Contact Dermatitis

The drug hypersensitivity syndrome (DHS) is a rare but serious and potentially life-threatening reaction to common drugs in predisposed individuals. The syndrome is a triad of fever, skin eruption, and internal organ involvement. Prompt identification and discontinuation of the offending drug with symptomatic treatment of toxic effects is the mainstay of therapy for DHS.

Case Report

A 28-year-old paraplegic woman (secondary to spina bifida) was admitted to the hospital for vacuum-assisted closure of a chronic nonhealing left ankle ulcer of 21 months' duration. The patient was on oral ciprofloxacin 500 mg twice daily1 and oral clindamycin hydrochloride 300 mg 4 times daily for treatment of repeated bacterial infections. While in the hospital, a bone scan was performed and the results confirmed osteomyelitis of the left talonavicular region. The patient's oral therapeutic regimen was discontinued and she was given piperacillin-tazobactam (PT) 3.375 g by intravenous infusion every 6 hours. She responded well to this treatment, with a subsequent decrease in ulcer size. Two weeks following therapy, the patient developed fever, skin rash, nausea, and headache. The next day, the patient became anuric. There was no family history of renal or hepatic disease. Results of a physical examination revealed the patient was febrile (temperature, 39.4°C); a wide-spread, symmetrical, morbilliform skin eruption was noted on her face, trunk, forearms, and legs. She had slight facial edema, with erythema and enlarged cervical lymph nodes bilaterally. Results of laboratory investigations revealed the patient had an elevated white blood cell count of 18.4X109/L (reference range, 4.5–11.0X109/L), with a differential of 62% lymphocytes, 23% neutrophils, 5% bands, 2% monocytes, and 8% eosinophils (reference ranges, 34%, 56%, 3%, 4%, and 2.7%, respectively). The patient's liver enzyme levels were elevated including aspartate aminotransferase, 1545 U/L (reference range, 20–48 U/L); alanine aminotransferase, 383 U/L (reference range, 10–40 U/L); alkaline phosphatase, 297 U/L (reference range, 50–120 U/L); γ-glutamyltransferase, 235 U/L (reference range, 0–30 U/L); and lactate dehydrogenase, 5638 U/L (reference range, 50–200 U/L); synthetic liver function remained within reference range. The patient's serum creatinine (SCr) level was 212 μmol/L (reference range, 53–106 μmol/L), with a baseline of 45 μmol/L. Results of a urinalysis were within reference range; results of a urine culture were negative. An ultrasound of the abdomen did not reveal a cause for renal failure or liver dysfunction. A diagnosis of PT-induced hypersensitivity reaction with acute toxic hepatitis and interstitial nephritis was made. The intravenous antibiotics were discontinued and the patient was given prednisone and hemodialysis 3 times weekly. Her SCr levels fluctuated during the treatment, reaching a peak of 461 μmol/L. The patient responded well to therapy, though her liver enzyme and SCr levels did not return to baseline at the time of hospital discharge (aspartate aminotransferase, 42 U/L; alanine aminotransferase, 72 U/L; alkaline phosphatase, 72 U/L; γ-glutamyltransferase, 122 U/L; lactate dehydrogenase, 300 U/L; SCr, 123 μmol/L). The patient was followed as an outpatient.

Comment
Drug hypersensitivity syndrome (DHS) is characterized by a triad of fever, skin eruption, and internal organ involvement.2 DHS also is known as DRESS syndrome (drug rash with eosinophilia and systemic symptoms)3 and DIDMOHS (drug-induced delayed multiorgan hypersensitivity syndrome).4 DHS also has been described as multisystem hypersensitivity, pseudolymphoma, febrile mucocutaneous syndrome, Kawasakilike syndrome, mononucleosislike illness, and graft-versus-hostlike illness.5 DHS is a result of a specific, severe, idiosyncratic reaction. The incidence of DHS ranges between 1 in 1000 and 1 in 10,000 exposures. DHS occurs more often in women than in men.5 A number of drugs have been reported to cause this syndrome, including sulfonamide antibiotics, trimethoprim, dapsone, and aromatic anticonvulsants (eg, phenytoin, phenobarbital, carbamazepine),6-9 as well as lamotrigine,10 minocycline,11-12 and allopurinol.13-14 Antiviral medications such as abacavir and nevirapine also have been reported.15 DHS occurs on the first exposure to the offending drug, with the symptoms starting 2 to 6 weeks after initiation of the medication. Reexposure to the same offending drug may cause symptoms to develop within 24 hours. The symptoms may last for weeks or even months after discontinuing the medication. The most common presentations in patients with DHS are fever, which ranges from 38°C to 40°C and occurs in 85% of cases, malaise, pharyngitis, and cervical lymphadenopathy. A generalized exanthematous morbilliform rash develops in 75% of cases, either with or soon after the fever. Cutaneous manifestations can present in a number of ways including exfoliative erythroderma, follicular or nonfollicular pustules, purpuric lesions or blisters, and tense bullae induced by dermal edema.5 The face, upper trunk, and extremities usually are involved. Facial edema is a common finding. Additionally, hypotension, bleeding, interstitial nephritis, arthralgia, arthritis, myositis, thyroiditis, pneumonitis, respiratory distress syndrome, pericarditis, myocarditis, pancreatitis, colitis, orchitis, encephalitis, and aseptic meningitis have been reported.5 Hematologic involvement includes prominent eosinophilia, which occurs in 90% of cases; mononucleosislike atypical lymphocytosis, which occurs in 40% of cases; neutrophilia or neutropenia; thrombocytopenia; and hemolytic anemia. Elevated levels of liver transaminase, alkaline phosphatase, bilirubin, and prothrombin time are seen in 50% of cases. Fulminant hepatitis is the major cause of death associated with this syndrome, occurring in 5% to 10% of cases.16 Pathogenesis of DHS—The pathogenesis of DHS is unknown but likely is multifactorial. Exposure to a drug is the causal agent, but it is not enough to elicit DHS. It is postulated that a specific alteration in the metabolism and detoxification of a particular drug can occur in phenotypic susceptible individuals, which leads to an increased risk of toxic consequences of reactive oxidative drug metabolites.2,5,17 Aromatic anticonvulsants are metabolized by cytochrome P450 to reactive metabolites that are detoxified by epoxide hydroxylase. If the detoxification process is defective, the toxic metabolite acts as a hapten, initiating an immune response. In 70% to 75% of DHS cases, cross-reactivity is shown between the different aromatic anticonvulsants. Lamotrigine has been reported to cause DHS, though it is not one of the aromatic anticonvulsants. The concurrent use of lamotrigine with valproic acid increases the risk of reaction because valproic acid prolongs the elimination half-life of lamotrigine.5,18 There is a familial susceptibility of hypersensitivity to anticonvulsants, thus counseling of family members is essential.2,19 Sulfonamide antibiotics are metabolized by slow acetylators to reactive metabolites, mainly hydroxylamines and nitroso compounds, causing cytotoxicity. In patients with glutathione deficiency, detoxification of these toxic metabolites is not possible and can lead to DHS. There is an increased risk (25%) of first-degree relatives having a similar defect.20 Aromatic amines (eg, dapsone, acebutolol, procainamide) are metabolized to the same compounds and hence there is a potential for cross-reactivity occurring in these individuals. There is no cross-reactivity between sulfonamides and other nonaromatic amines such as furosemide, thiazide diuretics, acetazolamide, celecoxib, and sulfonylureas.21 The drugs associated with DHS are summarized in the Table.

