk, extremities, face. Mucous membranes may be involved. A predilection for the lateral aspects of the hands and feet may be observed.
LYMPHADENOPATHY (often in epitrochlear region).
MUSCULOSKELETAL (50%) Arthralgia, polyarthritis.
NEUROLOGIC Peripheral neuritis, radiculitis, optic neuritis, cerebral edema.
RENAL Glomerulonephritis.
Serum sickness can be confused with urticaria, angioedema, urticarial vasculitis, a viral exanthem, TEN, or subacute bacterial endocarditis.
DERMATOPATHOLOGY Engorged blood vessels with edema and perivascular inflammation.
HEMATOLOGY ± Eosinophilia, elevated ESR, hypocomplementemia.
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