Case and Review Received: November 13, 2012 Accepted after revision: June 10, 2013 Published online: October 11, 2013
Dermatology 2013;227:209–213 DOI: 10.1159/000353584
Linear IgA Bullous Disease Presenting as Toxic Epidermal Necrolysis: A Case Report and Review of the Literature Rohit Kakar Holly Paugh Christine Jaworsky Department of Dermatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA
Abstract A 91-year-old female presented with widespread skin sloughing and bullae clinically mimicking toxic epidermal necrolysis (TEN). The patient was on multiple antibiotics, including vancomycin and piperacillin/tazobactam. Histopathology and direct immunofluorescence were consistent with a diagnosis of linear IgA bullous disease (LABD). In a PubMed review of the literature from 1975 to the present, there have been 15 cases of LABD presenting as TEN clinically and with characteristic linear IgA deposits on direct immunofluorescence studies. Vancomycin and phenytoin were the most commonly implicated medications. Twelve patients saw a resolution or healing of skin lesions after discontinuation of the implicated medication. There were, however, 5 patients who died of complications related to their comorbidities. It is important to include LABD in the differential diagnosis when evaluating patients who clinically present with TEN. © 2013 S. Karger AG, Basel
Introduction
Linear IgA bullous disease (LABD) most likely encompasses a heterogeneous group of subepidermal autoimmune blistering diseases characterized by tissuebound IgA deposits along the basement membrane zone. Autoantibodies have been found to target different autoantigens [1]. In children, LABD often presents with bullae arranged in an annular distribution resembling a string or cluster of pearls [1]. In adults, LABD can present with a variety of skin manifestations (table 1) ranging from vesicles resembling dermatitis herpetiformis to bullae mimicking bullous pemphigoid and rarely toxic epidermal necrolysis (TEN) [2]. Associations with a variety of conditions and triggers have been anecdotally reported, but prospective epidemiological studies are required to assess and define their significance. The characteristic feature in routine sections is tagging of basilar keratinocytes by neutrophils in a linear fashion, and corresponding linear deposition of IgA along the basement membrane zone on direct immunofluorescence. The latter are not characteristic for LABD but are found in other subepidermal autoimmune diseases [3–10]. We present a
© 2013 S. Karger AG, Basel 1018–8665/13/2273–0209$38.00/0 E-Mail [email protected] www.karger.com/drm
case of LABD mimicking TEN and review other documented cases in the international literature. Case Report
A 91-year-old female was transferred to the MetroHealth Medical Center burn unit for possible TEN. Two weeks prior to presentation the patient had been admitted to an outside hospital for acute cholecystitis, complicated by choledochoduodenal fistula and sepsis. During her hospital course she received multiple antibiotics including vancomycin, piperacillin/tazobactam, ceftazidime, ampicillin/sulbactam and augmentin. Her medical history was significant for end-stage renal disease on hemodialysis, diabetes mellitus type II, Crohn’s disease, hypothyroidism, atrial fibrillation, and history of a deep venous thrombosis with an inferior vena cava filter. Two days prior to admission to the burn unit the patient had been noted to have vesicles on her soft palate. Over the next day, she developed bullae on her back prompting transfer to the burn unit for further evaluation and treatment of possible TEN. On admission (fig. 1) she had large flaccid
Rohit Kakar, MD 110 Irving Street NW, Room CI-1121 Washington, DC 20010-2975 (USA) E-Mail rohit.x.kakar @ gunet.georgetown.edu
Downloaded by: Northern Illinois University 131.156.157.31 - 1/26/2015 8:34:34 PM
Key Words Bullous disease · Linear IgA bullous dermatosis · Toxic epidermal necrolysis
Color version available online
Table 1. LABD: clinical mimics
Dermatitis herpetiformis Vasculitis Neutrophilic dermatosis Cicatricial pemphigoid Ocular mucous membrane pemphigoid Pemphigus vulgaris Erythema multiforme Lichen planus Toxic epidermal necrolysis
Fig. 1. The patient on admission. Involving the trunk and extremities there were multiple
coalescent flaccid bullae and sloughing with approximately 40% skin involvement.