The association of the human herpesvirus family—specifically, human herpesvirus 6—and DHS has been questioned. Descamps et al22 explored the issues regarding viral infection and DHS. Hashimoto et al23 suggested that the prolonged course, slow resolution, and/or relapse of cases of DHS may be attributed to human herpesvirus 6 reactivation. Condat et al24 have shown that reactivation of human herpesvirus 6 coincides with the course of DHS, but the direct causal effect of the virus is yet to be established. Patients with human immunodeficiency virus are at a higher susceptibility to toxic drug metabolites.25 This susceptibility could be explained by the reduced level of glutathione, selenium, and other antioxidants in these patients. Glutathione plays an important role in the antioxidant defense of cells. Immune mechanisms also are thought to contribute to the pathogenesis of DHS in these patients, though the immune mechanism of DHS still is not clear. The changes in DHS suggest both TH1 and TH2 cytokine production. Transient increase in the level of interleukin 5 has been demonstrated early in the disease process in some patients.26 Interleukin 5 released by activated T lymphocytes contributes to the eosinophilia. The differential diagnosis of DHS includes other drug eruptions, viral infection, idiopathic hypereosinophilic syndrome, pseudolymphoma, serum sicknesslike illness, and drug-induced vasculitis. PT is an extended-spectrum synthetic penicillin combined with β-lactamase inhibitor. PT is effective against methicillin-sensitive, coagulase-negative staphylococci; Streptococcus pyogenes; and penicillin-sensitive Streptococcus pneumoniae, Enterobacteriaceae, Haemophilus influenza, Moraxella catarrhalis, Pseudomonus aeruginosa, Enterococcus faecalis, and anaerobes. The main indications of PT include nosocomial pneumonia, intra-abdominal infections, skin and soft tissue infections, pelvic inflammatory disease, septicemia, neutropenic fever, osteomyelitis, and septic arthritis.27 Multiple adverse effects with the administration of PT have been reported, including fever, leucopenia, thrombocytopenia, hemolytic anemia, hypercoagulopathy, and transient bone marrow suppression.28-29 Acute interstitial nephritis,30-31 encephalopathy,32 recurrent paralysis,33 allergic skin eruptions,34 and hemorrhagic cystitis35 have been documented after the administration of PT. There is only one reported case (a letter to the editor36) of hypersensitivity reaction during prolonged use of PT in the treatment of osteomyelitis; the patient developed rash, lymphadenopathy, and hematologic changes. Our patient developed DHS after 2 weeks of initiating therapy with PT for osteomyelitis. The reaction caused severe parenchymal nephritis, leading to anuria that necessitated hemodialysis. Interestingly, our patient complained of numbness and paresthesia of the forearm during intravenous PT infusion 2 days prior to developing DHS; a similar symptom was reported by Behbahani and Kostman36 with numbness of the patient's upper chest during intravenous infusion. Treatment of DHS depends on discontinuation of the offending drug early in the course of the disease. Adding systemic corticosteroids (0.5–1.0 mg/kg/d) to the treatment regimen is essential, especially in life-threatening involvement of the lungs, heart, liver, or kidneys. Systemic corticosteroids should be slowly tapered to avoid a relapse of nephritis and skin eruption. Topical steroids have been used in milder cases of DHS to improve the cutaneous manifestations. Interferon-γ has been used in a few cases of long-standing DHS,37 but studies are not available to establish the role of this drug in treatment. 

Conclusion

DHA is an iatrogenic disease that affects multiple organs. The pathogenesis of DHS still is largely unclear. Multiple factors likely are responsible for DHS, such as the offending drug with a drug-drug interaction, susceptible individuals with impaired ability to detoxify toxic drug metabolites, immunologic factors, and viral infection. Identification and discontinuation of the offending drug is crucial, as is a multidisciplinary approach in managing affected patients.

The drug hypersensitivity syndrome (DHS) is a rare but serious and potentially life-threatening reaction to common drugs in predisposed individuals. The syndrome is a triad of fever, skin eruption, and internal organ involvement. Prompt identification and discontinuation of the offending drug with symptomatic treatment of toxic effects is the mainstay of therapy for DHS.

Case Report

A 28-year-old paraplegic woman (secondary to spina bifida) was admitted to the hospital for vacuum-assisted closure of a chronic nonhealing left ankle ulcer of 21 months' duration. The patient was on oral ciprofloxacin 500 mg twice daily1 and oral clindamycin hydrochloride 300 mg 4 times daily for treatment of repeated bacterial infections. While in the hospital, a bone scan was performed and the results confirmed osteomyelitis of the left talonavicular region. The patient's oral therapeutic regimen was discontinued and she was given piperacillin-tazobactam (PT) 3.375 g by intravenous infusion every 6 hours. She responded well to this treatment, with a subsequent decrease in ulcer size. Two weeks following therapy, the patient developed fever, skin rash, nausea, and headache. The next day, the patient became anuric. There was no family history of renal or hepatic disease. Results of a physical examination revealed the patient was febrile (temperature, 39.4°C); a wide-spread, symmetrical, morbilliform skin eruption was noted on her face, trunk, forearms, and legs. She had slight facial edema, with erythema and enlarged cervical lymph nodes bilaterally. Results of laboratory investigations revealed the patient had an elevated white blood cell count of 18.4X109/L (reference range, 4.5–11.0X109/L), with a differential of 62% lymphocytes, 23% neutrophils, 5% bands, 2% monocytes, and 8% eosinophils (reference ranges, 34%, 56%, 3%, 4%, and 2.7%, respectively). The patient's liver enzyme levels were elevated including aspartate aminotransferase, 1545 U/L (reference range, 20–48 U/L); alanine aminotransferase, 383 U/L (reference range, 10–40 U/L); alkaline phosphatase, 297 U/L (reference range, 50–120 U/L); γ-glutamyltransferase, 235 U/L (reference range, 0–30 U/L); and lactate dehydrogenase, 5638 U/L (reference range, 50–200 U/L); synthetic liver function remained within reference range. The patient's serum creatinine (SCr) level was 212 μmol/L (reference range, 53–106 μmol/L), with a baseline of 45 μmol/L. Results of a urinalysis were within reference range; results of a urine culture were negative. An ultrasound of the abdomen did not reveal a cause for renal failure or liver dysfunction. A diagnosis of PT-induced hypersensitivity reaction with acute toxic hepatitis and interstitial nephritis was made. The intravenous antibiotics were discontinued and the patient was given prednisone and hemodialysis 3 times weekly. Her SCr levels fluctuated during the treatment, reaching a peak of 461 μmol/L. The patient responded well to therapy, though her liver enzyme and SCr levels did not return to baseline at the time of hospital discharge (aspartate aminotransferase, 42 U/L; alanine aminotransferase, 72 U/L; alkaline phosphatase, 72 U/L; γ-glutamyltransferase, 122 U/L; lactate dehydrogenase, 300 U/L; SCr, 123 μmol/L). The patient was followed as an outpatient.

