Patient Presentation
A 53-year-old man with a past medical history significant for hypertension and chronic renal disease presented to an emergency department with a mucocutaneous eruption. He had been started on allopurinol approximately 1 month prior for hyperuricemia, and 1 week before he was seen by us had been evaluated for vesicles on the soft palate by his primary medical physician, who prescribed an antiviral medication for presumed herpes simplex. The patient denied any allergen exposure, ingestion, or prior surgical history and complained of difficulty swallowing and both pain and pruritus of his skin. After a rapid decline, he was transferred to our intensive care unit.
Physical examination revealed a well-developed and well-nourished but poorly responsive male in acute distress. He appeared toxic with low-grade fever but was able to communicate his discomfort. Multiple scattered flaccid bullae were present on the chest and shoulders with large denuded areas surrounded by patches of hyperpigmentation. Examination of the oral mucosa revealed scattered small erythematous patches and erosions without active bleeding. Ocular involvement was present with conjunctival injection and periorbital edema. Scattered flaccid bullae were also present on the penis and inguinal region. Background erythema was present on the chest, back, shoulders and groin and Nikolsky sign was positive on the shoulder’s erythematous patch.
Renal function studies included blood urea nitrogen of 46 mg/dl (normal: 5 to 22 mg/dl) and creatinine of 5.8 mg/dl (normal: 0.5 to 1.4 mg/dl). This was increased from his baseline creatinine of 2.4 mg/dl. Hepatic enzymes showed aspartate aminotransferase of 89 u/l (normal: 15 to 38 u/l) and alanine aminotransferase of 55 u/l (normal: 5 to 37 u/l). Complete blood cell count with differential revealed lymphocytosis with a mild eosinophilia.Diagnosis: Allopurinol-Induced DRESS Syndrome: A Delayed Drug Eruption
Diagnosis: Allopurinol-Induced DRESS Syndrome:
A Delayed Drug Eruption
The patient was diagnosed with allopurinol-induced DRESS (drug rash with eosinophilia and systemic symptoms; AI-DRESS) syndrome.1,2
The terminology encompassing drug eruptions can be confusing. Other diagnoses, including allopurinol hypersensitivity syndrome or allopurinol-induced erythema multiforme, may also be used depending on preference and subjective criteria. The term DRESS is useful in that it groups a variety of similar drug reactions into one diagnosis.3 DRESS syndrome most often involves the skin, kidneys, liver, lungs and heart but may involve the bone marrow, lymphatic system, thyroid and salivary/lacrimal glands.2,3 The goal is to utilize a diagnostic title that signifies the clinical finding, the causative agent and potential subsequent sequelae.
Drug rash with eosinophilia and systemic symptoms (DRESS) was proposed in 1996 by Bocquet et al.4 Subsequently, numerous reports followed of varying medications causing DRESS syndrome.
Pathophysiology
Allopurinol (4-hydroxypyrazole[3,4-d]pyrimidine) is a xanthine oxidase inhibitor that is commonly used to treat hyperuricemia. AI-DRESS is an uncommon drug eruption that often presents a diagnostic challenge due to its long delay, often occurring 6 weeks or longer between initiation of allopurinol and the resultant cutaneous eruption.5 Allopurinol is rapidly metabolized to oxypurinol, which requires adequate renal function for excretion.
The pathophysiology of allopurinol-induced drug eruptions is not certain; however, different theories including oxypurinol accumulation and reactivation of human herpes virus 6 are reported.6 More than 80% of reported cases of AI-DRESS had evidence of prior renal impairment, which may play a role in etiology.7 Hepatic involvement is also commonly seen with AI-DRESS, but not usually prior to the drug eruption.