Color version available online
bullae with a positive Nikolsky’s sign and skin sloughing involving approximately 40% of her body surface. The palms and soles were involved; however, there was no ocular involvement. Over the course of 24 h the skin lesions progressed to involve 75% of her skin (fig. 2). The initial biopsy from the outside hospital showed a subepidermal bulla with a neutrophilic infiltrate and no epidermal necrosis. A repeat biopsy on admission was similar (fig. 3). Direct immunofluorescence showed linear IgA deposition along the basement membrane zone, corresponding to the distribution of neutrophils (fig. 4). These findings were consistent with LABD. A search for circulating antibodies was not performed. Treatment with dapsone was proposed; however, due to the patient’s worsening clinical status and comorbidities, the family decided for comfort care measures and the patient passed away on the following day. Discussion
210
Fig. 2. Over the course of 24 h, rapid progression to large geographic areas of full-thickness
skin sloughing occurred, involving close to 75% of body surface area.
bidities or were older in age, but were not a direct result of their LABD. Classical LABD presents as tense bullae and erythematous patches on the trunk and extremities as well as mucous membrane involvement [22]. In cases of LABD
Dermatology 2013;227:209–213 DOI: 10.1159/000353584
presenting as TEN, mucous membrane involvement was present in 8 of the 13 cases in which mucosal involvement was reported. The palms and soles were involved in 9 of 11 patients. Of the reports that included the percentage of body surface involve-
Kakar/Paugh/Jaworsky
Downloaded by: Northern Illinois University 131.156.157.31 - 1/26/2015 8:34:34 PM
A review of the literature shows 15 previously reported cases of LABD clinically presenting as TEN (table 2). Including our case, 7 cases have been reported in the USA, 3 in France, 1 in the Slovak Republic, 1 in Germany, 1 in Ireland, 1 in Australia, 1 in Portugal, and 1 in Taiwan [2, 11–24]. Patients in these reports ranged in age from 41 to 91 years, with an average age of 69. Ten were females and 6 males. Vancomycin and phenytoin were the most commonly implicated medications. Twelve patients in total saw a resolution or healing of skin lesions after discontinuation of the implicated medication; however, there were 5 of the patients who died of complications. Negative outcomes were generally found in patients who suffered from severe comor-
Color version available online
Fig. 4. Direct immunofluorescence. Linear IgA deposition at the basement membrane
zone, corresponding to the distribution of neutrophils.
Treatment of drug-triggered LABD has typically consisted of discontinuation of the offending medication. All of the patients reviewed who survived their comorbidities showed resolution of lesions after discontinuation of the putative agent
after 2 or more weeks. However, 6 of the cases reviewed did receive treatment for LABD: dapsone in 1 case, methylprednisone in 4 cases, and intravenous immunoglobulin in 1 case. Although dapsone, prednisone, and intravenous immuno-
Dermatology 2013;227:209–213 DOI: 10.1159/000353584
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Linear IgA Bullous Disease Presenting as Toxic Epidermal Necrolysis
Fig. 3. Biopsy on admission. Neutrophils aligned at the dermal-epidermal junction with subepidermal splitting. HE. Magnification ×100.
Color version available online
ment, the value ranged from 15 to 90%, with an average of 47.6%. In addition, 8 of the 10 cases checked for Nikolsky’s sign found it to be positive, 1 case reported negative findings and 1 was uncertain. Based on these reports, it appears that many patients show palmoplantar involvement and a positive Nikolsky’s sign, while mucous membrane involvement is highly variable. The pathophysiologic mechanisms that result in LABD are not entirely clear. Several of the target antigens involved in the pathogenesis of LABD have been identified: 97-kDa, 120-kDa antigens, BP180, and BP230 [1, 25–28]. Both the 97-kDa and 120-kDa antigens are proteolytic cleavage products of the BP180 ectodomain [29, 30]. The variety of target antigens involved and location may explain the heterogeneous clinical and immunopathologic characteristics of LABD [19, 31]. A copresence of IgA and IgG has also been seen as part of LABD’s heterogeneity [1]. Many medications have been implicated in LABD, but only a few cases have conclusively proven a drug’s culpability [21, 32]. We were similarly unable to determine direct culpability in our current case. Among the LABD cases we have reviewed with a presentation similar to TEN, vancomycin and phenytoin are the predominant culprits with 10 cases including vancomycin as a possible cause and 4 including phenytoin as an implicated drug. Phenytoin has been previously associated with both TEN and LABD [21, 33]. Vancomycin and phenytoin have both been reported to induce LABD, but vancomycin being most consistently implicated [2, 34]. Vancomycin has also been reported to cause localized LABD confined to the palms at supratherapeutic levels [35]. Diclofenac, azithromycin, trimethoprim-sulfamethoxazole, piperacillin, tazobactam, ciprofloxacin, ceftriaxone, zanamivir, rimantadine, enalapril, and furosemide were also discussed in the reported cases of LABD mimicking TEN that may be implicated or could not be excluded based on timing of presentation. Although rechallenge would prove the drug-induced nature of LABD mimicking TEN, such cases present in a striking manner with rapid onset and usually rapid resolution even without therapy, leaving little or no doubt as to the drug-induced etiology of such eruptions [32]. Of interest, idiopathic LABD has also been reported to mimic TEN [11].