Comment
Drug hypersensitivity syndrome (DHS) is characterized by a triad of fever, skin eruption, and internal organ involvement.2 DHS also is known as DRESS syndrome (drug rash with eosinophilia and systemic symptoms)3 and DIDMOHS (drug-induced delayed multiorgan hypersensitivity syndrome).4 DHS also has been described as multisystem hypersensitivity, pseudolymphoma, febrile mucocutaneous syndrome, Kawasakilike syndrome, mononucleosislike illness, and graft-versus-hostlike illness.5 DHS is a result of a specific, severe, idiosyncratic reaction. The incidence of DHS ranges between 1 in 1000 and 1 in 10,000 exposures. DHS occurs more often in women than in men.5 A number of drugs have been reported to cause this syndrome, including sulfonamide antibiotics, trimethoprim, dapsone, and aromatic anticonvulsants (eg, phenytoin, phenobarbital, carbamazepine),6-9 as well as lamotrigine,10 minocycline,11-12 and allopurinol.13-14 Antiviral medications such as abacavir and nevirapine also have been reported.15 DHS occurs on the first exposure to the offending drug, with the symptoms starting 2 to 6 weeks after initiation of the medication. Reexposure to the same offending drug may cause symptoms to develop within 24 hours. The symptoms may last for weeks or even months after discontinuing the medication. The most common presentations in patients with DHS are fever, which ranges from 38°C to 40°C and occurs in 85% of cases, malaise, pharyngitis, and cervical lymphadenopathy. A generalized exanthematous morbilliform rash develops in 75% of cases, either with or soon after the fever. Cutaneous manifestations can present in a number of ways including exfoliative erythroderma, follicular or nonfollicular pustules, purpuric lesions or blisters, and tense bullae induced by dermal edema.5 The face, upper trunk, and extremities usually are involved. Facial edema is a common finding. Additionally, hypotension, bleeding, interstitial nephritis, arthralgia, arthritis, myositis, thyroiditis, pneumonitis, respiratory distress syndrome, pericarditis, myocarditis, pancreatitis, colitis, orchitis, encephalitis, and aseptic meningitis have been reported.5 Hematologic involvement includes prominent eosinophilia, which occurs in 90% of cases; mononucleosislike atypical lymphocytosis, which occurs in 40% of cases; neutrophilia or neutropenia; thrombocytopenia; and hemolytic anemia. Elevated levels of liver transaminase, alkaline phosphatase, bilirubin, and prothrombin time are seen in 50% of cases. Fulminant hepatitis is the major cause of death associated with this syndrome, occurring in 5% to 10% of cases.16 Pathogenesis of DHS—The pathogenesis of DHS is unknown but likely is multifactorial. Exposure to a drug is the causal agent, but it is not enough to elicit DHS. It is postulated that a specific alteration in the metabolism and detoxification of a particular drug can occur in phenotypic susceptible individuals, which leads to an increased risk of toxic consequences of reactive oxidative drug metabolites.2,5,17 Aromatic anticonvulsants are metabolized by cytochrome P450 to reactive metabolites that are detoxified by epoxide hydroxylase. If the detoxification process is defective, the toxic metabolite acts as a hapten, initiating an immune response. In 70% to 75% of DHS cases, cross-reactivity is shown between the different aromatic anticonvulsants. Lamotrigine has been reported to cause DHS, though it is not one of the aromatic anticonvulsants. The concurrent use of lamotrigine with valproic acid increases the risk of reaction because valproic acid prolongs the elimination half-life of lamotrigine.5,18 There is a familial susceptibility of hypersensitivity to anticonvulsants, thus counseling of family members is essential.2,19 Sulfonamide antibiotics are metabolized by slow acetylators to reactive metabolites, mainly hydroxylamines and nitroso compounds, causing cytotoxicity. In patients with glutathione deficiency, detoxification of these toxic metabolites is not possible and can lead to DHS. There is an increased risk (25%) of first-degree relatives having a similar defect.20 Aromatic amines (eg, dapsone, acebutolol, procainamide) are metabolized to the same compounds and hence there is a potential for cross-reactivity occurring in these individuals. There is no cross-reactivity between sulfonamides and other nonaromatic amines such as furosemide, thiazide diuretics, acetazolamide, celecoxib, and sulfonylureas.21 The drugs associated with DHS are summarized in the Table.

The association of the human herpesvirus family—specifically, human herpesvirus 6—and DHS has been questioned. Descamps et al22 explored the issues regarding viral infection and DHS. Hashimoto et al23 suggested that the prolonged course, slow resolution, and/or relapse of cases of DHS may be attributed to human herpesvirus 6 reactivation. Condat et al24 have shown that reactivation of human herpesvirus 6 coincides with the course of DHS, but the direct causal effect of the virus is yet to be established. Patients with human immunodeficiency virus are at a higher susceptibility to toxic drug metabolites.25 This susceptibility could be explained by the reduced level of glutathione, selenium, and other antioxidants in these patients. Glutathione plays an important role in the antioxidant defense of cells. Immune mechanisms also are thought to contribute to the pathogenesis of DHS in these patients, though the immune mechanism of DHS still is not clear. The changes in DHS suggest both TH1 and TH2 cytokine production. Transient increase in the level of interleukin 5 has been demonstrated early in the disease process in some patients.26 Interleukin 5 released by activated T lymphocytes contributes to the eosinophilia. The differential diagnosis of DHS includes other drug eruptions, viral infection, idiopathic hypereosinophilic syndrome, pseudolymphoma, serum sicknesslike illness, and drug-induced vasculitis. PT is an extended-spectrum synthetic penicillin combined with β-lactamase inhibitor. PT is effective against methicillin-sensitive, coagulase-negative staphylococci; Streptococcus pyogenes; and penicillin-sensitive Streptococcus pneumoniae, Enterobacteriaceae, Haemophilus influenza, Moraxella catarrhalis, Pseudomonus aeruginosa, Enterococcus faecalis, and anaerobes. The main indications of PT include nosocomial pneumonia, intra-abdominal infections, skin and soft tissue infections, pelvic inflammatory disease, septicemia, neutropenic fever, osteomyelitis, and septic arthritis.27 Multiple adverse effects with the administration of PT have been reported, including fever, leucopenia, thrombocytopenia, hemolytic anemia, hypercoagulopathy, and transient bone marrow suppression.28-29 Acute interstitial nephritis,30-31 encephalopathy,32 recurrent paralysis,33 allergic skin eruptions,34 and hemorrhagic cystitis35 have been documented after the administration of PT. There is only one reported case (a letter to the editor36) of hypersensitivity reaction during prolonged use of PT in the treatment of osteomyelitis; the patient developed rash, lymphadenopathy, and hematologic changes. Our patient developed DHS after 2 weeks of initiating therapy with PT for osteomyelitis. The reaction caused severe parenchymal nephritis, leading to anuria that necessitated hemodialysis. Interestingly, our patient complained of numbness and paresthesia of the forearm during intravenous PT infusion 2 days prior to developing DHS; a similar symptom was reported by Behbahani and Kostman36 with numbness of the patient's upper chest during intravenous infusion. Treatment of DHS depends on discontinuation of the offending drug early in the course of the disease. Adding systemic corticosteroids (0.5–1.0 mg/kg/d) to the treatment regimen is essential, especially in life-threatening involvement of the lungs, heart, liver, or kidneys. Systemic corticosteroids should be slowly tapered to avoid a relapse of nephritis and skin eruption. Topical steroids have been used in milder cases of DHS to improve the cutaneous manifestations. Interferon-γ has been used in a few cases of long-standing DHS,37 but studies are not available to establish the role of this drug in treatment. 

Conclusion

DHA is an iatrogenic disease that affects multiple organs. The pathogenesis of DHS still is largely unclear. Multiple factors likely are responsible for DHS, such as the offending drug with a drug-drug interaction, susceptible individuals with impaired ability to detoxify toxic drug metabolites, immunologic factors, and viral infection. Identification and discontinuation of the offending drug is crucial, as is a multidisciplinary approach in managing affected patients.

The drug hypersensitivity syndrome (DHS) is a rare but serious and potentially life-threatening reaction to common drugs in predisposed individuals. The syndrome is a triad of fever, skin eruption, and internal organ involvement. Prompt identification and discontinuation of the offending drug with symptomatic treatment of toxic effects is the mainstay of therapy for DHS.

