Pharmacology and therapeutics
Paracetamol induced Stevens-Johnson syndrome – toxic epidermal necrolysis overlap syndrome Sasmita Biswal, MBBS, MD, and Swayam Sourav Sahoo, M.PHARM
SCB Medical College & Hospital, Cuttack, Odisha, India Correspondence Sasmita Biswal, MBBS, MD VSS Medical College and Hospital Burla Odisha India E-mail: [email protected] Conflicts of interest: None.
Abstract Background Though any drug can be a potential cause of such hypersensitivity reactions, paracetamol, an over-the-counter drug used extensively as an analgesic and antipyretic agent, is considered to be relatively safe, with hepatotoxicity as a major adverse effect only in large doses. Materials and methods We report an instance of a severe case of SJS-TEN overlap syndrome in a 12-year-old girl, induced by three over-the-counter doses of 500 mg of paracetamol taken at 8-hour intervals for fever. Results and discussion Stevens-Johnson Syndrome and its severe variant toxic epidermal necrolysis (TEN) are idiosyncratic, delayed hypersensitivity inflammatory adverse drug reactions that are associated with increased morbidity and mortality. However, treatment with antibiotics and intravenous corticosteroids along with supportive therapy improved the course of the disorder. Conclusion This case report addresses the fact that severe hypersensitivity reactions can occur with paracetamol, which can be potentially dangerous and life threatening. It is hence important for the clinicians to be alert to such severe hypersensitivity reactions even with drugs which are considered to be potentially safe such as paracetamol.
Introduction
1042
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are hypersensitive life-threatening dermatological conditions caused by viral infections, malignancies, or adverse drug reactions to any drug.1 Mucocutaneous nonpruritic lesions appear in clusters in SJS, while TEN is characterized by multiple large blisters that subsequently coalesce with extensive sloughing of skin and mucous membranes.2 The difference between the two is the severity and extent of epidermal detachment; it is less than 10% in SJS, more than 30% in TEN, and 10–30% in SJS/TEN overlap syndrome.3 Paracetamol is one of the most extensively used overthe-counter analgesics and antipyretics, which in recommended doses its adverse effects are usually mild to almost nonexistent.4 The World Health Organization also recommends paracetamol use in children with temperature greater than 38.5°C, suggesting its well-established role as a pediatric medicine. We report a rare case of SJS/ TEN overlap syndrome in a previously healthy child, after three 500 mg paracetamol tablets given at an interval of eight hours. International Journal of Dermatology 2014, 53, 1042–1044
An 11-year-old female child with no comorbid condition developed high fever of 39°C for which she took one tablet of 500 mg paracetamol as over-the-counter drug, after which the fever subsided only to recur the
Figure 1 Bilateral conjunctivitis, and edema, eroded and hemorrhagic crusting of lips and eyelids ª 2013 The International Society of Dermatology
Biswal and Sahoo
Figure 2 Easily detachable plaques (over 3 cm wide) due to coalesced bullae, with severe desquamation over 20% of the body surface with positive Nikolsky’s sign (on the face, limbs, abdomen, and back) which peeled off the next day
next morning. On taking the same dose, she developed a few rashes and edematous lips with burning sensation in her eyes. Unfortunately, persistent high fever compelled her to take the third dose of paracetamol after which she reported to our emergency department with generalized skin eruptions, mucosal erosions, and fever. On general examination, she was febrile (38.8°C) and lethargic, with skin rashes and occasional flaccid, large bullae over her body. It was diagnosed as a hypersensitivity reaction, and she was administered intravenous ketorolac (30 mg) and discharged. She returned within 24 hours with a widespread rash covering approximately 80% of the total body surface with 40% of intact bullae, bilateral conjunctivitis, edema, and eroded and hemorrhagic crusting of lips and eyelids with blisters on the genitalia (Figs. 1 and 2). There were large easily detachable plaques (over 3 cm wide) due to coalesced bullae, with severe desquamation over 20% of the body surface with a positive Nikolsky’s sign (on the face, limbs, abdomen, and back), which peeled off the next day (Fig. 1). The oral cavity was also blistered and eroded, causing difficulty in eating. Histological analysis of the peeled off skin revealed full-thickness epidermal necrosis due to extensive keratinocyte apoptosis. Her heart rate was 110/min, blood pressure was 110/80 mmHg, hemoglobin 10.3 g/dl, leukocytes 4.6 9 109/l, neutrophils 84%, lymphocytes 12.0%, eosinophils 0.2%, platelets 129 9 109/l, serum sodium 140 mM, potassium 3.3 mM, chloride 108, bicarbonate 18.8 mM, and serum albumin 1.2 g/dl. All other tests were within normal limits. There were episodes of diarrhea and itching with paracetamol use in the past and after intake of wheat products, potatoes, and certain ª 2013 The International Society of Dermatology
Paracetamol and SJS-TEN syndrome
Pharmacology and therapeutics