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Dermatology 2013;227:209–213 DOI: 10.1159/000353584
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Kakar/Paugh/Jaworsky
71 years, France F
Paul et al. [12]
ESRD on hemodialysis, DM II, Crohn’s disease, cholecystoduodenal fistula, sepsis
Bacterial meningitis
Coronary artery disease; adenocarcinoma of the colon
CVA, hemicraniectomy, MRSA pneumonia
CVA, sepsis, MRSA UTI
CVA, urosepsis
Vancomycin, piperacillintazobactam, ceftazidime, ampicillin/sulbactam, augmentin
Vancomycin, ceftriaxone
Verapamil
Piperacillin-tazobactam, trimethoprim-sulfamethoxazole, vancomycin, furosemide
Phenytoin, vancomycin, furosemide, amiodarone
Azithromycin, zanamivir, rimantadine
Vancomycin
Vancomycin
Vancomycin, piperacillin, tazobactam, ciprofloxacin
Phenytoin
Vancomycin, phenytoin, enalapril
Vancomycin, phenytoin
Unknown; Modenol, Aspirin
Vancomycin, gentamycin
Diclofenac
None
Implicated medication(s)
Positive
Not stated
Positive
Negative
Negative
Positive
Negative
Negative
Positive
Negative
Negative
Positive
Positive
Unknown
Positive
Positive
Mucous membrane involvement
Positive
Negative
Not stated
Not stated
Positive
Not stated
Positive
Not stated
Positive
Positive
Positive
Negative
Positive
Unknown
Positive
Positive
Palmoplantar involvement
75%, positive
Not stated, positive
20%, positive
20%, not stated
75%, positive
Not stated, negative
40%, positive
46%, uncertain
90%, not stated
Not stated, positive
15%, not stated
Not stated
Not stated, positive
Unknown
Not stated
Not stated, positive
Body surface involvement, Nikolsky’s sign
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Unknown
IgA: 7.5 g/l IgG: 17.3 g/l IgM: 1.17 g/l
IgA: 10.5 g/l IgG: 39.5 g/l
Circulating antibodies
Supportive care
DC vancomycin, ceftriaxone
DC verapamil, cyclosporine
DC vancomycin, methylprednisolone
IVIg, DC phenytoin and antibiotics
Methylprednisolone, fexofenadine, prednisone, pentoxifylline
Methylprednisolone (vancomycin only prescribed for 10-day course)
DC vancomycin; silvadene dressing changes and dapsone
Not stated; antibiotics given for 5 days
Supportive care and DC phenytoin
DC vancomycin, phenytoin
Methylprednisone and DC phenytoin, vancomycin
Dapsone
DC antibiotics
DC diclofenac
Hydrocortisone, triamcinolone, infadolan ointment, Kenalog Orabase, sulfonate
Treatment
Died on day 5 from complications
Resolution in 2 weeks
Resolution in 12 h
Resolution in 3 weeks
Improvement after 48 h of treatment; died on day 6 of treatment due to complications related to CVA
Healing on 16th day
Resolution in 2 weeks
Skin lesions resolved within 3 weeks; died from cardiac complications
Died from septic shock 22 days after rash had appeared
Healing over months
Died from complications of intracranial hemorrhage
Resolution in 2 weeks
Healing over months
Healing over 5 weeks
Resolution in 2 weeks
Resolution in 8 weeks
Outcome
M = Male; F = female; CVA = cerebrovascular accident; DC = discontinued; URI = upper respiratory infection; UTI = urinary tract infection; MRSA = methicillin-resistant Staphylococcus aureus; CABG = coronary artery bypass graft; ESRD = end-stage renal disease; DM II = diabetes mellitus type II; IVIg = intravenous immunoglobulin.
91 years, USA F
Khan et al. [21]
Current patient
Cummings et al. [20]
41 years, Taiwan F
57 years, Ireland F
Coelho et al. [19]
Jheng-Wei et al. [24]
54 years, USA M
Waldman et al. [18]
91 years, France F
67 years, Portugal F
Dellavalle et al. [2]
Schroeder et al. [23]
Perforated sigmoid colon, liver/splenic abscesses, sepsis, CVA
77 years, USA M
Tran et al. [17]
49 years, USA M
URI
74 years, USA M
Hughes and Callen [16]
Trufant et al. [22]
Pneumonia, rheumatoid arthritis (on prednisone)
77 years, USA M
60 years, Australia Glioblastoma F multiforme
CABG, sepsis, respiratory failure, acute renal failure, atrial fibrillation
87 years, USA F
Mofid et al. [15]
CVA, suspected UTI
73 years, Germany URI, hypertension F
Epilepsy
Schneck et al. [14]
Wetterwald 70 years, France et al. [13] F
66 years, Slovak None M Republic
Buchvald et al. [11]
Back pain
Age, sex Country
Reference
Comorbidities
Table 2. Reported cases of LABD presenting as TEN
globulin have all been previously reported in the literature as therapeutic options, dapsone is often proposed as the first choice [1]. LABD is important to include in the differential diagnosis of vesiculobullous diseases presenting as TEN. While the routine histologies of TEN and LABD differ, localization of IgA dermal-epidermal junction in a linear fashion on direct immunofluo-
rescence confirms the diagnosis. Serum antibody studies have not been routinely undertaken in this acute clinical setting. Clinical features at presentation and exposure to medications must be thoroughly evaluated in making a diagnosis, ultimately guiding the clinician to the diagnosis of LABD.