Case Report

A 28-year-old paraplegic woman (secondary to spina bifida) was admitted to the hospital for vacuum-assisted closure of a chronic nonhealing left ankle ulcer of 21 months' duration. The patient was on oral ciprofloxacin 500 mg twice daily1 and oral clindamycin hydrochloride 300 mg 4 times daily for treatment of repeated bacterial infections. While in the hospital, a bone scan was performed and the results confirmed osteomyelitis of the left talonavicular region. The patient's oral therapeutic regimen was discontinued and she was given piperacillin-tazobactam (PT) 3.375 g by intravenous infusion every 6 hours. She responded well to this treatment, with a subsequent decrease in ulcer size. Two weeks following therapy, the patient developed fever, skin rash, nausea, and headache. The next day, the patient became anuric. There was no family history of renal or hepatic disease. Results of a physical examination revealed the patient was febrile (temperature, 39.4°C); a wide-spread, symmetrical, morbilliform skin eruption was noted on her face, trunk, forearms, and legs. She had slight facial edema, with erythema and enlarged cervical lymph nodes bilaterally. Results of laboratory investigations revealed the patient had an elevated white blood cell count of 18.4X109/L (reference range, 4.5–11.0X109/L), with a differential of 62% lymphocytes, 23% neutrophils, 5% bands, 2% monocytes, and 8% eosinophils (reference ranges, 34%, 56%, 3%, 4%, and 2.7%, respectively). The patient's liver enzyme levels were elevated including aspartate aminotransferase, 1545 U/L (reference range, 20–48 U/L); alanine aminotransferase, 383 U/L (reference range, 10–40 U/L); alkaline phosphatase, 297 U/L (reference range, 50–120 U/L); γ-glutamyltransferase, 235 U/L (reference range, 0–30 U/L); and lactate dehydrogenase, 5638 U/L (reference range, 50–200 U/L); synthetic liver function remained within reference range. The patient's serum creatinine (SCr) level was 212 μmol/L (reference range, 53–106 μmol/L), with a baseline of 45 μmol/L. Results of a urinalysis were within reference range; results of a urine culture were negative. An ultrasound of the abdomen did not reveal a cause for renal failure or liver dysfunction. A diagnosis of PT-induced hypersensitivity reaction with acute toxic hepatitis and interstitial nephritis was made. The intravenous antibiotics were discontinued and the patient was given prednisone and hemodialysis 3 times weekly. Her SCr levels fluctuated during the treatment, reaching a peak of 461 μmol/L. The patient responded well to therapy, though her liver enzyme and SCr levels did not return to baseline at the time of hospital discharge (aspartate aminotransferase, 42 U/L; alanine aminotransferase, 72 U/L; alkaline phosphatase, 72 U/L; γ-glutamyltransferase, 122 U/L; lactate dehydrogenase, 300 U/L; SCr, 123 μmol/L). The patient was followed as an outpatient.

Comment
Drug hypersensitivity syndrome (DHS) is characterized by a triad of fever, skin eruption, and internal organ involvement.2 DHS also is known as DRESS syndrome (drug rash with eosinophilia and systemic symptoms)3 and DIDMOHS (drug-induced delayed multiorgan hypersensitivity syndrome).4 DHS also has been described as multisystem hypersensitivity, pseudolymphoma, febrile mucocutaneous syndrome, Kawasakilike syndrome, mononucleosislike illness, and graft-versus-hostlike illness.5 DHS is a result of a specific, severe, idiosyncratic reaction. The incidence of DHS ranges between 1 in 1000 and 1 in 10,000 exposures. DHS occurs more often in women than in men.5 A number of drugs have been reported to cause this syndrome, including sulfonamide antibiotics, trimethoprim, dapsone, and aromatic anticonvulsants (eg, phenytoin, phenobarbital, carbamazepine),6-9 as well as lamotrigine,10 minocycline,11-12 and allopurinol.13-14 Antiviral medications such as abacavir and nevirapine also have been reported.15 DHS occurs on the first exposure to the offending drug, with the symptoms starting 2 to 6 weeks after initiation of the medication. Reexposure to the same offending drug may cause symptoms to develop within 24 hours. The symptoms may last for weeks or even months after discontinuing the medication. The most common presentations in patients with DHS are fever, which ranges from 38°C to 40°C and occurs in 85% of cases, malaise, pharyngitis, and cervical lymphadenopathy. A generalized exanthematous morbilliform rash develops in 75% of cases, either with or soon after the fever. Cutaneous manifestations can present in a number of ways including exfoliative erythroderma, follicular or nonfollicular pustules, purpuric lesions or blisters, and tense bullae induced by dermal edema.5 The face, upper trunk, and extremities usually are involved. Facial edema is a common finding. Additionally, hypotension, bleeding, interstitial nephritis, arthralgia, arthritis, myositis, thyroiditis, pneumonitis, respiratory distress syndrome, pericarditis, myocarditis, pancreatitis, colitis, orchitis, encephalitis, and aseptic meningitis have been reported.5 Hematologic involvement includes prominent eosinophilia, which occurs in 90% of cases; mononucleosislike atypical lymphocytosis, which occurs in 40% of cases; neutrophilia or neutropenia; thrombocytopenia; and hemolytic anemia. Elevated levels of liver transaminase, alkaline phosphatase, bilirubin, and prothrombin time are seen in 50% of cases. Fulminant hepatitis is the major cause of death associated with this syndrome, occurring in 5% to 10% of cases.16 Pathogenesis of DHS—The pathogenesis of DHS is unknown but likely is multifactorial. Exposure to a drug is the causal agent, but it is not enough to elicit DHS. It is postulated that a specific alteration in the metabolism and detoxification of a particular drug can occur in phenotypic susceptible individuals, which leads to an increased risk of toxic consequences of reactive oxidative drug metabolites.2,5,17 Aromatic anticonvulsants are metabolized by cytochrome P450 to reactive metabolites that are detoxified by epoxide hydroxylase. If the detoxification process is defective, the toxic metabolite acts as a hapten, initiating an immune response. In 70% to 75% of DHS cases, cross-reactivity is shown between the different aromatic anticonvulsants. Lamotrigine has been reported to cause DHS, though it is not one of the aromatic anticonvulsants. The concurrent use of lamotrigine with valproic acid increases the risk of reaction because valproic acid prolongs the elimination half-life of lamotrigine.5,18 There is a familial susceptibility of hypersensitivity to anticonvulsants, thus counseling of family members is essential.2,19 Sulfonamide antibiotics are metabolized by slow acetylators to reactive metabolites, mainly hydroxylamines and nitroso compounds, causing cytotoxicity. In patients with glutathione deficiency, detoxification of these toxic metabolites is not possible and can lead to DHS. There is an increased risk (25%) of first-degree relatives having a similar defect.20 Aromatic amines (eg, dapsone, acebutolol, procainamide) are metabolized to the same compounds and hence there is a potential for cross-reactivity occurring in these individuals. There is no cross-reactivity between sulfonamides and other nonaromatic amines such as furosemide, thiazide diuretics, acetazolamide, celecoxib, and sulfonylureas.21 The drugs associated with DHS are summarized in the Table.

The association of the human herpesvirus family—specifically, human herpesvirus 6—and DHS has been questioned. Descamps et al22 explored the issues regarding viral infection and DHS. Hashimoto et al23 suggested that the prolonged course, slow resolution, and/or relapse of cases of DHS may be attributed to human herpesvirus 6 reactivation. Condat et al24 have shown that reactivation of human herpesvirus 6 coincides with the course of DHS, but the direct causal effect of the virus is yet to be established. Patients with human immunodeficiency virus are at a higher susceptibility to toxic drug metabolites.25 This susceptibility could be explained by the reduced level of glutathione, selenium, and other antioxidants in these patients. Glutathione plays an important role in the antioxidant defense of cells. Immune mechanisms also are thought to contribute to the pathogenesis of DHS in these patients, though the immune mechanism of DHS still is not clear. The changes in DHS suggest both TH1 and TH2 cytokine production. Transient increase in the level of interleukin 5 has been demonstrated early in the disease process in some patients.26 Interleukin 5 released by activated T lymphocytes contributes to the eosinophilia. The differential diagnosis of DHS includes other drug eruptions, viral infection, idiopathic hypereosinophilic syndrome, pseudolymphoma, serum sicknesslike illness, and drug-induced vasculitis. PT is an extended-spectrum synthetic penicillin combined with β-lactamase inhibitor. PT is effective against methicillin-sensitive, coagulase-negative staphylococci; Streptococcus pyogenes; and penicillin-sensitive Streptococcus pneumoniae, Enterobacteriaceae, Haemophilus influenza, Moraxella catarrhalis, Pseudomonus aeruginosa, Enterococcus faecalis, and anaerobes. The main indications of PT include nosocomial pneumonia, intra-abdominal infections, skin and soft tissue infections, pelvic inflammatory disease, septicemia, neutropenic fever, osteomyelitis, and septic arthritis.27 Multiple adverse effects with the administration of PT have been reported, including fever, leucopenia, thrombocytopenia, hemolytic anemia, hypercoagulopathy, and transient bone marrow suppression.28-29 Acute interstitial nephritis,30-31 encephalopathy,32 recurrent paralysis,33 allergic skin eruptions,34 and hemorrhagic cystitis35 have been documented after the administration of PT. There is only one reported case (a letter to the editor36) of hypersensitivity reaction during prolonged use of PT in the treatment of osteomyelitis; the patient developed rash, lymphadenopathy, and hematologic changes. Our patient developed DHS after 2 weeks of initiating therapy with PT for osteomyelitis. The reaction caused severe parenchymal nephritis, leading to anuria that necessitated hemodialysis. Interestingly, our patient complained of numbness and paresthesia of the forearm during intravenous PT infusion 2 days prior to developing DHS; a similar symptom was reported by Behbahani and Kostman36 with numbness of the patient's upper chest during intravenous infusion. Treatment of DHS depends on discontinuation of the offending drug early in the course of the disease. Adding systemic corticosteroids (0.5–1.0 mg/kg/d) to the treatment regimen is essential, especially in life-threatening involvement of the lungs, heart, liver, or kidneys. Systemic corticosteroids should be slowly tapered to avoid a relapse of nephritis and skin eruption. Topical steroids have been used in milder cases of DHS to improve the cutaneous manifestations. Interferon-γ has been used in a few cases of long-standing DHS,37 but studies are not available to establish the role of this drug in treatment. 

