|Year : 2014 | Volume
| Issue : 5 | Page : 39-43
Phenylbutazone-induced generalized bullous fixed drug eruption masquerading Stevens-Johnson syndrome/toxic epidermal necrolysis
Hari Kishan Kumar Yadalla1, Anagha Ramesh Babu2
1 Department of Dermatology, Raja Rajeswari Medical College and Hospital, Kambipura, India
2 Department of Dermatology, MVJ Medical College and Research Hospital, Hoskote, Bangalore, Karnataka, India
|Date of Web Publication||19-Dec-2014|
Hari Kishan Kumar Yadalla
Skin Care Clinic, 70, Padma Nivasa, 3rd Cross MG Extension, HV Halli, Raja Rajeswari Nagar, Bangalore - 560 098, Karnataka
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Widespread bullous fixed drug eruption (FDE) is the most severe form of FDE and may be mistaken clinically for Stevens-Johnson syndrome or toxic epidermal necrolysis (SJS/TEN). Herein, we report a case of generalized bullous fixed drug eruption (GBFDE) with extensive epidermal necrosis and detachment mimicking SJS/TEN overlap and TEN. A 50-year-old female presented with sudden-onset widespread dusky red patches and denuded areas after intake of phenylbutazone [nonsteroidal anti-inflammatory drug (NSAID)] for her arthritis. Severe FDE was suspected due to lack of involvement of two mucosal sites and presence of mild constitutional symptoms. Histopathology of the lesion showed spongiosis, basal cell degeneration with numerous necrotic keratinocytes, and a superficial and deep perivascular infiltrate containing lymphocytes and eosinophils, along with melanin incontinence. These findings were consistent with FDE. The present paper highlights the clinical importance of severe bullous FDE mimicking SJS and TEN, and the necessity of histopathologic confirmation in such cases.
Keywords: Generalized bullous fixed drug eruption, histopathology, phenylbutazone
|How to cite this article:|
Yadalla HK, Babu AR. Phenylbutazone-induced generalized bullous fixed drug eruption masquerading Stevens-Johnson syndrome/toxic epidermal necrolysis. Int J Nutr Pharmacol Neurol Dis 2014;4, Suppl S1:39-43
|How to cite this URL:|
Yadalla HK, Babu AR. Phenylbutazone-induced generalized bullous fixed drug eruption masquerading Stevens-Johnson syndrome/toxic epidermal necrolysis. Int J Nutr Pharmacol Neurol Dis [serial online] 2014 [cited 2020 Nov 27];4, Suppl S1:39-43. Available from: https://www.ijnpnd.com/text.asp?2014/4/5/39/147465
| Introduction|| |
Fixed drug eruption (FDE) is a specific drug reaction that tends to recur in identical sites each time the responsible drug is taken. It is characterized by solitary or multiple round or oval erythematous patches with dusky red centers, some of which may progress to bulla formation. FDE lesions usually resolve in 7-10 days, often leaving behind hyperpigmentation. One characteristic feature is recurrence on the same sites a few hours after rechallenge with the same medication.  Initially reported in association with antipyrine, FDE can be associated with various analgesics, antibiotics, laxatives, and other medications. The exact incidence of FDE is not known, but it is suspected to vary greatly by geographic area.  With repeated challenges, additional patches or blistering lesions may arise and evolve into a severe generalized bullous form of FDE. , Generalized bullous FDE (GBFDE) is an extensive form of FDE characterized by multiple, large, ill-defined, dull, purplish-livid patches, at times with flaccid blisters.  Distribution of lesions is often symmetrical with a predilection for the extremities, genital and intertriginous sites. Mucosal sites are usually spared and constitutional symptoms are mild. GBFDE is defined as typical FDE lesions with blisters involving at least 10% of the body surface area on at least three of six different anatomic sites.  The overlapping clinical features of FDE, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN) make differentiation between them difficult, especially if FDE is multifocal and extensive. Nonsteroidal anti-inflammatory drugs (NSAIDs) are a commonly reported cause of FDEs, but the bullous and generalized variants are relatively rare. We present a case of multifocal bullous FDE due to phenylbutazone mimicking SJS/TEN and to highlight the importance of histopathology in differentiating these entities.