Disclosure Statement
The authors have no conflicts of interest to disclose. Neither Case Western University, MetroHealth Hospital, nor any of the investigators, study personnel, or their relatives received or expect to receive compensation, supplies, equipment or any other inducements, directly or indirectly, from participation in this study.
1 Fortuna G, Marinkovich PM: Linear immunoglobulin A bullous dermatosis. Clin Dermatol 2012;30:38–50. 2 Dellavalle RP, Burch JM, Tayal S, Golitz LE, Fitzpatrick JE, Walsh P: Vancomycin associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. J Am Acad Dermatol 2003;48:S56–S57. 3 Leonard JN, Griffith CEM, Powles AV, et al: Experience with a gluten free diet in the treatment of linear IgA disease. Acta Derm Venereol 1987;67:145–148. 4 Egan CA, Meadows KP, Zone J: Ulcerative colitis and immunobullous disease cured by colectomy. Arch Dermatol 1999;135:214–215. 5 Barberis C, Doutre MS, Bioulac-Sage P, et al: Dermatose bulleuse à IgA linéaire associée à une maladie de Crohn. Gastroenterol Clin Biol 1988;12:76–77. 6 McEvoy MT, Connolly SM: Linear IgA bullous dermatosis: association with malignancy. J Am Acad Dermatol 1990;22:59–63. 7 Sekula SA, Tschen JA, Bean SF, Wolf JE Jr: Linear IgA bullous disease in a patient with transitional cell carcinoma of the bladder. Cutis 1986;38:354–356, 362. 8 Lacour JP, Vitetta A, Ortonne JP: Linear IgA dermatosis and thyroid carcinoma. J Am Acad Dermatol 1992;26:257–259. 9 Barrow-Wade L, Jordan RE, Arnett FC Jr: Linear IgA bullous dermatosis associated with dermatomyositis (letter). Arch Dermatol 1992;128:413–414. 10 Blickenstaff RD, Perry HO, Peters MS: Linear IgA deposition associated with cutaneous varicella-zoster infection: a case report. J Cutan Pathol 1988;15:49–52. 11 Buchvald J, Filo V, Horvathova J: IgA-linear dermatosis imitating Lyell syndrome. Bratisl Lek Listy 1987;88:211–217. 12 Paul D, Wolkenstein P, Prost C, Caux F, Rostoker G, Heller M, Wechsler J, Revuz J, Roujeau JC: Drug-induced linear IgA disease: target antigens are heterogeneous. Br J Dermatol 1997;136:406–411. 13 Wetterwald E, Le Cleach L, Wechsler J, Roujeau JC, Revuz J, Bagot M: Bullous drug eruption masquerading as toxic epidermal necrolysis. Eur Rencontres Hop 1999;45:15–18. 14 Schneck B, Termeer C, Mockenhaupt M, Augustin M, Schöpf E: Linear IgA dermato-
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sis in an adult with clinical signs of StevensJohnson syndrome. Hautarzt 1999; 50: 288– 291. Mofid MZ, Costarangos C, Bernstein B, Wong L, Munster A, Nousari HC: Drug-induced linear immunoglobulin A bullous disease that clinically mimics toxic epidermal necrolysis. J Burn Care Rehabil 2000;21:246–247. Hughes AP, Callen JP: Drug-induced linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Dermatology 2001; 202: 138–139. Tran D, Kossard S, Shumack S: Phenytoininduced linear IgA dermatosis mimicking toxic epidermal necrolysis. Australas J Dermatol 2003;44:284–286. Waldman MA, Black DR, Callen JP: Vancomycin-induced linear IgA bullous disease presenting as toxic epidermal necrolysis. Clin Exp Dermatol 2004;29:633–636. Coelho S, Tellechea O, Reis JP, Mariano