Conclusion

DHA is an iatrogenic disease that affects multiple organs. The pathogenesis of DHS still is largely unclear. Multiple factors likely are responsible for DHS, such as the offending drug with a drug-drug interaction, susceptible individuals with impaired ability to detoxify toxic drug metabolites, immunologic factors, and viral infection. Identification and discontinuation of the offending drug is crucial, as is a multidisciplinary approach in managing affected patients.

Seborrheic dermatitis (SD) is one of the most common dermatoses of infancy. SD is an inflammatory process that presents as tiny papules covered by scales typically localized to the seborrheic region. We report a case of a 2-month-old infant with SD who went on to develop atopic dermatitis (AD). Additionally, we discuss epidemiology, etiology, diagnosis, differential diagnosis, and treatment modalities for SD, as well as an association of SD and AD.

Case Report

A 2-month-old white infant presented with diffuse hyperkeratosis of the scalp of 2 weeks' duration. He also had fine macerated erythema of the retroauricular area, neck, axillae, and groin. These lesions were consistent with a clinical diagnosis of infantile seborrheic dermatitis (ISD). Application of mineral oil to the scalp resulted in softening and improvement of scalp lesions. The body lesions were ameliorated by the application of a mixture of hydrocortisone and nystatin creams to the neck, axillae, and groin. The lesions recurred, requiring periodic reapplication of the medicaments. Eventually, the lesions occurred less frequently and the scalp lesions resolved completely over the next 2 months. However, the patient developed typical atopic dermatitis (AD) as a 6-month-old, typified by erythematous excoriated plaques in the antecubital and popliteal regions. 

Comment
SD was first described by Unna in 1887.1 SD is a common chronic inflammatory disease characterized by erythema accompanied by greasy scales in the so-called seborrheic region, which includes the scalp, forehead/glabella, eyebrows, malar eminences, paranasal and nasolabial folds, retroauricular area, chest, and axillae. SD occurs most frequently in infants and adults aged 30 to 60 years. Its prevalence in immunocompetent adults is estimated to be between 1% and 3%.2 The incidence of SD is unusually high among patients with AIDS, ranging from 30% to 83%.2-4 There also is an increased incidence of SD in patients with tinea versicolor, depression, spinal cord injuries, and parkinsonism, and in patients receiving psoralen and UVA therapy.5-9 SD usually develops in neonates within the first 3 to 4 weeks of life. Spontaneous recovery generally occurs at about 6 to 7 months of age, though persistence until 2 years of age can be seen. SD in adults affects men more often than women; ISD shows no gender predilection. The occurrence of SD in prepubertal children (aged 2–5 years) is uncommon. The etiology of SD is poorly understood. SD may be hormonally dependent, which could explain why the condition appears briefly in infancy and recurs in puberty. The role of sebum excretion in the pathogenesis of SD is controversial. In fact, sebum excretion has been shown to be either normal or subnormal in many patients with SD.10,11 Commensal yeast Malassezia also has been thought to be causative.12 The response of SD to topical antifungal agents such as ketoconazole and selenium sulfide indicates that Malassezia yeast may be pathogenic. Research suggests that SD is not caused by an overgrowth of Malassezia but an abnormal host response.12 The evidence supporting this theory lies in the increased incidence of SD in immunocompromised patients. In a study of fatty acids in the serum of infants with ISD, Tollesson et al13 demonstrated evidence of impaired function of the enzyme -6-desaturase, which desaturates linoleic acid to dihomogammalinolenic and arachidonic acids. The study indicated the function of the enzyme appeared to normalize in the infants by about 6 to 7 months of age, the age at which spontaneous recovery from ISD usually occurs.13 ISD is a self-limited process that usually involves the scalp. The scalp lesions can present as small dry patches of hyperkeratosis overlying mildly erythematous skin that may become so thickened that it forms a cap, meriting its description as cradle cap (Figure).14 Scalp hyperkeratosis often is the only manifestation of ISD and usually appears 3 or 4 weeks after birth.15,16 The scales may be white, off-white, or yellowish. The central part of the face; forehead; neck; ears; and intertriginous areas such as the axillae, groin, and inner thigh folds, also may be involved. SD begins as erythematous macules and papules that gradually become confluent to form scaly patches and slightly elevated plaques.15,16 In adolescents, SD has a clinical picture similar to ISD but is focused in the head and neck region.

The diagnosis of ISD usually is straightforward and is based on clinical findings about the distribution and appearance of the lesions. However, failure to respond to therapy must lead clinicians to reconsider the diagnosis.15 ISD must be differentiated from AD, psoriasis, and tinea capitis. ISD and AD have similar sites of predilection including the face, scalp, retroauricular area, diaper area, and extensor limb surfaces. The distinction is made on clinical grounds. Axillary and anterior neck involvement favors the diagnosis of ISD, as do the lack of evidence of pruritus and the absence of oozing and weeping. Infants with AD tend to be aged 3 to 12 months and usually have at least one parent or sibling with a positive history of atopy. Sometimes, however, overlap of ISD and AD can be seen, particularly in infants aged 2 to 6 months.15,16 Our patient went on to develop AD. The relationship between ISD and infantile AD (IAD) is controversial. According to some authors, more than 50% of children with widespread ISD have or will develop AD.17 Conversely, Moises-Alfaro et al¹⁸ conducted a small and not as convincing study that led them to conclude that there is no relationship between ISD and IAD. Our patient supports the association of IAD and ISD. Recent studies have demonstrated that patients with head and neck AD have immunoglobulin E antibodies to Malassezia furfur, the yeast causative of ISD. This supports the overlap and possible progression between IAD and ISD through sensitization to cutaneous Malassezia. Inflammatory reaction to Malassezia (ie, ISD) may be the inciting event in the development of IAD, though this has not been proven so far in children.19,20 Occasionally, psoriasis has predilection for seborrheic areas (inverse psoriasis), making it difficult to clinically decide whether the patient has psoriasis or SD; however, psoriasis is more sharply demarcated.21 Rarely, both appear concurrently. In rare cases, infants are affected with a scaling eruption resembling ISD on the scalp in association with fever and other systemic signs of acute disseminated Langerhans cell histiocytosis.15 Persistent erythematous scaling (especially if hemorrhagic and therapy resistant) in an infant who is doing poorly or has hepatosplenomegaly requires a biopsy to exclude Langerhans cell histiocytosis. Severe treatment-resistant SD may be associated with human immunodeficiency virus infection and is common in infants who develop human immunodeficiency virus—related immune suppression in the first year of life.^22-24 As the immune deficiency in these patients becomes progressively worse, so does SD. SD occasionally progresses to erythroderma, a cradle cap of scales sometimes associated with nonscarring alopecia or postinflammatory hyperpigmentation or hypopigmentation.15 In prepubertal children, AD or tinea capitis are more likely diagnoses for hyperkeratotic scalp lesions than SD; therefore, tinea capitis must be excluded by a fungal culture of the scalp.25,26 When SD is diagnosed in a prepubertal child, precocious puberty should be suspected. However, AD is a more likely diagnosis for scalp hyperkeratosis, but it is not impossible to see SD in prepubertal children.27 In most instances, the diagnosis of SD is clinically obvious. When the diagnosis is not so obvious, a biopsy may be necessary to differentiate SD from other skin diseases by histologic examination. Sections of tissue of the biopsy specimens show characteristic changes, namely superficial perivascular and interstitial infiltrates of lymphocytes, slight spongiosis, scale crusts and mounds of parakeratosis that reside at the lips of infundibular ostia and at interinfundibular sites, markedly dilated venules and capillaries of the superficial plexus, and psoriasiform hyperplasia in more long-standing lesions of SD.21,28 