Clinical Signs and Symptoms
Patients often present with a progressive systemic illness marked by fever, delayed diffuse skin reactions and eosinophilia.7 The average time to develop cutaneous manifestations of AI-DRESS is approximately 4 to 6 weeks; but, this may vary.1 The characteristic hypersensitivity reaction to allopurinol includes a pruritic eruption, fever, eosinophilia, hepatic abnormalities and renal failure. Lupton and Odom1 outline the characteristic laboratory ranges often seen. Briefly, patients present with a temperature approximating 39° to 39.5° C. White blood cell count is variable, yet typically elevated. Eosinophilia (>4%) is also variable but was present in up to 87% of patients.1 Renal and hepatic laboratory abnormalities are seen in 95% and 100%, respectively, of patients.1
Diagnosis is typically made by physical examination combined with knowledge of the inciting medication and then confirmed by laboratory and histologic confirmation. The histologic findings can be variable as with any drug reaction, but show an overall pattern similar to drug eruption versus erythema multiforme. As with the laboratory values, eosinophilia may vary within the biopsy specimen. Additionally, the stage at which the biopsy is performed will certainly dictate the histologic pattern seen.
Approximately 10% of patients taking allopurinol develop mild and self-limiting eruptions.1 Other reactions reported to occur in patients taking allopurinol include alopecia, ichthyosis, gastrointestinal upset, macular hemorrhages, granulomatous hepatitis, acute cholangitis, interstitial nephritis, temporal arteritis with seizures, agranulocytosis, bone marrow depression and hepatic necrosis.1
The clinical differential diagnosis based on physical examination is broad but quickly narrows with the appropriate history. Nevertheless, the differential diagnosis of the clinical examination primarily includes various drug eruptions, including erythema multiforme and toxic epidermal necrolysis, but may also include pressure-induced bullae, connective tissue disease, photoeruptive reactions and dermatoses with an infectious etiology.
The histologic differential diagnosis includes drug eruption, erythema multiforme, toxic epidermal necrolysis — primarily graft versus host disease. The degree of eosinophilia and the duration of the eruption warrant clinical correlation for accurate diagnosis.
Management
Treatment of AI-DRESS may vary based on the medical history of the patient and the severity of cutaneous manifestations. Systemic corticosteroids have been reported to be effective by multiple authors but remain controversial.1,9 Supportive care and topical corticosteroids are also useful. Patients admitted with this diagnosis are often cared for in the intensive-care setting, which allows for efficient multi-specialty care. Initiation of early wound care and supportive care interventions proves invaluable. We recommend specific instructions regarding wound care and dressings if performed by other services. Dietary considerations and intravenous fluid administration are critical. Cutaneous biopsy, laboratory examination (complete blood cell count, complete metabolic profile, renal function, hepatic function, coagulation studies, amylase, lipase), chest radiograph, cutaneous and blood cultures should be considered as appropriate for rapid diagnosis. Additionally, an IgA level may be warranted if intravenous immunoglobulin therapy is considered. Ophthalmologic consultation is also critical if the ocular mucosa is involved. Prompt diagnosis and discontinuation of allopurinol are certainly the key steps in management.10
Patient Presentation
A 53-year-old man with a past medical history significant for hypertension and chronic renal disease presented to an emergency department with a mucocutaneous eruption. He had been started on allopurinol approximately 1 month prior for hyperuricemia, and 1 week before he was seen by us had been evaluated for vesicles on the soft palate by his primary medical physician, who prescribed an antiviral medication for presumed herpes simplex. The patient denied any allergen exposure, ingestion, or prior surgical history and complained of difficulty swallowing and both pain and pruritus of his skin. After a rapid decline, he was transferred to our intensive care unit.
Physical examination revealed a well-developed and well-nourished but poorly responsive male in acute distress. He appeared toxic with low-grade fever but was able to communicate his discomfort. Multiple scattered flaccid bullae were present on the chest and shoulders with large denuded areas surrounded by patches of hyperpigmentation. Examination of the oral mucosa revealed scattered small erythematous patches and erosions without active bleeding. Ocular involvement was present with conjunctival injection and periorbital edema. Scattered flaccid bullae were also present on the penis and inguinal region. Background erythema was present on the chest, back, shoulders and groin and Nikolsky sign was positive on the shoulder’s erythematous patch.
