Drug-Induced Bullous Disorders Workup

  • Author: David F Butler, MD; Chief Editor: William D James, MD  more...
Updated: Mar 29, 2016

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.[32] 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.


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.

Contributor Information and Disclosures

David F Butler, MD Section Chief of Dermatology, Central Texas Veterans Healthcare System; Professor of Dermatology, Texas A&M University College of Medicine; Founding Chair, Department of Dermatology, Scott and White Clinic

David F Butler, MD is a member of the following medical societies: American Medical Association, Alpha Omega Alpha, Association of Military Dermatologists, American Academy of Dermatology, American Society for Dermatologic Surgery, American Society for MOHS Surgery, Phi Beta Kappa

Disclosure: Nothing to disclose.

Specialty Editor Board

Michael J Wells, MD, FAAD Associate Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine

Michael J Wells, MD, FAAD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Dermatology, American Medical Association, Texas Medical Association

Disclosure: Nothing to disclose.

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, Texas Medical Association

Disclosure: Nothing to disclose.

Chief Editor

William D James, MD Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine

William D James, MD is a member of the following medical societies: American Academy of Dermatology, Society for Investigative Dermatology

Disclosure: Nothing to disclose.

Additional Contributors

Ponciano D Cruz, Jr, MD Professor and Vice-Chair, Paul R Bergstresser Chair, 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: Received consulting fee from RCTS for independent contractor; Received honoraria from Mary Kay Cosmetics for consulting; Received grant/research funds from Galderma for principal investigator.

  1. Fortuna G, Salas-Alanis JC, Guidetti E, Marinkovich MP. A critical reappraisal of the current data on drug-induced linear immuglobulin A bullous dermatosis: A real and separate nosological entity?. J Am Acad Dermatol. 2011 Dec 9. [Medline].

  2. Gumaste PV, Cohen DE, Stein JA. Bullous Systemic Contact Dermatitis Caused by an Intra-articular Steroid Injection. Br J Dermatol. 2014 Jul 12. [Medline].

  3. Miyamoto J, Böckle BC, Zillikens D, Schmidt E, Schmuth M. Eczematous reaction to intravenous immunoglobulin: an alternative cause of eczema. JAMA Dermatol. 2014 Oct. 150 (10):1120-2. [Medline].

  4. Pernet C, Guillot B, Bessis D. Eczematous drug eruption after ustekinumab treatment. Arch Dermatol. 2012 Aug. 148 (8):959-60. [Medline].

  5. Hausermann P, Scherer K, Weber M, Bircher AJ. Ciprofloxacin-induced acute generalized exanthematous pustulosis mimicking bullous drug eruption confirmed by a positive patch test. Dermatology. 2005. 211(3):277-80. [Medline].

  6. Noce R, Paredes BE, Pichler WJ, Krähenbühl S. Acute generalized exanthematic pustulosis (AGEP) in a patient treated with furosemide. Am J Med Sci. 2000 Nov. 320(5):331-3. [Medline].

  7. Kubin ME, Jackson P, Riekki R. Acute Generalized Exanthematous Pustulosis Secondary to Acyclovir Confirmed by Positive Patch Testing. Acta Derm Venereol. 2016 Feb 2. [Medline].

  8. Charfi O, Kastalli S, Sahnoun R, Lakhoua G. Hydroxychloroquine-induced acute generalized exanthematous pustulosis with positive patch-testing. Indian J Pharmacol. 2015 Nov-Dec. 47 (6):693-4. [Medline].

  9. Wei CY, Ko TM, Shen CY, Chen YT. A Recent Update of Pharmacogenomics in Drug-Induced Severe Skin Reactions. Drug Metab Pharmacokinet. 2011 Nov 1. [Medline].

  10. Handisurya A, Moritz KB, Riedl E, Reinisch C, Stingl G, Wöhrl S. Fixed drug eruption caused by mefenamic acid: a case series and diagnostic algorithms. J Dtsch Dermatol Ges. 2011 May. 9(5):374-8. [Medline].

  11. Khaldi N, Miras A, Gromb S. Toxic epidermal necrolysis and clarithromycin. Can J Clin Pharmacol. 2005 Fall. 12(3):e264-8. [Medline].

  12. Jongen-Lavrencic M, Schneeberger PM, van der Hoeven JG. Ciprofloxacin-induced toxic epidermal necrolysis in a patient with systemic lupus erythematosus. Infection. 2003 Dec. 31(6):428-9. [Medline].

  13. Dyson SW, Lin C, Jaworsky C. Enoxaparin sodium-induced bullous pemphigoid-like eruption: a report of 2 cases. J Am Acad Dermatol. 2004 Jul. 51(1):141-2. [Medline].

  14. Leivo T, Heikkilä H. Naproxen-induced generalized bullous fixed drug eruption. Br J Dermatol. 2004 Jul. 151(1):232. [Medline].

  15. Layton D, Marshall V, Boshier A, Friedmann P, Shakir SA. Serious skin reactions and selective COX-2 inhibitors: a case series from prescription-event monitoring in England. Drug Saf. 2006. 29(8):687-96. [Medline].