Therapy Therapy for SD is based on the age of the patient and the extent of the disease. The usual therapeutic approach for ISD of the scalp is conservative. In mild cases, an emollient such as white petrolatum or mineral oil may be used to soften the cradle cap so that it can be gently removed by brushing off the scales.14,15 Crusts are soaked overnight with slightly warmed oil and washed off in the morning. A mild nonmedicated shampoo should be used at the start of therapy in conjunction with brushing off scales with a baby's toothbrush. If a mild shampoo is not helpful, a shampoo containing ketoconazole 2% can be used.14,29 Coal tar—based shampoos must be avoided because of the carcinogenicity of coal tar.30 Mild topical corticosteroid lotions can be used adjunctively to reduce erythema of the scalp. Salicylic acid shampoos are contraindicated in ISD because of concerns about percutaneous absorption of the substance and the risk of metabolic acidosis and salicylism.31 ISD involving intertriginous areas is treated with gentle skin care and topical medicaments. Topical ketoconazole or nystatin are safe and effective therapies, particularly when combined with a mild topical corticosteroid.32 Topical tacrolimus ointment or pimecrolimus cream can be substituted for a topical corticosteroid; however, the use of tacrolimus and pimecrolimus is off-label and should not be used in children younger than 2 years, according to the US Food and Drug Administration.33 Calcineurin inhibitors are used in topical corticosteroid—resistant AD patients 2 years and older. Similar guidelines are prudent for SD therapy. Recently, the US Food and Drug Administration issued a warning regarding a biologic potential for skin cancers and lymphomas with the use of topical calcineurin inhibitors; however, human data have not supported these risks.33 Adolescents with SD should be treated similar to adults. Because SD is chronic, the initial therapy for the condition should be followed by a maintenance regimen. Conventional therapy for SD of the scalp is the use of a medicated shampoo 2 to 3 times per week. Shampoos containing salicylic acid, selenium sulfide, an antifungal agent, or zinc pyrithione are effective.15 In more severe cases, a topical corticosteroid in a lotion, oil, or solution base may be used once or twice daily, often in addition to a medicated shampoo. Seborrheic blepharitis is managed by the gentle removal of scales and crusts using a cotton ball dipped in diluted baby shampoo.15 In severe cases involving the eyelids, the eyelids may be covered with sodium sulfacetamide 10% solution or ketoconazole 2% cream.14,15 In our experience, nonsteroidal anti-inflammatory preparations, such as tacrolimus ointment and pimecrolimus cream, also can be used safely on the eyelids in children under the same guidelines as other cutaneous application sites. 

Conclusion

In summary, a number of factors such as immune function and heredity are important in the pathogenesis of SD. The role of Malassezia in SD needs to be clarified. In most instances, SD is easily diagnosed on clinical grounds alone. Safe and effective treatment modalities are available. More studies are needed to determine whether a relationship between SD and AD exists; however, our clinical experience supports this associator. 

Seborrheic dermatitis (SD) is one of the most common dermatoses of infancy. SD is an inflammatory process that presents as tiny papules covered by scales typically localized to the seborrheic region. We report a case of a 2-month-old infant with SD who went on to develop atopic dermatitis (AD). Additionally, we discuss epidemiology, etiology, diagnosis, differential diagnosis, and treatment modalities for SD, as well as an association of SD and AD.

Case Report

A 2-month-old white infant presented with diffuse hyperkeratosis of the scalp of 2 weeks' duration. He also had fine macerated erythema of the retroauricular area, neck, axillae, and groin. These lesions were consistent with a clinical diagnosis of infantile seborrheic dermatitis (ISD). Application of mineral oil to the scalp resulted in softening and improvement of scalp lesions. The body lesions were ameliorated by the application of a mixture of hydrocortisone and nystatin creams to the neck, axillae, and groin. The lesions recurred, requiring periodic reapplication of the medicaments. Eventually, the lesions occurred less frequently and the scalp lesions resolved completely over the next 2 months. However, the patient developed typical atopic dermatitis (AD) as a 6-month-old, typified by erythematous excoriated plaques in the antecubital and popliteal regions. 

Comment
SD was first described by Unna in 1887.1 SD is a common chronic inflammatory disease characterized by erythema accompanied by greasy scales in the so-called seborrheic region, which includes the scalp, forehead/glabella, eyebrows, malar eminences, paranasal and nasolabial folds, retroauricular area, chest, and axillae. SD occurs most frequently in infants and adults aged 30 to 60 years. Its prevalence in immunocompetent adults is estimated to be between 1% and 3%.2 The incidence of SD is unusually high among patients with AIDS, ranging from 30% to 83%.2-4 There also is an increased incidence of SD in patients with tinea versicolor, depression, spinal cord injuries, and parkinsonism, and in patients receiving psoralen and UVA therapy.5-9 SD usually develops in neonates within the first 3 to 4 weeks of life. Spontaneous recovery generally occurs at about 6 to 7 months of age, though persistence until 2 years of age can be seen. SD in adults affects men more often than women; ISD shows no gender predilection. The occurrence of SD in prepubertal children (aged 2–5 years) is uncommon. The etiology of SD is poorly understood. SD may be hormonally dependent, which could explain why the condition appears briefly in infancy and recurs in puberty. The role of sebum excretion in the pathogenesis of SD is controversial. In fact, sebum excretion has been shown to be either normal or subnormal in many patients with SD.10,11 Commensal yeast Malassezia also has been thought to be causative.12 The response of SD to topical antifungal agents such as ketoconazole and selenium sulfide indicates that Malassezia yeast may be pathogenic. Research suggests that SD is not caused by an overgrowth of Malassezia but an abnormal host response.12 The evidence supporting this theory lies in the increased incidence of SD in immunocompromised patients. In a study of fatty acids in the serum of infants with ISD, Tollesson et al13 demonstrated evidence of impaired function of the enzyme -6-desaturase, which desaturates linoleic acid to dihomogammalinolenic and arachidonic acids. The study indicated the function of the enzyme appeared to normalize in the infants by about 6 to 7 months of age, the age at which spontaneous recovery from ISD usually occurs.13 ISD is a self-limited process that usually involves the scalp. The scalp lesions can present as small dry patches of hyperkeratosis overlying mildly erythematous skin that may become so thickened that it forms a cap, meriting its description as cradle cap (Figure).14 Scalp hyperkeratosis often is the only manifestation of ISD and usually appears 3 or 4 weeks after birth.15,16 The scales may be white, off-white, or yellowish. The central part of the face; forehead; neck; ears; and intertriginous areas such as the axillae, groin, and inner thigh folds, also may be involved. SD begins as erythematous macules and papules that gradually become confluent to form scaly patches and slightly elevated plaques.15,16 In adolescents, SD has a clinical picture similar to ISD but is focused in the head and neck region.