vegetables. Apart from this, other personal and family history were not suggestive. Supportive and symptomatic treatment included 100 mg of hydrocortisone every eight hours, and clemastine 1 mg intravenously every 12 hours for five days along with gentamicin eye drops, clobetasol ointment for cutaneous lesions, 0.05% fluticasone propionate cream for facial lesions, and mouthwash for oral hygiene. During her hospital stay, she had dysphagia, which suggested esophageal involvement of SJS-TEN overlap for which she was kept on a soft semi-solid diet. Hypokalemia (3.3 mM) and reduced bicarbonate levels (18.8 mM) were corrected by potassium and fluid supplements. She responded to the administered treatment protocol and on subsidence of the rashes, she was discharged on the 10th day with oral prednisolone, which tapered off over two weeks, cetrizine, and topical medications. Exposure to the sun was avoided by sun blocks due to the sequelae of scarring and hyperpigmentation. Rechallenge was not done, as it was clinically unjustifiable and ethically unacceptable. However, SJS and TEN are described as very frequent druginduced hypersensitive reactions, but the underlying pathophysiological mechanism is still unknown. A number of theories have been proposed, one of which is the role of an immunological-based mechanism. SJS can be differentiated from other skin conditions on three clinical criteria: the pattern of individual skin lesions; distribution of lesions; and extent of epidermal detachment. The characteristic findings in SJS are widespread erythematous or purpuric macules, which form flat atypical target lesions as the disease progresses to cause full thickness epithelial necrosis.2 However, our patient had developed macules that progressed to form vesicular and target lesions. The lesions were widespread as compared to erythema multiforme, another form of drug hypersensitive reaction, which is usually localized. Epidermal detachment was also seen in our patient, which was suggestive of TEN. The degree of confluence of lesions was higher in our patient than that found in SJS alone but lesser as compared to TEN. It was diagnosed as drug-induced based upon the fact that a temporal relationship with paracetamol existed and that the patient could correlate the repeated exposure to paracetamol with increased severity of the symptoms. The initial step in the management of such patients with drug-induced SJS is immediate withdrawal of the offending agent followed by supportive care and steroids.5,6 Management with steroids, however, remains debatable, as their use may be associated with increased wound healing time, risk of infection, and incidence of gastrointestinal bleeding.7,8 A better option is the use of intravenous immunoglobulins when given in combination International Journal of Dermatology 2014, 53, 1042–1044
1043
1044
Pharmacology and therapeutics
Paracetamol and SJS-TEN syndrome
with corticosteroids.9 However, their exorbitant cost limits their use in developing countries. A literature search revealed that Oxicam nonsteroidal anti-inflammatory drugs and sulfonamides are the most commonly implicated causative factor of SJS and TEN overlap syndrome in the United States.1n However, this is the first report of SJS/TEN overlap due to paracetamol, and there was a temporal relationship between paracetamol use with severity of the symptoms, and no other drug had been used during the occurrence of the syndrome. It is important for clinicians to be alert to such severe hypersensitivity reactions even with drugs considered potentially safe, such as paracetamol. References 1 Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Arch Dermatol 1990; 126: 43–44. 2 Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129: 92–96. 3 Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956; 68: 355–361.
International Journal of Dermatology 2014, 53, 1042–1044
Biswal and Sahoo
4 Meremikwu M, Oyo-Ita A. Paracetamol for treating fever in children. Cochrane Database Syst Rev 2002: CD003676. 5 Kelemen JJ, Cioffii WG, McManus WF, et al. Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995; 180: 273–278. 6 Halebian PH, Corder VJ, Madden MR, et al. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986; 204: 503–512. 7 Patterson R, Miller M, Kaplan M, et al. Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 1994; 73: 27–34. 8 Chen J, Wang B, Zeng Y, et al. High-dose intravenous immunoglobulins in the treatment of Stevens Johnson syndrome and toxic epidermal necrolysis in Chinese patients: a retrospective study of 82 cases. Eur J Dermatol 2010; 20: 743–747. 9 French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharmacol 2006; 6: 543–549. 10 Fernando SL, Broadfoot AJ. Prevention of severe cutaneous adverse drug reactions: the emerging value of pharmacogenetic screening. CMAJ 2010; 182: 476–480.
ª 2013 The International Society of Dermatology
Paracetamol induced Stevens-Johnson syndrome – toxic epidermal necrolysis overlap syndrome Sasmita Biswal, MBBS, MD, and Swayam Sourav Sahoo, M.PHARM
SCB Medical College & Hospital, Cuttack, Odisha, India Correspondence Sasmita Biswal, MBBS, MD VSS Medical College and Hospital Burla Odisha India E-mail: [email protected] Conflicts of interest: None.