A, Figueiredo A: Vancomycin-associated linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Int J Dermatol 2006; 137: 995–996. Cummings JE, Snyder RR, Kelly EB, Raimer SS: Drug-induced linear immunoglobulin A bullous dermatosis mimicking Stevens-Johnson syndrome: a case report. Cutis 2007; 79: 203–207. Khan I, Hughes R, Curran R, Marren P: Drugassociated linear IgA disease mimicking toxic epidermal necrolysis. Clin Exp Dermatol 2009;34:715–717. Trufant JW, Christensen SR, McNiff JM, Choi JN: Erythroderma and spontaneous blistering in a 49-year-old man. Arch Dermatol 2010; 146:1419–1424. Schroeder D, Saada D, Rafaa M, IngenHousz-Oro S, Valeyrie-Alannore L, Siggal ML: Verapamil-induced linear IgA disease mimicking toxic-epidermal necrolysis. Ann Dermatol Venereol 2011;138:302–306. Jheng-Wei L, Yi-Chin S, Wen-Hung C: Vancomycin-induced linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Indian J Dermatol Venereol Leprol 2011; 77: 537. Zone JJ, Taylor TB, Kadunce DP, Meyer LJ: Identification of the cutaneous basement membrane zone antigen and isolation of anti-
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body in linear immunoglobulin A bullous dermatosis. J Clin Invest 1990;85:812–820. Marinkovich MP, Taylor TB, Keene DR, Burgeson RE, Zone JJ: LAD-1, the linear IgA bullous dermatosis autoantigen, is a novel 120-kDa anchoring filament protein synthesized by epidermal cells. J Invest Dermatol 1996;106:734–738. Collier P, Wojnarowska F, Allen J, Kirtschig G: Molecular overlap of the IgA target antigens in the subepidermal blistering diseases. Dermatology 1994;189(suppl 1):105–107. Kanitakis J, Mauduit G, Cozzani E, Badinand P, Faure M, Claudy A: Linear IgA bullous dermatosis of childhood with autoantibodies to a 230 kDa epidermal antigen. Pediatr Dermatol 1994;11:139–144. Hirako Y, Usukura J, Uematsu J, Hashimoto T, Kitajima Y, Owaribe K: Cleavage of BP180, a 180-kDa bullous pemphigoid antigen, yields a 120-kDa collagenous extracellular polypeptide. J Biol Chem 1998;273:9711–9717. Zone JJ, Taylor TB, Meyer LJ, Petersen MJ: The 97 kDa linear IgA bullous disease antigen is identical to a portion of the extracellular domain of the 180 kDa bullous pemphigoid antigen, BPAg2. J Invest Dermatol 1998; 110: 207–210. Allen J, Phan TT, Hughes MA, Cherry GW, Wojnarowska F: The cellular origins of the linear IgA disease target antigens: an indirect immunofluorescence study using cultured human keratinocytes and fibroblasts. Br J Dermatol 2003;148:945–953. Fortuna G, Salas-Alanis JC, Guidetti E, Marinkovich MP: A critical reappraisal of the current data on drug induced linear immunoglobulin A bullous dermatosis: a real and separate nosological entity? J Am Acad Dermatol 2012;66:988–994. Lissia M, Mulas P, Bulla A, Rubino C: Toxic epidermal necrolysis (Lyell’s disease). Burns 2010;36:152–163. Klein PA, Callen JP: Drug-induced linear IgA bullous dermatosis after vancomycin discontinuance in a patient with renal insufficiency. J Am Acad Dermatol 2000;42:316–323. Walsh S, Kerchner K, Sangueza OP: Localized palmar vancomycin-induced linear IgA bullous dermatosis occurring at supratherapeutic levels. Arch Dermatol 2009;145:603–604.