The diagnosis of ISD usually is straightforward and is based on clinical findings about the distribution and appearance of the lesions. However, failure to respond to therapy must lead clinicians to reconsider the diagnosis.15 ISD must be differentiated from AD, psoriasis, and tinea capitis. ISD and AD have similar sites of predilection including the face, scalp, retroauricular area, diaper area, and extensor limb surfaces. The distinction is made on clinical grounds. Axillary and anterior neck involvement favors the diagnosis of ISD, as do the lack of evidence of pruritus and the absence of oozing and weeping. Infants with AD tend to be aged 3 to 12 months and usually have at least one parent or sibling with a positive history of atopy. Sometimes, however, overlap of ISD and AD can be seen, particularly in infants aged 2 to 6 months.15,16 Our patient went on to develop AD. The relationship between ISD and infantile AD (IAD) is controversial. According to some authors, more than 50% of children with widespread ISD have or will develop AD.17 Conversely, Moises-Alfaro et al¹⁸ conducted a small and not as convincing study that led them to conclude that there is no relationship between ISD and IAD. Our patient supports the association of IAD and ISD. Recent studies have demonstrated that patients with head and neck AD have immunoglobulin E antibodies to Malassezia furfur, the yeast causative of ISD. This supports the overlap and possible progression between IAD and ISD through sensitization to cutaneous Malassezia. Inflammatory reaction to Malassezia (ie, ISD) may be the inciting event in the development of IAD, though this has not been proven so far in children.19,20 Occasionally, psoriasis has predilection for seborrheic areas (inverse psoriasis), making it difficult to clinically decide whether the patient has psoriasis or SD; however, psoriasis is more sharply demarcated.21 Rarely, both appear concurrently. In rare cases, infants are affected with a scaling eruption resembling ISD on the scalp in association with fever and other systemic signs of acute disseminated Langerhans cell histiocytosis.15 Persistent erythematous scaling (especially if hemorrhagic and therapy resistant) in an infant who is doing poorly or has hepatosplenomegaly requires a biopsy to exclude Langerhans cell histiocytosis. Severe treatment-resistant SD may be associated with human immunodeficiency virus infection and is common in infants who develop human immunodeficiency virus—related immune suppression in the first year of life.^22-24 As the immune deficiency in these patients becomes progressively worse, so does SD. SD occasionally progresses to erythroderma, a cradle cap of scales sometimes associated with nonscarring alopecia or postinflammatory hyperpigmentation or hypopigmentation.15 In prepubertal children, AD or tinea capitis are more likely diagnoses for hyperkeratotic scalp lesions than SD; therefore, tinea capitis must be excluded by a fungal culture of the scalp.25,26 When SD is diagnosed in a prepubertal child, precocious puberty should be suspected. However, AD is a more likely diagnosis for scalp hyperkeratosis, but it is not impossible to see SD in prepubertal children.27 In most instances, the diagnosis of SD is clinically obvious. When the diagnosis is not so obvious, a biopsy may be necessary to differentiate SD from other skin diseases by histologic examination. Sections of tissue of the biopsy specimens show characteristic changes, namely superficial perivascular and interstitial infiltrates of lymphocytes, slight spongiosis, scale crusts and mounds of parakeratosis that reside at the lips of infundibular ostia and at interinfundibular sites, markedly dilated venules and capillaries of the superficial plexus, and psoriasiform hyperplasia in more long-standing lesions of SD.21,28 

Therapy Therapy for SD is based on the age of the patient and the extent of the disease. The usual therapeutic approach for ISD of the scalp is conservative. In mild cases, an emollient such as white petrolatum or mineral oil may be used to soften the cradle cap so that it can be gently removed by brushing off the scales.14,15 Crusts are soaked overnight with slightly warmed oil and washed off in the morning. A mild nonmedicated shampoo should be used at the start of therapy in conjunction with brushing off scales with a baby's toothbrush. If a mild shampoo is not helpful, a shampoo containing ketoconazole 2% can be used.14,29 Coal tar—based shampoos must be avoided because of the carcinogenicity of coal tar.30 Mild topical corticosteroid lotions can be used adjunctively to reduce erythema of the scalp. Salicylic acid shampoos are contraindicated in ISD because of concerns about percutaneous absorption of the substance and the risk of metabolic acidosis and salicylism.31 ISD involving intertriginous areas is treated with gentle skin care and topical medicaments. Topical ketoconazole or nystatin are safe and effective therapies, particularly when combined with a mild topical corticosteroid.32 Topical tacrolimus ointment or pimecrolimus cream can be substituted for a topical corticosteroid; however, the use of tacrolimus and pimecrolimus is off-label and should not be used in children younger than 2 years, according to the US Food and Drug Administration.33 Calcineurin inhibitors are used in topical corticosteroid—resistant AD patients 2 years and older. Similar guidelines are prudent for SD therapy. Recently, the US Food and Drug Administration issued a warning regarding a biologic potential for skin cancers and lymphomas with the use of topical calcineurin inhibitors; however, human data have not supported these risks.33 Adolescents with SD should be treated similar to adults. Because SD is chronic, the initial therapy for the condition should be followed by a maintenance regimen. Conventional therapy for SD of the scalp is the use of a medicated shampoo 2 to 3 times per week. Shampoos containing salicylic acid, selenium sulfide, an antifungal agent, or zinc pyrithione are effective.15 In more severe cases, a topical corticosteroid in a lotion, oil, or solution base may be used once or twice daily, often in addition to a medicated shampoo. Seborrheic blepharitis is managed by the gentle removal of scales and crusts using a cotton ball dipped in diluted baby shampoo.15 In severe cases involving the eyelids, the eyelids may be covered with sodium sulfacetamide 10% solution or ketoconazole 2% cream.14,15 In our experience, nonsteroidal anti-inflammatory preparations, such as tacrolimus ointment and pimecrolimus cream, also can be used safely on the eyelids in children under the same guidelines as other cutaneous application sites. 

Conclusion

In summary, a number of factors such as immune function and heredity are important in the pathogenesis of SD. The role of Malassezia in SD needs to be clarified. In most instances, SD is easily diagnosed on clinical grounds alone. Safe and effective treatment modalities are available. More studies are needed to determine whether a relationship between SD and AD exists; however, our clinical experience supports this associator. 

Seborrheic dermatitis (SD) is one of the most common dermatoses of infancy. SD is an inflammatory process that presents as tiny papules covered by scales typically localized to the seborrheic region. We report a case of a 2-month-old infant with SD who went on to develop atopic dermatitis (AD). Additionally, we discuss epidemiology, etiology, diagnosis, differential diagnosis, and treatment modalities for SD, as well as an association of SD and AD.

Case Report

A 2-month-old white infant presented with diffuse hyperkeratosis of the scalp of 2 weeks' duration. He also had fine macerated erythema of the retroauricular area, neck, axillae, and groin. These lesions were consistent with a clinical diagnosis of infantile seborrheic dermatitis (ISD). Application of mineral oil to the scalp resulted in softening and improvement of scalp lesions. The body lesions were ameliorated by the application of a mixture of hydrocortisone and nystatin creams to the neck, axillae, and groin. The lesions recurred, requiring periodic reapplication of the medicaments. Eventually, the lesions occurred less frequently and the scalp lesions resolved completely over the next 2 months. However, the patient developed typical atopic dermatitis (AD) as a 6-month-old, typified by erythematous excoriated plaques in the antecubital and popliteal regions. 