Renal function studies included blood urea nitrogen of 46 mg/dl (normal: 5 to 22 mg/dl) and creatinine of 5.8 mg/dl (normal: 0.5 to 1.4 mg/dl). This was increased from his baseline creatinine of 2.4 mg/dl. Hepatic enzymes showed aspartate aminotransferase of 89 u/l (normal: 15 to 38 u/l) and alanine aminotransferase of 55 u/l (normal: 5 to 37 u/l). Complete blood cell count with differential revealed lymphocytosis with a mild eosinophilia.Diagnosis: Allopurinol-Induced DRESS Syndrome: A Delayed Drug Eruption
Diagnosis: Allopurinol-Induced DRESS Syndrome:
A Delayed Drug Eruption
The patient was diagnosed with allopurinol-induced DRESS (drug rash with eosinophilia and systemic symptoms; AI-DRESS) syndrome.1,2
The terminology encompassing drug eruptions can be confusing. Other diagnoses, including allopurinol hypersensitivity syndrome or allopurinol-induced erythema multiforme, may also be used depending on preference and subjective criteria. The term DRESS is useful in that it groups a variety of similar drug reactions into one diagnosis.3 DRESS syndrome most often involves the skin, kidneys, liver, lungs and heart but may involve the bone marrow, lymphatic system, thyroid and salivary/lacrimal glands.2,3 The goal is to utilize a diagnostic title that signifies the clinical finding, the causative agent and potential subsequent sequelae.
Drug rash with eosinophilia and systemic symptoms (DRESS) was proposed in 1996 by Bocquet et al.4 Subsequently, numerous reports followed of varying medications causing DRESS syndrome.
Pathophysiology
Allopurinol (4-hydroxypyrazole[3,4-d]pyrimidine) is a xanthine oxidase inhibitor that is commonly used to treat hyperuricemia. AI-DRESS is an uncommon drug eruption that often presents a diagnostic challenge due to its long delay, often occurring 6 weeks or longer between initiation of allopurinol and the resultant cutaneous eruption.5 Allopurinol is rapidly metabolized to oxypurinol, which requires adequate renal function for excretion.
The pathophysiology of allopurinol-induced drug eruptions is not certain; however, different theories including oxypurinol accumulation and reactivation of human herpes virus 6 are reported.6 More than 80% of reported cases of AI-DRESS had evidence of prior renal impairment, which may play a role in etiology.7 Hepatic involvement is also commonly seen with AI-DRESS, but not usually prior to the drug eruption.
Clinical Signs and Symptoms
Patients often present with a progressive systemic illness marked by fever, delayed diffuse skin reactions and eosinophilia.7 The average time to develop cutaneous manifestations of AI-DRESS is approximately 4 to 6 weeks; but, this may vary.1 The characteristic hypersensitivity reaction to allopurinol includes a pruritic eruption, fever, eosinophilia, hepatic abnormalities and renal failure. Lupton and Odom1 outline the characteristic laboratory ranges often seen. Briefly, patients present with a temperature approximating 39° to 39.5° C. White blood cell count is variable, yet typically elevated. Eosinophilia (>4%) is also variable but was present in up to 87% of patients.1 Renal and hepatic laboratory abnormalities are seen in 95% and 100%, respectively, of patients.1
Diagnosis is typically made by physical examination combined with knowledge of the inciting medication and then confirmed by laboratory and histologic confirmation. The histologic findings can be variable as with any drug reaction, but show an overall pattern similar to drug eruption versus erythema multiforme. As with the laboratory values, eosinophilia may vary within the biopsy specimen. Additionally, the stage at which the biopsy is performed will certainly dictate the histologic pattern seen.
Approximately 10% of patients taking allopurinol develop mild and self-limiting eruptions.1 Other reactions reported to occur in patients taking allopurinol include alopecia, ichthyosis, gastrointestinal upset, macular hemorrhages, granulomatous hepatitis, acute cholangitis, interstitial nephritis, temporal arteritis with seizures, agranulocytosis, bone marrow depression and hepatic necrosis.1
The clinical differential diagnosis based on physical examination is broad but quickly narrows with the appropriate history. Nevertheless, the differential diagnosis of the clinical examination primarily includes various drug eruptions, including erythema multiforme and toxic epidermal necrolysis, but may also include pressure-induced bullae, connective tissue disease, photoeruptive reactions and dermatoses with an infectious etiology.