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References
Dermatology 2013;227:209–213 DOI: 10.1159/000353584
Linear IgA Bullous Disease Presenting as Toxic Epidermal Necrolysis: A Case Report and Review of the Literature Rohit Kakar Holly Paugh Christine Jaworsky Department of Dermatology, MetroHealth Medical Center, Case Western Reserve University, Cleveland, Ohio, USA
Abstract A 91-year-old female presented with widespread skin sloughing and bullae clinically mimicking toxic epidermal necrolysis (TEN). The patient was on multiple antibiotics, including vancomycin and piperacillin/tazobactam. Histopathology and direct immunofluorescence were consistent with a diagnosis of linear IgA bullous disease (LABD). In a PubMed review of the literature from 1975 to the present, there have been 15 cases of LABD presenting as TEN clinically and with characteristic linear IgA deposits on direct immunofluorescence studies. Vancomycin and phenytoin were the most commonly implicated medications. Twelve patients saw a resolution or healing of skin lesions after discontinuation of the implicated medication. There were, however, 5 patients who died of complications related to their comorbidities. It is important to include LABD in the differential diagnosis when evaluating patients who clinically present with TEN. © 2013 S. Karger AG, Basel
Introduction
Linear IgA bullous disease (LABD) most likely encompasses a heterogeneous group of subepidermal autoimmune blistering diseases characterized by tissuebound IgA deposits along the basement membrane zone. Autoantibodies have been found to target different autoantigens [1]. In children, LABD often presents with bullae arranged in an annular distribution resembling a string or cluster of pearls [1]. In adults, LABD can present with a variety of skin manifestations (table 1) ranging from vesicles resembling dermatitis herpetiformis to bullae mimicking bullous pemphigoid and rarely toxic epidermal necrolysis (TEN) [2]. Associations with a variety of conditions and triggers have been anecdotally reported, but prospective epidemiological studies are required to assess and define their significance. The characteristic feature in routine sections is tagging of basilar keratinocytes by neutrophils in a linear fashion, and corresponding linear deposition of IgA along the basement membrane zone on direct immunofluorescence. The latter are not characteristic for LABD but are found in other subepidermal autoimmune diseases [3–10]. We present a
© 2013 S. Karger AG, Basel 1018–8665/13/2273–0209$38.00/0 E-Mail [email protected] www.karger.com/drm
case of LABD mimicking TEN and review other documented cases in the international literature. Case Report
A 91-year-old female was transferred to the MetroHealth Medical Center burn unit for possible TEN. Two weeks prior to presentation the patient had been admitted to an outside hospital for acute cholecystitis, complicated by choledochoduodenal fistula and sepsis. During her hospital course she received multiple antibiotics including vancomycin, piperacillin/tazobactam, ceftazidime, ampicillin/sulbactam and augmentin. Her medical history was significant for end-stage renal disease on hemodialysis, diabetes mellitus type II, Crohn’s disease, hypothyroidism, atrial fibrillation, and history of a deep venous thrombosis with an inferior vena cava filter. Two days prior to admission to the burn unit the patient had been noted to have vesicles on her soft palate. Over the next day, she developed bullae on her back prompting transfer to the burn unit for further evaluation and treatment of possible TEN. On admission (fig. 1) she had large flaccid
Rohit Kakar, MD 110 Irving Street NW, Room CI-1121 Washington, DC 20010-2975 (USA) E-Mail rohit.x.kakar @ gunet.georgetown.edu
Downloaded by: Northern Illinois University 131.156.157.31 - 1/26/2015 8:34:34 PM
Key Words Bullous disease · Linear IgA bullous dermatosis · Toxic epidermal necrolysis
Color version available online
Table 1. LABD: clinical mimics
Dermatitis herpetiformis Vasculitis Neutrophilic dermatosis Cicatricial pemphigoid Ocular mucous membrane pemphigoid Pemphigus vulgaris Erythema multiforme Lichen planus Toxic epidermal necrolysis
Fig. 1. The patient on admission. Involving the trunk and extremities there were multiple
coalescent flaccid bullae and sloughing with approximately 40% skin involvement.
Color version available online
bullae with a positive Nikolsky’s sign and skin sloughing involving approximately 40% of her body surface. The palms and soles were involved; however, there was no ocular involvement. Over the course of 24 h the skin lesions progressed to involve 75% of her skin (fig. 2). The initial biopsy from the outside hospital showed a subepidermal bulla with a neutrophilic infiltrate and no epidermal necrosis. A repeat biopsy on admission was similar (fig. 3). Direct immunofluorescence showed linear IgA deposition along the basement membrane zone, corresponding to the distribution of neutrophils (fig. 4). These findings were consistent with LABD. A search for circulating antibodies was not performed. Treatment with dapsone was proposed; however, due to the patient’s worsening clinical status and comorbidities, the family decided for comfort care measures and the patient passed away on the following day. Discussion
210
Fig. 2. Over the course of 24 h, rapid progression to large geographic areas of full-thickness
skin sloughing occurred, involving close to 75% of body surface area.