| Case Report|| |
A 50-year-old female patient presented to our OPD with history of reddish multiple fluid-filled lesions all over the body since 2 days. She gave history of intake of Tablet phenylbutazone for her arthritis which was prescribed by a local practitioner, just 6 h before the onset of skin lesions. Also, she gave history of similar lesions 1 year back, but of lesser severity. No other co-morbidities were noted. On examination, patient was febrile with pulse rate 58 beats/minute and blood pressure (BP) 100/70 mmHg. Cutaneous examination revealed multiple flaccid bullae with a livid hue on an erythematous base and well-defined hyperpigmented macules with surrounding erythema and few eroded areas present all over the body sparing the scalp [Figure 1], [Figure 2] and [Figure 3]. Crusting over lips was noted, buccal mucosa was normal, and there were no genital lesions. A Clinical diagnosis of bullous FDE was made with differentials of SJS/TEN.
|Figure 1: Multiple well-defined hyperpigmented macules with surrounding erythema and few vesicles, bullae, and eroded areas present all over the body|
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|Figure 2: Hyperpigmented macules with surrounding erythema and interspersed bullae seen over trunk and upper extremities|
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|Figure 3: Close-up view showing multiple flaccid bullae with a livid hue on an erythematous base|
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The patient was admitted for further care and management. Routine blood investigations showed high total count (11,400 cells/mm 3 ). Other blood parameters were normal. Electrocardiography (ECG) showed bradycardia. HIV, venereal disease research laboratory test (VDRL), and hepatitis B surface antigen (HBsAg) were non-reactive. Thyroid function test showed rise in thyroid stimulating hormone (TSH) suggestive of hypothyroidism. A skin biopsy was done from the suggestive lesion to confirm the diagnosis. Histopathology revealed spongiosis, basal cell degeneration with numerous necrotic keratinocytes, and a superficial and deep perivascular infiltrate containing lymphocytes, neutrophils, and eosinophils along with melanophages. These findings were consistent with FDE [Figure 4] and [Figure 5]. Hence, a final diagnosis of GBFDE secondary to phenylbutazone was made.
|Figure 4: Histopathology of low-power view showing intraepidermal vesiculation and necrotic keratinocytes with melanin incontinence cells having superficial and deep perivascular infiltration (H and E, ×10)|
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|Figure 5: High-power view showing dermal perivascular infiltrate consisting of lymphocytes, neutrophils, and eosinophils, along with notable melanin incontinence cells (H and E, ×40)|
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General measures with strict barrier nursing were followed, and the offending drug was immediately stopped. Tablet paracetamol thrice a day and IV fluids were administered for dehydration and bradycardia. Later the patient was started on Tablet prednisonlone 20 mg twice daily for a week and topical application of fusidic acid. The general condition of the patient improved within a day and all the skin lesions healed with hyperpigmentation within a week.
| Discussion|| |
TEN is the most severe form of drug eruption. , It represents the extreme expression in the spectrum of erythema multiforme (EM), SJS, and TEN. TEN is defined as extensive confluence of macules or flat atypical targetoid lesions, resulting in epidermal detachment over 30% of the Body surface area (BSA).  SJS is defined as epidermal detachment over less than 10% of the BSA plus widespread erythematous or purpuric macules, or flat atypical targets.
When the area of detachment is between 10 and 30%, the rash is classified as SJS/TEN overlap. FDE appears to have a similar spectrum of severity, ranging from isolated patches to generalized bullous lesions, with the most severe form indistinguishable from TEN clinically.
Although the bullous form of FDE is well recognized, only a few studies have emphasized its clinical resemblance to EM, SJS, and TEN. , Classically the pathogenesis of FDE is due to activation of intraepidermal CD8+ T cells. The presence of increased numbers of T lymphocyte subsets in both TEN and FDE , suggests a common pathogenesis for both these disorders, probably involving a cell-mediated cytotoxic response.
GBFDE is a rare variant of FDE. It is an extensive form of FDE characterized by multiple, large, ill-defined, dull, purplish-livid patches, at times with flaccid blisters.  GBFDE is defined as typical FDE lesions with blisters involving at least 10% of the body surface area on at least three of six different anatomic sites. Distribution of lesions is often symmetrical with a predilection for the extremities, genital and intertriginous sites. Mucosal sites are usually spared and constitutional symptoms are mild. Recovery is rapid and complete without sequelae. Medical history reveals drug intake (most often sulfonamides, barbiturates, quinine, and butazone) and prior episodes of lesions at the same sites, but of lesser extent following the intake of the offending drug. , Numerous drugs have been implicated to cause FDEs; these include antibacterials, antifungals, antiepileptics, anti-inflammatory drugs, and herbal supplements.  An FDE has even been reported following an influenza vaccination.  In recent studies, the most common offending agents were antimicrobials (39-65%) such as co-trimoxazole and dapsone, NSAIDs (16-35%), and antiepileptics (16-30%). 