The histologic differential diagnosis includes drug eruption, erythema multiforme, toxic epidermal necrolysis — primarily graft versus host disease. The degree of eosinophilia and the duration of the eruption warrant clinical correlation for accurate diagnosis.
Management
Treatment of AI-DRESS may vary based on the medical history of the patient and the severity of cutaneous manifestations. Systemic corticosteroids have been reported to be effective by multiple authors but remain controversial.1,9 Supportive care and topical corticosteroids are also useful. Patients admitted with this diagnosis are often cared for in the intensive-care setting, which allows for efficient multi-specialty care. Initiation of early wound care and supportive care interventions proves invaluable. We recommend specific instructions regarding wound care and dressings if performed by other services. Dietary considerations and intravenous fluid administration are critical. Cutaneous biopsy, laboratory examination (complete blood cell count, complete metabolic profile, renal function, hepatic function, coagulation studies, amylase, lipase), chest radiograph, cutaneous and blood cultures should be considered as appropriate for rapid diagnosis. Additionally, an IgA level may be warranted if intravenous immunoglobulin therapy is considered. Ophthalmologic consultation is also critical if the ocular mucosa is involved. Prompt diagnosis and discontinuation of allopurinol are certainly the key steps in management.10
Patient Presentation
A 53-year-old man with a past medical history significant for hypertension and chronic renal disease presented to an emergency department with a mucocutaneous eruption. He had been started on allopurinol approximately 1 month prior for hyperuricemia, and 1 week before he was seen by us had been evaluated for vesicles on the soft palate by his primary medical physician, who prescribed an antiviral medication for presumed herpes simplex. The patient denied any allergen exposure, ingestion, or prior surgical history and complained of difficulty swallowing and both pain and pruritus of his skin. After a rapid decline, he was transferred to our intensive care unit.
Physical examination revealed a well-developed and well-nourished but poorly responsive male in acute distress. He appeared toxic with low-grade fever but was able to communicate his discomfort. Multiple scattered flaccid bullae were present on the chest and shoulders with large denuded areas surrounded by patches of hyperpigmentation. Examination of the oral mucosa revealed scattered small erythematous patches and erosions without active bleeding. Ocular involvement was present with conjunctival injection and periorbital edema. Scattered flaccid bullae were also present on the penis and inguinal region. Background erythema was present on the chest, back, shoulders and groin and Nikolsky sign was positive on the shoulder’s erythematous patch.
Renal function studies included blood urea nitrogen of 46 mg/dl (normal: 5 to 22 mg/dl) and creatinine of 5.8 mg/dl (normal: 0.5 to 1.4 mg/dl). This was increased from his baseline creatinine of 2.4 mg/dl. Hepatic enzymes showed aspartate aminotransferase of 89 u/l (normal: 15 to 38 u/l) and alanine aminotransferase of 55 u/l (normal: 5 to 37 u/l). Complete blood cell count with differential revealed lymphocytosis with a mild eosinophilia.Diagnosis: Allopurinol-Induced DRESS Syndrome: A Delayed Drug Eruption
Diagnosis: Allopurinol-Induced DRESS Syndrome:
A Delayed Drug Eruption
The patient was diagnosed with allopurinol-induced DRESS (drug rash with eosinophilia and systemic symptoms; AI-DRESS) syndrome.1,2
The terminology encompassing drug eruptions can be confusing. Other diagnoses, including allopurinol hypersensitivity syndrome or allopurinol-induced erythema multiforme, may also be used depending on preference and subjective criteria. The term DRESS is useful in that it groups a variety of similar drug reactions into one diagnosis.3 DRESS syndrome most often involves the skin, kidneys, liver, lungs and heart but may involve the bone marrow, lymphatic system, thyroid and salivary/lacrimal glands.2,3 The goal is to utilize a diagnostic title that signifies the clinical finding, the causative agent and potential subsequent sequelae.