bidities or were older in age, but were not a direct result of their LABD. Classical LABD presents as tense bullae and erythematous patches on the trunk and extremities as well as mucous membrane involvement [22]. In cases of LABD
Dermatology 2013;227:209–213 DOI: 10.1159/000353584
presenting as TEN, mucous membrane involvement was present in 8 of the 13 cases in which mucosal involvement was reported. The palms and soles were involved in 9 of 11 patients. Of the reports that included the percentage of body surface involve-
Kakar/Paugh/Jaworsky
Downloaded by: Northern Illinois University 131.156.157.31 - 1/26/2015 8:34:34 PM
A review of the literature shows 15 previously reported cases of LABD clinically presenting as TEN (table 2). Including our case, 7 cases have been reported in the USA, 3 in France, 1 in the Slovak Republic, 1 in Germany, 1 in Ireland, 1 in Australia, 1 in Portugal, and 1 in Taiwan [2, 11–24]. Patients in these reports ranged in age from 41 to 91 years, with an average age of 69. Ten were females and 6 males. Vancomycin and phenytoin were the most commonly implicated medications. Twelve patients in total saw a resolution or healing of skin lesions after discontinuation of the implicated medication; however, there were 5 of the patients who died of complications. Negative outcomes were generally found in patients who suffered from severe comor-
Color version available online
Fig. 4. Direct immunofluorescence. Linear IgA deposition at the basement membrane
zone, corresponding to the distribution of neutrophils.
Treatment of drug-triggered LABD has typically consisted of discontinuation of the offending medication. All of the patients reviewed who survived their comorbidities showed resolution of lesions after discontinuation of the putative agent
after 2 or more weeks. However, 6 of the cases reviewed did receive treatment for LABD: dapsone in 1 case, methylprednisone in 4 cases, and intravenous immunoglobulin in 1 case. Although dapsone, prednisone, and intravenous immuno-
Dermatology 2013;227:209–213 DOI: 10.1159/000353584
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Linear IgA Bullous Disease Presenting as Toxic Epidermal Necrolysis
Fig. 3. Biopsy on admission. Neutrophils aligned at the dermal-epidermal junction with subepidermal splitting. HE. Magnification ×100.
Color version available online
ment, the value ranged from 15 to 90%, with an average of 47.6%. In addition, 8 of the 10 cases checked for Nikolsky’s sign found it to be positive, 1 case reported negative findings and 1 was uncertain. Based on these reports, it appears that many patients show palmoplantar involvement and a positive Nikolsky’s sign, while mucous membrane involvement is highly variable. The pathophysiologic mechanisms that result in LABD are not entirely clear. Several of the target antigens involved in the pathogenesis of LABD have been identified: 97-kDa, 120-kDa antigens, BP180, and BP230 [1, 25–28]. Both the 97-kDa and 120-kDa antigens are proteolytic cleavage products of the BP180 ectodomain [29, 30]. The variety of target antigens involved and location may explain the heterogeneous clinical and immunopathologic characteristics of LABD [19, 31]. A copresence of IgA and IgG has also been seen as part of LABD’s heterogeneity [1]. Many medications have been implicated in LABD, but only a few cases have conclusively proven a drug’s culpability [21, 32]. We were similarly unable to determine direct culpability in our current case. Among the LABD cases we have reviewed with a presentation similar to TEN, vancomycin and phenytoin are the predominant culprits with 10 cases including vancomycin as a possible cause and 4 including phenytoin as an implicated drug. Phenytoin has been previously associated with both TEN and LABD [21, 33]. Vancomycin and phenytoin have both been reported to induce LABD, but vancomycin being most consistently implicated [2, 34]. Vancomycin has also been reported to cause localized LABD confined to the palms at supratherapeutic levels [35]. Diclofenac, azithromycin, trimethoprim-sulfamethoxazole, piperacillin, tazobactam, ciprofloxacin, ceftriaxone, zanamivir, rimantadine, enalapril, and furosemide were also discussed in the reported cases of LABD mimicking TEN that may be implicated or could not be excluded based on timing of presentation. Although rechallenge would prove the drug-induced nature of LABD mimicking TEN, such cases present in a striking manner with rapid onset and usually rapid resolution even without therapy, leaving little or no doubt as to the drug-induced etiology of such eruptions [32]. Of interest, idiopathic LABD has also been reported to mimic TEN [11].