Abstract Background Though any drug can be a potential cause of such hypersensitivity reactions, paracetamol, an over-the-counter drug used extensively as an analgesic and antipyretic agent, is considered to be relatively safe, with hepatotoxicity as a major adverse effect only in large doses. Materials and methods We report an instance of a severe case of SJS-TEN overlap syndrome in a 12-year-old girl, induced by three over-the-counter doses of 500 mg of paracetamol taken at 8-hour intervals for fever. Results and discussion Stevens-Johnson Syndrome and its severe variant toxic epidermal necrolysis (TEN) are idiosyncratic, delayed hypersensitivity inflammatory adverse drug reactions that are associated with increased morbidity and mortality. However, treatment with antibiotics and intravenous corticosteroids along with supportive therapy improved the course of the disorder. Conclusion This case report addresses the fact that severe hypersensitivity reactions can occur with paracetamol, which can be potentially dangerous and life threatening. It is hence important for the clinicians to be alert to such severe hypersensitivity reactions even with drugs which are considered to be potentially safe such as paracetamol.
Introduction
1042
Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are hypersensitive life-threatening dermatological conditions caused by viral infections, malignancies, or adverse drug reactions to any drug.1 Mucocutaneous nonpruritic lesions appear in clusters in SJS, while TEN is characterized by multiple large blisters that subsequently coalesce with extensive sloughing of skin and mucous membranes.2 The difference between the two is the severity and extent of epidermal detachment; it is less than 10% in SJS, more than 30% in TEN, and 10–30% in SJS/TEN overlap syndrome.3 Paracetamol is one of the most extensively used overthe-counter analgesics and antipyretics, which in recommended doses its adverse effects are usually mild to almost nonexistent.4 The World Health Organization also recommends paracetamol use in children with temperature greater than 38.5°C, suggesting its well-established role as a pediatric medicine. We report a rare case of SJS/ TEN overlap syndrome in a previously healthy child, after three 500 mg paracetamol tablets given at an interval of eight hours. International Journal of Dermatology 2014, 53, 1042–1044
An 11-year-old female child with no comorbid condition developed high fever of 39°C for which she took one tablet of 500 mg paracetamol as over-the-counter drug, after which the fever subsided only to recur the
Figure 1 Bilateral conjunctivitis, and edema, eroded and hemorrhagic crusting of lips and eyelids ª 2013 The International Society of Dermatology
Biswal and Sahoo
Figure 2 Easily detachable plaques (over 3 cm wide) due to coalesced bullae, with severe desquamation over 20% of the body surface with positive Nikolsky’s sign (on the face, limbs, abdomen, and back) which peeled off the next day
next morning. On taking the same dose, she developed a few rashes and edematous lips with burning sensation in her eyes. Unfortunately, persistent high fever compelled her to take the third dose of paracetamol after which she reported to our emergency department with generalized skin eruptions, mucosal erosions, and fever. On general examination, she was febrile (38.8°C) and lethargic, with skin rashes and occasional flaccid, large bullae over her body. It was diagnosed as a hypersensitivity reaction, and she was administered intravenous ketorolac (30 mg) and discharged. She returned within 24 hours with a widespread rash covering approximately 80% of the total body surface with 40% of intact bullae, bilateral conjunctivitis, edema, and eroded and hemorrhagic crusting of lips and eyelids with blisters on the genitalia (Figs. 1 and 2). There were large easily detachable plaques (over 3 cm wide) due to coalesced bullae, with severe desquamation over 20% of the body surface with a positive Nikolsky’s sign (on the face, limbs, abdomen, and back), which peeled off the next day (Fig. 1). The oral cavity was also blistered and eroded, causing difficulty in eating. Histological analysis of the peeled off skin revealed full-thickness epidermal necrosis due to extensive keratinocyte apoptosis. Her heart rate was 110/min, blood pressure was 110/80 mmHg, hemoglobin 10.3 g/dl, leukocytes 4.6 9 109/l, neutrophils 84%, lymphocytes 12.0%, eosinophils 0.2%, platelets 129 9 109/l, serum sodium 140 mM, potassium 3.3 mM, chloride 108, bicarbonate 18.8 mM, and serum albumin 1.2 g/dl. All other tests were within normal limits. There were episodes of diarrhea and itching with paracetamol use in the past and after intake of wheat products, potatoes, and certain ª 2013 The International Society of Dermatology
Paracetamol and SJS-TEN syndrome
Pharmacology and therapeutics