Drug rash with eosinophilia and systemic symptoms (DRESS) was proposed in 1996 by Bocquet et al.4 Subsequently, numerous reports followed of varying medications causing DRESS syndrome.
Pathophysiology
Allopurinol (4-hydroxypyrazole[3,4-d]pyrimidine) is a xanthine oxidase inhibitor that is commonly used to treat hyperuricemia. AI-DRESS is an uncommon drug eruption that often presents a diagnostic challenge due to its long delay, often occurring 6 weeks or longer between initiation of allopurinol and the resultant cutaneous eruption.5 Allopurinol is rapidly metabolized to oxypurinol, which requires adequate renal function for excretion.
The pathophysiology of allopurinol-induced drug eruptions is not certain; however, different theories including oxypurinol accumulation and reactivation of human herpes virus 6 are reported.6 More than 80% of reported cases of AI-DRESS had evidence of prior renal impairment, which may play a role in etiology.7 Hepatic involvement is also commonly seen with AI-DRESS, but not usually prior to the drug eruption.
Clinical Signs and Symptoms
Patients often present with a progressive systemic illness marked by fever, delayed diffuse skin reactions and eosinophilia.7 The average time to develop cutaneous manifestations of AI-DRESS is approximately 4 to 6 weeks; but, this may vary.1 The characteristic hypersensitivity reaction to allopurinol includes a pruritic eruption, fever, eosinophilia, hepatic abnormalities and renal failure. Lupton and Odom1 outline the characteristic laboratory ranges often seen. Briefly, patients present with a temperature approximating 39° to 39.5° C. White blood cell count is variable, yet typically elevated. Eosinophilia (>4%) is also variable but was present in up to 87% of patients.1 Renal and hepatic laboratory abnormalities are seen in 95% and 100%, respectively, of patients.1
Diagnosis is typically made by physical examination combined with knowledge of the inciting medication and then confirmed by laboratory and histologic confirmation. The histologic findings can be variable as with any drug reaction, but show an overall pattern similar to drug eruption versus erythema multiforme. As with the laboratory values, eosinophilia may vary within the biopsy specimen. Additionally, the stage at which the biopsy is performed will certainly dictate the histologic pattern seen.
Approximately 10% of patients taking allopurinol develop mild and self-limiting eruptions.1 Other reactions reported to occur in patients taking allopurinol include alopecia, ichthyosis, gastrointestinal upset, macular hemorrhages, granulomatous hepatitis, acute cholangitis, interstitial nephritis, temporal arteritis with seizures, agranulocytosis, bone marrow depression and hepatic necrosis.1
The clinical differential diagnosis based on physical examination is broad but quickly narrows with the appropriate history. Nevertheless, the differential diagnosis of the clinical examination primarily includes various drug eruptions, including erythema multiforme and toxic epidermal necrolysis, but may also include pressure-induced bullae, connective tissue disease, photoeruptive reactions and dermatoses with an infectious etiology.
The histologic differential diagnosis includes drug eruption, erythema multiforme, toxic epidermal necrolysis — primarily graft versus host disease. The degree of eosinophilia and the duration of the eruption warrant clinical correlation for accurate diagnosis.
Management
Treatment of AI-DRESS may vary based on the medical history of the patient and the severity of cutaneous manifestations. Systemic corticosteroids have been reported to be effective by multiple authors but remain controversial.1,9 Supportive care and topical corticosteroids are also useful. Patients admitted with this diagnosis are often cared for in the intensive-care setting, which allows for efficient multi-specialty care. Initiation of early wound care and supportive care interventions proves invaluable. We recommend specific instructions regarding wound care and dressings if performed by other services. Dietary considerations and intravenous fluid administration are critical. Cutaneous biopsy, laboratory examination (complete blood cell count, complete metabolic profile, renal function, hepatic function, coagulation studies, amylase, lipase), chest radiograph, cutaneous and blood cultures should be considered as appropriate for rapid diagnosis. Additionally, an IgA level may be warranted if intravenous immunoglobulin therapy is considered. Ophthalmologic consultation is also critical if the ocular mucosa is involved. Prompt diagnosis and discontinuation of allopurinol are certainly the key steps in management.10