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Kakar/Paugh/Jaworsky
71 years, France F
Paul et al. [12]
ESRD on hemodialysis, DM II, Crohn’s disease, cholecystoduodenal fistula, sepsis
Bacterial meningitis
Coronary artery disease; adenocarcinoma of the colon
CVA, hemicraniectomy, MRSA pneumonia
CVA, sepsis, MRSA UTI
CVA, urosepsis
Vancomycin, piperacillintazobactam, ceftazidime, ampicillin/sulbactam, augmentin
Vancomycin, ceftriaxone
Verapamil
Piperacillin-tazobactam, trimethoprim-sulfamethoxazole, vancomycin, furosemide
Phenytoin, vancomycin, furosemide, amiodarone
Azithromycin, zanamivir, rimantadine
Vancomycin
Vancomycin
Vancomycin, piperacillin, tazobactam, ciprofloxacin
Phenytoin
Vancomycin, phenytoin, enalapril
Vancomycin, phenytoin
Unknown; Modenol, Aspirin
Vancomycin, gentamycin
Diclofenac
None
Implicated medication(s)
Positive
Not stated
Positive
Negative
Negative
Positive
Negative
Negative
Positive
Negative
Negative
Positive
Positive
Unknown
Positive
Positive
Mucous membrane involvement
Positive
Negative
Not stated
Not stated
Positive
Not stated
Positive
Not stated
Positive
Positive
Positive
Negative
Positive
Unknown
Positive
Positive
Palmoplantar involvement
75%, positive
Not stated, positive
20%, positive
20%, not stated
75%, positive
Not stated, negative
40%, positive
46%, uncertain
90%, not stated
Not stated, positive
15%, not stated
Not stated
Not stated, positive
Unknown
Not stated
Not stated, positive
Body surface involvement, Nikolsky’s sign
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Not done
Unknown
IgA: 7.5 g/l IgG: 17.3 g/l IgM: 1.17 g/l
IgA: 10.5 g/l IgG: 39.5 g/l
Circulating antibodies
Supportive care
DC vancomycin, ceftriaxone
DC verapamil, cyclosporine
DC vancomycin, methylprednisolone
IVIg, DC phenytoin and antibiotics
Methylprednisolone, fexofenadine, prednisone, pentoxifylline
Methylprednisolone (vancomycin only prescribed for 10-day course)
DC vancomycin; silvadene dressing changes and dapsone
Not stated; antibiotics given for 5 days
Supportive care and DC phenytoin
DC vancomycin, phenytoin
Methylprednisone and DC phenytoin, vancomycin
Dapsone
DC antibiotics
DC diclofenac
Hydrocortisone, triamcinolone, infadolan ointment, Kenalog Orabase, sulfonate
Treatment
Died on day 5 from complications
Resolution in 2 weeks
Resolution in 12 h
Resolution in 3 weeks
Improvement after 48 h of treatment; died on day 6 of treatment due to complications related to CVA
Healing on 16th day
Resolution in 2 weeks
Skin lesions resolved within 3 weeks; died from cardiac complications
Died from septic shock 22 days after rash had appeared
Healing over months
Died from complications of intracranial hemorrhage
Resolution in 2 weeks
Healing over months
Healing over 5 weeks
Resolution in 2 weeks
Resolution in 8 weeks
Outcome
M = Male; F = female; CVA = cerebrovascular accident; DC = discontinued; URI = upper respiratory infection; UTI = urinary tract infection; MRSA = methicillin-resistant Staphylococcus aureus; CABG = coronary artery bypass graft; ESRD = end-stage renal disease; DM II = diabetes mellitus type II; IVIg = intravenous immunoglobulin.
91 years, USA F
Khan et al. [21]
Current patient
Cummings et al. [20]
41 years, Taiwan F
57 years, Ireland F
Coelho et al. [19]
Jheng-Wei et al. [24]
54 years, USA M
Waldman et al. [18]
91 years, France F
67 years, Portugal F
Dellavalle et al. [2]
Schroeder et al. [23]
Perforated sigmoid colon, liver/splenic abscesses, sepsis, CVA
77 years, USA M
Tran et al. [17]
49 years, USA M
URI
74 years, USA M
Hughes and Callen [16]
Trufant et al. [22]
Pneumonia, rheumatoid arthritis (on prednisone)
77 years, USA M
60 years, Australia Glioblastoma F multiforme
CABG, sepsis, respiratory failure, acute renal failure, atrial fibrillation
87 years, USA F
Mofid et al. [15]
CVA, suspected UTI
73 years, Germany URI, hypertension F
Epilepsy
Schneck et al. [14]
Wetterwald 70 years, France et al. [13] F
66 years, Slovak None M Republic
Buchvald et al. [11]
Back pain
Age, sex Country
Reference
Comorbidities
Table 2. Reported cases of LABD presenting as TEN
globulin have all been previously reported in the literature as therapeutic options, dapsone is often proposed as the first choice [1]. LABD is important to include in the differential diagnosis of vesiculobullous diseases presenting as TEN. While the routine histologies of TEN and LABD differ, localization of IgA dermal-epidermal junction in a linear fashion on direct immunofluo-
rescence confirms the diagnosis. Serum antibody studies have not been routinely undertaken in this acute clinical setting. Clinical features at presentation and exposure to medications must be thoroughly evaluated in making a diagnosis, ultimately guiding the clinician to the diagnosis of LABD.
Disclosure Statement
The authors have no conflicts of interest to disclose. Neither Case Western University, MetroHealth Hospital, nor any of the investigators, study personnel, or their relatives received or expect to receive compensation, supplies, equipment or any other inducements, directly or indirectly, from participation in this study.
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