  16. Pitsios C. Erythema multiforme caused by sildenafil in an HIV(+) subject. Eur Ann Allergy Clin Immunol. 2016 Mar. 48 (2):58-60. [Medline].

  17. Freed J, Wells M, Stetson C, Dongwoo L. Bullous reaction to topical methchlorethamine in mycosis fungoides. J Drugs Dermatol. 2006 Jan. 5(1):66-7. [Medline].

  18. Werchniak AE, Chaffee S, Dinulos JG. Methotrexate-induced bullous acral erythema in a child. J Am Acad Dermatol. 2005 May. 52(5 Suppl 1):S93-5. [Medline].

  19. Korman NJ, Eyre RW, Zone J, Stanley JR. Drug-induced pemphigus: autoantibodies directed against the pemphigus antigen complexes are present in penicillamine and captopril-induced pemphigus. J Invest Dermatol. 1991 Feb. 96(2):273-6. [Medline].

  20. Pinto GM, Lamarao P, Vale T. Captopril-induced pemphigus vegetans with Charcot-Leyden crystals. J Am Acad Dermatol. 1992 Aug. 27(2 Pt 2):281-4. [Medline].

  21. Ben Salem C, Chenguel L, Ghariani N, Denguezli M, Hmouda H, Bouraoui K. Captopril-induced lichen planus pemphigoides. Pharmacoepidemiol Drug Saf. 2008 Jul. 17(7):722-4. [Medline].

  22. Perry A, Sparling JD, Pennington M. Bullous pemphigoid following therapy with an oral beta-blocker. J Drugs Dermatol. 2005 Nov-Dec. 4(6):746-8. [Medline].

  23. Atzori L, Conti B, Zucca M, Pau M. Bullous pemphigoid induced by m-TOR inhibitors in renal transplant recipients. J Eur Acad Dermatol Venereol. 2014 Aug 29. [Medline].

  24. Aksakal BA, Ozsoy E, Arnavut O, Ali Gurer M. Oral terbinafine-induced bullous pemphigoid. Ann Pharmacother. 2003 Nov. 37(11):1625-7. [Medline].

  25. Carpenter S, Berg D, Sidhu-Malik N, Hall RP 3rd, Rico MJ. Vancomycin-associated linear IgA dermatosis. A report of three cases. J Am Acad Dermatol. 1992 Jan. 26(1):45-8. [Medline].

  26. Waldman MA, Black DR, Callen JP. Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis. Clin Exp Dermatol. 2004 Nov. 29(6):633-6. [Medline].

  27. Whitworth JM, Thomas I, Peltz SA, Sullivan BC, Wolf AH, Cytryn AS. Vancomycin-induced linear IgA bullous dermatosis (LABD). J Am Acad Dermatol. 1996 May. 34(5 Pt 2):890-1. [Medline].

  28. Santos-Juanes J, Coto Hernandez R, Trapiella L, Caminal L, Sanchez del Rio J, Soto J. Amoxicillin-associated linear IgA bullous dermatosis. J Eur Acad Dermatol Venereol. 2007 Aug. 21(7):992-3. [Medline].

  29. Shimanovich I, Rose C, Sitaru C, Brocker EB, Zillikens D. Localized linear IgA disease induced by ampicillin/sulbactam. J Am Acad Dermatol. 2004 Jul. 51(1):95-8. [Medline].

  30. Hernández N, Borrego L, Soler E, Hernández J. Sulfasalazine-induced linear immunoglobulin A bullous dermatosis with DRESS. Actas Dermosifiliogr. 2013 May. 104(4):343-6. [Medline].

  31. Tolland JP, McKeown PP, Corbett JR. Voriconazole-induced pseudoporphyria. Photodermatol Photoimmunol Photomed. 2007 Feb. 23(1):29-31. [Medline].

  32. Hofmann M, Audring H, Sterry W, Trefzer U. Interleukin-2-associated bullous drug dermatosis. Dermatology. 2005. 210(1):74-5. [Medline].

  33. Viard I, Wehrli P, Bullani R, Schneider P, Holler N, Salomon D, et al. Inhibition of toxic epidermal necrolysis by blockade of CD95 with human intravenous immunoglobulin. Science. 1998 Oct 16. 282(5388):490-3. [Medline].

  34. Garcia-Doval I, LeCleach L, Bocquet H, Otero XL, Roujeau JC. Toxic epidermal necrolysis and Stevens-Johnson syndrome: does early withdrawal of causative drugs decrease the risk of death?. Arch Dermatol. 2000 Mar. 136(3):323-7. [Medline].

Small pustules on erythematous patch (acute generalized exanthematous pustulosis).
Annular hyperpigmented patch (fixed drug eruption).
Target or iris lesions on palm (erythema multiforme).
Coalescing eroded patches (Stevens-Johnson syndrome).
Stevens-Johnson syndrome.
Crusted erosions on scalp (drug-induced pemphigus).
Small vesicle at edge of urticarial plaque (drug-induced pemphigoid).
Tense vesicles in annular array (linear immunoglobulin A dermatosis).
Erosions, scars, milia, and vesicle (pseudoporphyria).
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