eMedicine Specialties > Dermatology > Bullous Diseases

Drug-Induced Bullous Disorders: Differential Diagnoses & Workup

Author: David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
Contributor Information and Disclosures

Updated: Jan 6, 2009

Differential Diagnoses

Atopic Dermatitis
Linear IgA Dermatosis
Bullous Disease of Diabetes
Lupus Erythematosus, Bullous
Bullous Disease of Dialysis
Nummular Dermatitis
Bullous Pemphigoid
Pemphigus Foliaceus
Candidiasis, Cutaneous
Pemphigus Vulgaris
Cicatricial Pemphigoid
Pemphigus, Paraneoplastic
Contact Dermatitis, Allergic
Porphyria Cutanea Tarda
Contact Dermatitis, Irritant
Psoriasis, Pustular
Dermatitis Herpetiformis
Reactive Arthritis
Epidermolysis Bullosa
Staphylococcal Scalded Skin Syndrome
Epidermolysis Bullosa Acquisita
Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis
Erythema Multiforme
Subcorneal Pustular Dermatosis
Id Reaction (Autoeczematization)
Impetigo
Lichen Planus

Other Problems to Be Considered

Eczematous drug eruption - Allergic or irritant contact dermatitis, intradermal reactions, photoallergic reactions, nummular dermatitis, atopic dermatitis

AGEP - Impetigo, staphylococcal scalded skin syndrome, pustular psoriasis, Reiter disease, subcorneal pustular dermatosis, pemphigus foliaceus, candidiasis, pustular dermatophyte infection

FDE - Erythema chronicum migrans, SJS-TEN, bullous disease of diabetes mellitus, bullous disease of dialysis, bullous reactions with drug overdose/coma and bullous phototoxic contact reactions to plants, postinflammatory hyperpigmentation, factitial dermatitis

EM - Paraneoplastic pemphigus, other autoimmune blistering diseases, lupus erythematosus, bullous lichen planus, urticaria, FDE

Drug-induced pemphigus - Pemphigus vulgaris, pemphigus foliaceus, pemphigus vegetans, bullous pemphigoid, dermatitis herpetiformis, PCT, TEN, EM, bullous contact dermatitis

Drug-induced pemphigoid - Reflex sympathetic dystrophy, linear IgA bullous dermatosis, bullous disease of diabetes mellitus, EM, bullous systemic lupus erythematosus, dermatitis herpetiformis, burn, epidermolysis bullosa, leukocytoclastic vasculitis, chronic actinic dermatitis, and cicatricial pemphigoid

Drug-induced LAD - Non–drug-induced LAD, dermatitis herpetiformis, bullous pemphigoid, cicatricial pemphigoid, EM

Pseudoporphyria - True PCT, bullous pemphigoid, epidermolysis bullosa acquisita, photoallergic dermatitis, allergic contact dermatitis

Workup

Laboratory Studies

  • Laboratory studies during an eczematous drug eruption may disclose eosinophilia, leukocytosis, and elevated sedimentation rate.
  • In AGEP, laboratory studies demonstrate neutrophilia in 90% of cases and eosinophilia in 30% of cases. Liver function is usually normal.
  • Laboratory studies in FDE may show leukocytosis, hypereosinophilia, and hypergammaglobulinemia. However, clinical and histologic features are the mainstay of diagnosis.
  • Apart from leukocytosis, laboratory studies may not be helpful in the evaluation of patients with EM. Patients with widespread lesions may develop electrolyte abnormalities and hypoalbuminemia. Immunofluorescence study results are negative.
  • Antinuclear antibodies may be found in patients with thiol drug-induced pemphigus.
  • Blood eosinophilia and increased amounts of soluble interleukin-2 receptors may be present in patients with drug-induced pemphigoid.20 The sera and blister fluids in drug-induced pemphigoid may show increased amounts of eosinophilic cationic protein and neutrophil-derived myeloperoxidase.
  • Laboratory studies are not particularly helpful in diagnosing drug-induced LAD.
  • In pseudoporphyria, laboratory studies do not demonstrate any abnormality in heme biosynthesis or hepatic abnormalities.

Other Tests

  • Results of patch testing suspected drugs that cause eczematous drug reactions may be positive.
  • Patch testing of the offending drug in AGEP may result in a pustular patch test reaction.
  • Patch testing and oral provocation testing may be used to implicate a specific drug in a FDE.
  • Apart from skin biopsy, other tests are not helpful in evaluating EM. First-degree relatives of patients with TEN have lymphocytes that are more susceptible to the toxic effect of the culprit drug than controls.
  • Results of direct and indirect immunofluorescence studies in drug-induced pemphigus are identical to studies in idiopathic pemphigus. Deposition of immunoglobulin G (IgG) and C3 is observed intercellularly on direct immunofluorescence. On indirect immunofluorescence, pemphigus antibodies are found in the patient's serum.
  • Linear deposits of IgG and C3 may be visualized along the basement membrane zone with direct immunofluorescence in patients with drug-induced pemphigoid. Indirect immunofluorescence studies are positive for circulating antibodies against the basement membrane zone. However, circulating antibodies are less commonly found in cicatricial pemphigoid.
  • Direct immunofluorescence studies reveal the presence of IgA at the basement membrane zone in LAD. Results of indirect immunofluorescence studies using monkey esophagus or saline split human skin are usually negative for IgA at the basement membrane zone.
  • Pseudoporphyria demonstrates normal urine and serum porphyrins.

