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ORIGINAL CONTRIBUTION |
Address correspondence to Timothy J. Craig, DO, Pennsylvania State University, The Milton S. Hershey Medical Center, Pulmonary, Allergy, and Critical Care Medicine, HO41, 500 University Dr., PO Box 850, Hershey, PA 17033-0850. E-mail: tcraig{at}psu.edu
Background: With the emergence of highly resistant betalactam gram-positive organisms, vancomycin hydrochloride usage has increased considerably. Consequently, adverse drug reactions, including unfavorable cutaneous events, have also increased. Important adverse skin reactions are linear IgA bullous dermatosis (LABD) and Stevens-Johnson syndrome (SJS). These blistering disorders can have clinical manifestations that are difficult to distinguish; however, it is important to make the distinction because treatment and prognosis are different.
Objective: The purpose of this study is to review the literature on LABD and SJS and compare important differentiating characteristics to assist physicians in making the correct diagnosis.
Methods: The authors used MEDLINE to search for all published studies on vancomycin adverse events, and combined LABD, SJS, exanthema, and skin rashes each separately with vancomycin adverse events. Furthermore, the authors searched PubMed for all meta-analyses and randomized controlled clinical trials relating to treatment of patients with SJS.
Results: Clinically, LABD and SJS both present similarly with bullae. Diagnosis is made by use of perilesional skin biopsy and direct immunofluorescence. Direct immunofluorescence shows linear IgA deposition along the basement membrane zone in LABD, whereas this is absent in SJS. The treatment for both vancomycin-induced SJS and vancomycin-induced LABD is prompt discontinuation of the drug. However, if SJS is diagnosed early, systemic corticosteroids appear to decrease morbidity.
Conclusions: In cases of SJS or LABD that are difficult to distinguish clinically, the authors recommend performing a skin biopsy and direct immunofluorescence early to confirm the diagnosis so that effective treatment can be instituted.
Widespread use of vancomycin has also led to increased reports of adverse events. Among these, unfavorable skin reactions are the most prevalent reason for discontinuation of the medication.2 Vancomycin-induced Stevens-Johnson syndrome (SJS) and linear IgA bullous dermatosis (LABD) are adverse cutaneous reactions that can be difficult to distinguish clinically. It is important to make a correct diagnosis, though, because the prognosis and therapy are dissimilar.3,4 The objective of this study is to review SJS and LABD and discuss important differentiating characteristics so appropriate treatment is rendered, unnecessary use of corticosteroids is prevented, and appropriate prognosis is discussed with the patient.
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In addition to the above classification systems, biopsy specimens can be examined to aid in diagnosis. A frozen section biopsy of denuded epidermis will show primarily infiltrates of macrophages and activated lymphocytes, mainly CD8 cells (Figure 3). Keratinocyte necrosis is also typical of SJS and toxic epidermal necrolysis.7,8 Results of immunofluorescence studies are negative.
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Linear IgA bullous dermatosis is a subepidermal bullous disease that is defined by the presence of homogeneous linear deposits of IgA at the dermal-epidermal basement membrane.9 The clinical presentation of LABD is presented in Table 3 and Figures 4 and 5.10-13
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Even with a detailed history and physical examination, the diagnosis of LABD is challenging because of its heterogenous clinical presentations. Skin biopsy is essential for a definitive diagnosis.9 Histologically, LABD is characterized by subepidermal bullae with a predominantly neutrophilic infiltrate (Figure 6) and basal cell vacuolization. Linear IgA bullous dermatosis can be distinguished from erythema multiforme, SJS, and toxic epidermal necrolysis by the absence of lymphocytic accumulations at the dermal-epidermal interface, subepidermal cleft formation, and keratinocyte necrosis.9
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Direct immunofluorescence of perilesional skin is the standard for diagnosis of LABD. Direct immunofluorescence demonstrates a unique linear deposition of IgA along the basement membrane zone at the dermal-epidermal junction (Figure 7).7,9,10,13 Direct immunofluorescence results are negative in SJS.
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SJS and LABD—Treatment
There is a lack of consensus on the treatment of patients with SJS. On a
review of the literature, only two randomized studies were
cited.14,15
The first was a prospective study of 16 children with erythema multiforme
major (diagnosed based on criteria proposed by Huff et
al6). Ten patients
received bolus infusions of methylprednisolone (4 mg/kg/d) for 3 to 7 days,
while six patients received only supportive treatment. The early use of
corticosteroids compared to supportive treatment resulted in significant
reduction of fever, acute eruption, and
prostration.14
The second study was a prospective analysis of 67 consecutive patients with SJS who were promptly treated with corticosteroids and had a favorable outcome.15 In contrast, retrospective studies demonstrated increased morbidity (higher rates of infections, gastrointestinal bleeding, longer hospital stay, and overall complications) and mortality in corticosteroidtreated patients with erythema multiforme major than in those treated symptomatically.15,16 Nonetheless, controlled studies suggest that early treatment with systemic corticosteroids is beneficial.
Intravenous immune globulin therapy,17,18 ulinastatin (urinary trypsin inhibitor),19 plasmapheresis, cyclosporine, and cyclophosphamide may be beneficial for SJS.20-22 But, the data are insufficient and limited to case reports.