vegetables. Apart from this, other personal and family history were not suggestive. Supportive and symptomatic treatment included 100 mg of hydrocortisone every eight hours, and clemastine 1 mg intravenously every 12 hours for five days along with gentamicin eye drops, clobetasol ointment for cutaneous lesions, 0.05% fluticasone propionate cream for facial lesions, and mouthwash for oral hygiene. During her hospital stay, she had dysphagia, which suggested esophageal involvement of SJS-TEN overlap for which she was kept on a soft semi-solid diet. Hypokalemia (3.3 mM) and reduced bicarbonate levels (18.8 mM) were corrected by potassium and fluid supplements. She responded to the administered treatment protocol and on subsidence of the rashes, she was discharged on the 10th day with oral prednisolone, which tapered off over two weeks, cetrizine, and topical medications. Exposure to the sun was avoided by sun blocks due to the sequelae of scarring and hyperpigmentation. Rechallenge was not done, as it was clinically unjustifiable and ethically unacceptable. However, SJS and TEN are described as very frequent druginduced hypersensitive reactions, but the underlying pathophysiological mechanism is still unknown. A number of theories have been proposed, one of which is the role of an immunological-based mechanism. SJS can be differentiated from other skin conditions on three clinical criteria: the pattern of individual skin lesions; distribution of lesions; and extent of epidermal detachment. The characteristic findings in SJS are widespread erythematous or purpuric macules, which form flat atypical target lesions as the disease progresses to cause full thickness epithelial necrosis.2 However, our patient had developed macules that progressed to form vesicular and target lesions. The lesions were widespread as compared to erythema multiforme, another form of drug hypersensitive reaction, which is usually localized. Epidermal detachment was also seen in our patient, which was suggestive of TEN. The degree of confluence of lesions was higher in our patient than that found in SJS alone but lesser as compared to TEN. It was diagnosed as drug-induced based upon the fact that a temporal relationship with paracetamol existed and that the patient could correlate the repeated exposure to paracetamol with increased severity of the symptoms. The initial step in the management of such patients with drug-induced SJS is immediate withdrawal of the offending agent followed by supportive care and steroids.5,6 Management with steroids, however, remains debatable, as their use may be associated with increased wound healing time, risk of infection, and incidence of gastrointestinal bleeding.7,8 A better option is the use of intravenous immunoglobulins when given in combination International Journal of Dermatology 2014, 53, 1042–1044
1043
1044
Pharmacology and therapeutics
Paracetamol and SJS-TEN syndrome
with corticosteroids.9 However, their exorbitant cost limits their use in developing countries. A literature search revealed that Oxicam nonsteroidal anti-inflammatory drugs and sulfonamides are the most commonly implicated causative factor of SJS and TEN overlap syndrome in the United States.1n However, this is the first report of SJS/TEN overlap due to paracetamol, and there was a temporal relationship between paracetamol use with severity of the symptoms, and no other drug had been used during the occurrence of the syndrome. It is important for clinicians to be alert to such severe hypersensitivity reactions even with drugs considered potentially safe, such as paracetamol. References 1 Chan HL, Stern RS, Arndt KA, et al. The incidence of erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis. Arch Dermatol 1990; 126: 43–44. 2 Bastuji-Garin S, Rzany B, Stern RS, et al. Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme. Arch Dermatol 1993; 129: 92–96. 3 Lyell A. Toxic epidermal necrolysis: an eruption resembling scalding of the skin. Br J Dermatol 1956; 68: 355–361.
International Journal of Dermatology 2014, 53, 1042–1044
Biswal and Sahoo
4 Meremikwu M, Oyo-Ita A. Paracetamol for treating fever in children. Cochrane Database Syst Rev 2002: CD003676. 5 Kelemen JJ, Cioffii WG, McManus WF, et al. Burn center care for patients with toxic epidermal necrolysis. J Am Coll Surg 1995; 180: 273–278. 6 Halebian PH, Corder VJ, Madden MR, et al. Improved burn center survival of patients with toxic epidermal necrolysis managed without corticosteroids. Ann Surg 1986; 204: 503–512. 7 Patterson R, Miller M, Kaplan M, et al. Effectiveness of early therapy with corticosteroids in Stevens-Johnson syndrome: experience with 41 cases and a hypothesis regarding pathogenesis. Ann Allergy 1994; 73: 27–34. 8 Chen J, Wang B, Zeng Y, et al. High-dose intravenous immunoglobulins in the treatment of Stevens Johnson syndrome and toxic epidermal necrolysis in Chinese patients: a retrospective study of 82 cases. Eur J Dermatol 2010; 20: 743–747. 9 French LE, Trent JT, Kerdel FA. Use of intravenous immunoglobulin in toxic epidermal necrolysis and Stevens-Johnson syndrome: our current understanding. Int Immunopharmacol 2006; 6: 543–549. 10 Fernando SL, Broadfoot AJ. Prevention of severe cutaneous adverse drug reactions: the emerging value of pharmacogenetic screening. CMAJ 2010; 182: 476–480.
ª 2013 The International Society of Dermatology