Histologic Findings

Eczematous drug eruptions

Frequently seen histologic findings include the following: hyperkeratosis, parakeratosis, exocytosis of lymphocytes, spongiosis, and a superficial perivascular lymphocytic infiltrate. Occasional histologic findings include the following: eosinophilic spongiosis, vesicle or bulla formation, papillary dermal edema, and extravasation of erythrocytes. Rarely, features suggestive of mycosis fungoides may be observed.

Acute generalized exanthematous pustulosis

Subcorneal or spongiform pustules and a mild superficial perivascular and interstitial infiltrate composed of lymphocytes, neutrophils, and eosinophils may be observed. Papillary dermal edema, extravasation of erythrocytes, and acantholytic keratinocytes may also be observed.

Fixed drug eruption

Histologic examination of FDE reveals an interface or spongiotic dermatitis pattern. In the acute phase, the epidermis is characterized by dyskeratotic cells, exocytosis, edema, nuclear pyknosis, and hydropic degeneration of basal cells. An acute infiltrate consisting of lymphocytes, histiocytes, neutrophils, and eosinophils may be found around superficial and deep blood vessels. The quiescent lesion contains macrophages replete with melanin in the upper dermis. Papillary dermal fibrosis may develop consequent to prior episodes of FDE at the same site.

Erythema multiforme

An interface dermatitis with individual cell necrosis (necrotic keratinocytes) beneath a normal basket weave stratum corneum is characteristic of EM. Other findings may include spongiosis, intrabasilar blister formation, a superficial perivascular lymphohistiocytic infiltrate with variable numbers of eosinophils and neutrophils, and papillary dermal edema. TEN shows massive and confluent necrosis of the basal cells (and possibly the entire epidermis), and the dermal infiltrate is scanty.

Drug-induced pemphigus

The hallmark of pemphigus is acantholysis, or the loss of cohesion between epidermal cells. This gives rise to an intraepidermal bulla, which may be located above the basal cell layer (low acantholysis) or subcorneally (high acantholysis). Bullae may lack inflammatory cells or may contain abundant neutrophils. A lymphocytic infiltrate may be found in the dermis in addition to numerous plasma cells and eosinophils.

Drug-induced pemphigoid

The histologic hallmark of drug-induced pemphigoid is a subepidermal blister. Neutrophils, eosinophils, and fibrin may be present in the blister cavity. The dermis is characterized by a superficial infiltrate containing neutrophils, lymphocytes, eosinophils, and occasionally plasma cells. In cicatricial pemphigoid lesions, eosinophils are sparse, whereas a dense lymphocytic inflammatory infiltrate exists in the dermis. Variable dermal fibrosis may be observed based upon chronicity of the lesions and prior involvement at the same site.

Linear IgA dermatosis

A subepidermal blister containing neutrophils and eosinophils with a dermal perivascular infiltrate may be present. IgA antibodies, sometimes accompanied by C3, localize to the dermal side of the basement membrane.

Pseudoporphyria

Pseudo-PCT demonstrates the same histologic features of PCT. These features include the following: subepidermal blister, cell-poor infiltrate, festooning of dermal papillae, and thickened vessel walls, which are periodic acid-Schiff positive.

More on Drug-Induced Bullous Disorders

Overview: Drug-Induced Bullous Disorders
Differential Diagnoses & Workup: Drug-Induced Bullous Disorders
Treatment & Medication: Drug-Induced Bullous Disorders
Follow-up: Drug-Induced Bullous Disorders
Multimedia: Drug-Induced Bullous Disorders
References
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Further Reading

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Keywords

blistering drug eruptions, vesiculobullous drug-induced disorders, drug-induced hypersensitivity reactions, drug-induced anaphylaxis, adverse cutaneous drug reactions, toxic epidermal necrolysis, Stevens-Johnson Syndrome

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Contributor Information and Disclosures

Author

David F Butler, MD, Professor of Dermatology, Texas A&M University College of Medicine; Chair, Department of Dermatology, Director, Dermatology Residency Training Program, Scott and White Clinic
David F Butler, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Association of Military Dermatologists, and Phi Beta Kappa
Disclosure: 3M Pharmaceutical Grant/research funds Other; Graceway Pharmaceuticals Grant/research funds Other

Medical Editor

Ponciano D Cruz Jr, MD, Vice-Chair, JB Shelmire Professor, Department of Dermatology, University of Texas Southwestern Medical Center
Ponciano D Cruz Jr, MD is a member of the following medical societies: Texas Medical Association
Disclosure: Nothing to disclose.

Pharmacy Editor

Michael J Wells, MD, Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center
Michael J Wells, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

Managing Editor

Lester F Libow, MD, Dermatopathologist, South Texas Dermatopathology Laboratory
Lester F Libow, MD is a member of the following medical societies: American Academy of Dermatology, American Society of Dermatopathology, and Texas Medical Association
Disclosure: Nothing to disclose.

CME Editor

Catherine Quirk, MD, Clinical Assistant Professor, Department of Dermatology, Brown University
Catherine Quirk, MD is a member of the following medical societies: Alpha Omega Alpha and American Academy of Dermatology
Disclosure: Nothing to disclose.

Chief Editor

Dirk M Elston, MD, Director, Department of Dermatology, Geisinger Medical Center
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.

 
 
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