If the diagnosis is uncertain, FDEs can be recreated with small increasing systemic doses of the offending agent, but a generalized eruption may result. Patch testing and intradermal skin testing are the alternative methods to confirm the diagnosis.  Time of onset of a patient's FDE can take days to weeks after first exposure to the offending drug, although FDEs typically present within minutes to hours (mean 2.1 h) after subsequent exposures.  Any skin or mucus membrane site can be involved, but some drugs are known to induce FDEs at specific sites. Tetracycline, for example, typically induces a solitary lesion on the glans penis. In approximately 30% of cases, an FDE will present with localized bullae. A GBFDE, however, is relatively rare, and when this occurs it can be confused with SJS or TEN. , Phenylbutazone-induced GBFDE is an uncommonly reported reaction.
GBFDE diagnosis is based on four criteria: (1) similar past reaction; (2) fewer than two mucus membranes involved, absence of spots or target lesions; (3) large, well-demarcated blisters and erosions; and (4) lesions and erosions on at least three different body sites. Two criteria are required for a probable case and three for a definite case. Differential diagnosis is made mostly on clinical features and sometimes substantiated by histology. Widespread bullous FDE may mimic SJS  and TEN  clinically. However, since widespread bullous FDE carries a more favorable prognosis than the other two, it is important to distinguish between them. In FDE, lesions occur quite early (within 10 h of drug intake); they may be multifocal and generally involve the same sites as were affected in the previous episodes. By contrast, recurrent lesions in SJS show no predilection for previously affected sites. In our patient, the picture was confusing due to multifocal nature of the disease. Rechallenge to note recurrence of lesions at similar sites as in the previous episodes is the most specific way to support the diagnosis of FDE. ,,,
Our patient had historical evidence of lesions at similar sites as in the first episode. If clinical and historical data are inadequate and rechallenge is impractical, a histologic differentiation between FDE, SJS, and TEN may help.  Epidermal changes cannot be differentiated and vary from a few scattered necrotic keratinocytes to full-thickness epidermal necrosis. Close examination of the dermis is helpful. In SJS and TEN, the infiltrate is lymphohistiocytic and tends to be located solely around the superficial plexus. In FDE, a mixed inflammatory infiltrate containing neutrophils and eosinophils (in addition to lymphocytes and histiocytes) is noted around superficial and deep plexuses, along with melanophages. ,, Presence of intraepidermal vesiculation with balloon degeneration and keratinocyte necrosis makes the diagnosis of FDE more likely. [Table 1] enumerates the salient features of GBFDE and SJS/TEN.
The most important and effective therapeutic measure in managing drug reactions is the discontinuation of the offending medication, if possible. Alternative medications with unrelated chemical structures should be substituted when available. The clinical consequences of medication cessation or substitution should be closely monitored. In the majority of patients, symptoms will resolve within 2 weeks if the diagnosis of drug hypersensitivity is correct. 
Additional therapy for drug hypersensitivity reactions as in GBFDE is largely supportive and symptomatic. Systemic corticosteroids may speed recovery in severe cases. Topical antibacterials, corticosteroids, and oral antihistamines may improve dermatologic symptoms. Non-eroded plaques can be treated with a potent topical corticosteroid. Erosions can be treated with fusidic acid or mupirocin and a dressing until the site is re-epithelialized. Post-inflammatory hyperpigmentation may persist for years and the patient should be advised to avoid excessive exposure and to use sunblock cream. The severe drug reactions of SJS and TEN require additional intensive therapy. 
Our case is being presented for its rarity and highlights the importance of considering severe bullous FDE in the differential diagnosis of patients with symptoms of SJS or TEN, and the necessity of histopathologic study to confirm such cases. The good outcome in these cases supports the notion that GBFDE may be associated with a more favorable prognosis than SJS/TEN.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5]