The treatment for patients with drug-induced LABD differs from treatment for patients with idiopathic LABD. Patients with drug-induced LABD have spontaneous resolution of skin lesions within 1 to 3 weeks after removal of the offending agent. Usually no other treatment is necessary. New lesions cease to appear 1 to 3 days after discontinuation of vancomycin.7,9,11,13 Corticosteroids and dapsone do not appear to influence the prognosis. Sequential biopsy specimens demonstrate resolution of the deposition of IgA without therapy.9
In contrast, it is recommended that patients with idiopathic LABD receive dapsone or sulfapyridine. With an inadequate response to dapsone, systemic corticosteroids are suggested.9,13 In refractory cases, interferon-alpha,2 colchicine,23 or co-trimoxazole may be tried.24 Therapy for idiopathic LABD is indicated, as only 10% to 50% of these cases have a spontaneous remission.9
SJS and LABD—Prognosis
Sepsis, generally caused by Staphylococcus aureus and
Pseudomonas aeruginosa, is the principal cause of death among
patients with SJS. Other important causes of death include gastrointestinal
bleeding and pulmonary
embolism.25 The
estimated mortality rate is less than 5% for SJS and approximately 30% for
toxic epidermal
necrolysis.8 The
patient's age, percentage of skin detachment, serum urea nitrogen level, and
level of neutropenia are the most important variables in determining
prognosis.25
The prognosis for patients with vancomycin-induced LABD is excellent. Once vancomycin is discontinued, the patient should be expected to have prompt improvement without residual skin lesions.9,12,23 The skin lesions usually resolve in 1 to 3 weeks, and no new lesions appear 1 to 3 days after the drug is stopped.7,9 If patients are rechallenged with vancomycin after having vancomycin-induced LABD, they may have a more severe recurrence, including a shorter latency and a longer course.7 Table 4 summarizes the treatment and prognosis for SJS and LABD.
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If SJS is diagnosed early, it seems that a brief course of systemic corticosteroids improves the outcome of the patients by reducing mortality, fever, and the period of an acute eruption. If the diagnosis is delayed and steroids are initiated late in the course of SJS, the prognosis may be worsened. Thus, a rapid diagnosis and therapeutic intervention are necessary in SJS.15,17 In contrast, for vancomycin-induced LABD, discontinuation of vancomycin is the only treatment necessary. The needless addition of corticosteroids increases the risk of adverse events such as psychosis, femoral head necrosis, hyperglycemia, and hypertension.
In either case, treatment of both diseases requires supportive therapy that includes pain control, fluid replacement, avoidance of any adhesive material, fluid and electrolyte management, nutritional support, and protection against infection and sepsis.8 Empiric, prophylactic antibiotics are not generally recommended.25
Prognosis is guarded in SJS and depends on the severity of the disorder and how prompt appropriate treatment is given. Conversely, the prognosis for LABD is excellent as long as the vancomycin is discontinued and not reintroduced. With the varied prognosis, early definitive diagnosis is essential.
In summary, early biopsy with immunofluorescence is necessary to ensure appropriate therapy is initiated and that appropriate prognosis is discussed with the patient when LABD and SJS are both potential diagnoses.
From the Milton S. Hershey Medical Center at Pennsylvania State University in Hershey, Pa.
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References |
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2. Korman TM, Turnidge JD, Grayson ML. Risk factors for adverse cutaneous reactions associated with intravenous vancomycin. J Antimicrob Chemother. 1997;39:315 -318.
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16. Assier H, Bastuji-Garin S, Revus J, Roujeau JC. Erythema multiforme with mucous membrane involvement and Stevens-Johnson syndrome are clinically different disorders with distinct causes. Arch Dermatol. 1995;131:539 -543.[Abstract]
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19. Inamo Y, Okubo T, Wada M, Fuchigami S, Hashimoto K, Fuchigami T, et al. Intravenous ulinastatin therapy for Stevens-Johnson syndrome and toxic epidermal necrolysis in pediatric patients. Int Arch Allergy Immunol. 2002;127:89 -94.[Medline]
20. Kamanabroo D, Schmitz-Landgraf W, Czarnetzki BM. Plasmaperesis in severe drug-induced toxic epidermal necrolysis. Arch Dermatol. 1985;121:1548 -1549.[Abstract]
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22. Heng MC, Allen SG. Efficacy of cyclophosphamide in toxic epidermal necrolysis: Clinical and pathophysiologic aspects. J Acad Dermatol. 1991;25:778 -786.
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26. Bickle KM, Roark TR, Hsu S. Autoimmune bullous dermatosis: A review. Am Fam Physician. 2002;65:1861 -1869.[Medline]
27. Yeung CK. Toxic epidermal necrolysis and Stevens-Johnson syndrome. Hong Kong Dermatology and Venereology Bulletin. 2002;10:57 -66.
This article has been cited by other articles:
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  S. E. Billet, K. R. Kortuem, L. E. Gibson, and R. el-Azhary A Morbilliform Variant of Vancomycin-Induced Linear IgA Bullous Dermatosis Arch Dermatol, June 1, 2008; 144(6): 774 - 778. [Abstract] [Full Text] [PDF]
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