Comment
SD was first described by Unna in 1887.1 SD is a common chronic inflammatory disease characterized by erythema accompanied by greasy scales in the so-called seborrheic region, which includes the scalp, forehead/glabella, eyebrows, malar eminences, paranasal and nasolabial folds, retroauricular area, chest, and axillae. SD occurs most frequently in infants and adults aged 30 to 60 years. Its prevalence in immunocompetent adults is estimated to be between 1% and 3%.2 The incidence of SD is unusually high among patients with AIDS, ranging from 30% to 83%.2-4 There also is an increased incidence of SD in patients with tinea versicolor, depression, spinal cord injuries, and parkinsonism, and in patients receiving psoralen and UVA therapy.5-9 SD usually develops in neonates within the first 3 to 4 weeks of life. Spontaneous recovery generally occurs at about 6 to 7 months of age, though persistence until 2 years of age can be seen. SD in adults affects men more often than women; ISD shows no gender predilection. The occurrence of SD in prepubertal children (aged 2–5 years) is uncommon. The etiology of SD is poorly understood. SD may be hormonally dependent, which could explain why the condition appears briefly in infancy and recurs in puberty. The role of sebum excretion in the pathogenesis of SD is controversial. In fact, sebum excretion has been shown to be either normal or subnormal in many patients with SD.10,11 Commensal yeast Malassezia also has been thought to be causative.12 The response of SD to topical antifungal agents such as ketoconazole and selenium sulfide indicates that Malassezia yeast may be pathogenic. Research suggests that SD is not caused by an overgrowth of Malassezia but an abnormal host response.12 The evidence supporting this theory lies in the increased incidence of SD in immunocompromised patients. In a study of fatty acids in the serum of infants with ISD, Tollesson et al13 demonstrated evidence of impaired function of the enzyme -6-desaturase, which desaturates linoleic acid to dihomogammalinolenic and arachidonic acids. The study indicated the function of the enzyme appeared to normalize in the infants by about 6 to 7 months of age, the age at which spontaneous recovery from ISD usually occurs.13 ISD is a self-limited process that usually involves the scalp. The scalp lesions can present as small dry patches of hyperkeratosis overlying mildly erythematous skin that may become so thickened that it forms a cap, meriting its description as cradle cap (Figure).14 Scalp hyperkeratosis often is the only manifestation of ISD and usually appears 3 or 4 weeks after birth.15,16 The scales may be white, off-white, or yellowish. The central part of the face; forehead; neck; ears; and intertriginous areas such as the axillae, groin, and inner thigh folds, also may be involved. SD begins as erythematous macules and papules that gradually become confluent to form scaly patches and slightly elevated plaques.15,16 In adolescents, SD has a clinical picture similar to ISD but is focused in the head and neck region.

The diagnosis of ISD usually is straightforward and is based on clinical findings about the distribution and appearance of the lesions. However, failure to respond to therapy must lead clinicians to reconsider the diagnosis.15 ISD must be differentiated from AD, psoriasis, and tinea capitis. ISD and AD have similar sites of predilection including the face, scalp, retroauricular area, diaper area, and extensor limb surfaces. The distinction is made on clinical grounds. Axillary and anterior neck involvement favors the diagnosis of ISD, as do the lack of evidence of pruritus and the absence of oozing and weeping. Infants with AD tend to be aged 3 to 12 months and usually have at least one parent or sibling with a positive history of atopy. Sometimes, however, overlap of ISD and AD can be seen, particularly in infants aged 2 to 6 months.15,16 Our patient went on to develop AD. The relationship between ISD and infantile AD (IAD) is controversial. According to some authors, more than 50% of children with widespread ISD have or will develop AD.17 Conversely, Moises-Alfaro et al¹⁸ conducted a small and not as convincing study that led them to conclude that there is no relationship between ISD and IAD. Our patient supports the association of IAD and ISD. Recent studies have demonstrated that patients with head and neck AD have immunoglobulin E antibodies to Malassezia furfur, the yeast causative of ISD. This supports the overlap and possible progression between IAD and ISD through sensitization to cutaneous Malassezia. Inflammatory reaction to Malassezia (ie, ISD) may be the inciting event in the development of IAD, though this has not been proven so far in children.19,20 Occasionally, psoriasis has predilection for seborrheic areas (inverse psoriasis), making it difficult to clinically decide whether the patient has psoriasis or SD; however, psoriasis is more sharply demarcated.21 Rarely, both appear concurrently. In rare cases, infants are affected with a scaling eruption resembling ISD on the scalp in association with fever and other systemic signs of acute disseminated Langerhans cell histiocytosis.15 Persistent erythematous scaling (especially if hemorrhagic and therapy resistant) in an infant who is doing poorly or has hepatosplenomegaly requires a biopsy to exclude Langerhans cell histiocytosis. Severe treatment-resistant SD may be associated with human immunodeficiency virus infection and is common in infants who develop human immunodeficiency virus—related immune suppression in the first year of life.^22-24 As the immune deficiency in these patients becomes progressively worse, so does SD. SD occasionally progresses to erythroderma, a cradle cap of scales sometimes associated with nonscarring alopecia or postinflammatory hyperpigmentation or hypopigmentation.15 In prepubertal children, AD or tinea capitis are more likely diagnoses for hyperkeratotic scalp lesions than SD; therefore, tinea capitis must be excluded by a fungal culture of the scalp.25,26 When SD is diagnosed in a prepubertal child, precocious puberty should be suspected. However, AD is a more likely diagnosis for scalp hyperkeratosis, but it is not impossible to see SD in prepubertal children.27 In most instances, the diagnosis of SD is clinically obvious. When the diagnosis is not so obvious, a biopsy may be necessary to differentiate SD from other skin diseases by histologic examination. Sections of tissue of the biopsy specimens show characteristic changes, namely superficial perivascular and interstitial infiltrates of lymphocytes, slight spongiosis, scale crusts and mounds of parakeratosis that reside at the lips of infundibular ostia and at interinfundibular sites, markedly dilated venules and capillaries of the superficial plexus, and psoriasiform hyperplasia in more long-standing lesions of SD.21,28 

Therapy Therapy for SD is based on the age of the patient and the extent of the disease. The usual therapeutic approach for ISD of the scalp is conservative. In mild cases, an emollient such as white petrolatum or mineral oil may be used to soften the cradle cap so that it can be gently removed by brushing off the scales.14,15 Crusts are soaked overnight with slightly warmed oil and washed off in the morning. A mild nonmedicated shampoo should be used at the start of therapy in conjunction with brushing off scales with a baby's toothbrush. If a mild shampoo is not helpful, a shampoo containing ketoconazole 2% can be used.14,29 Coal tar—based shampoos must be avoided because of the carcinogenicity of coal tar.30 Mild topical corticosteroid lotions can be used adjunctively to reduce erythema of the scalp. Salicylic acid shampoos are contraindicated in ISD because of concerns about percutaneous absorption of the substance and the risk of metabolic acidosis and salicylism.31 ISD involving intertriginous areas is treated with gentle skin care and topical medicaments. Topical ketoconazole or nystatin are safe and effective therapies, particularly when combined with a mild topical corticosteroid.32 Topical tacrolimus ointment or pimecrolimus cream can be substituted for a topical corticosteroid; however, the use of tacrolimus and pimecrolimus is off-label and should not be used in children younger than 2 years, according to the US Food and Drug Administration.33 Calcineurin inhibitors are used in topical corticosteroid—resistant AD patients 2 years and older. Similar guidelines are prudent for SD therapy. Recently, the US Food and Drug Administration issued a warning regarding a biologic potential for skin cancers and lymphomas with the use of topical calcineurin inhibitors; however, human data have not supported these risks.33 Adolescents with SD should be treated similar to adults. Because SD is chronic, the initial therapy for the condition should be followed by a maintenance regimen. Conventional therapy for SD of the scalp is the use of a medicated shampoo 2 to 3 times per week. Shampoos containing salicylic acid, selenium sulfide, an antifungal agent, or zinc pyrithione are effective.15 In more severe cases, a topical corticosteroid in a lotion, oil, or solution base may be used once or twice daily, often in addition to a medicated shampoo. Seborrheic blepharitis is managed by the gentle removal of scales and crusts using a cotton ball dipped in diluted baby shampoo.15 In severe cases involving the eyelids, the eyelids may be covered with sodium sulfacetamide 10% solution or ketoconazole 2% cream.14,15 In our experience, nonsteroidal anti-inflammatory preparations, such as tacrolimus ointment and pimecrolimus cream, also can be used safely on the eyelids in children under the same guidelines as other cutaneous application sites. 

Conclusion

In summary, a number of factors such as immune function and heredity are important in the pathogenesis of SD. The role of Malassezia in SD needs to be clarified. In most instances, SD is easily diagnosed on clinical grounds alone. Safe and effective treatment modalities are available. More studies are needed to determine whether a relationship between SD and AD exists; however, our clinical experience supports this associator. 

Cutaneous leishmaniasis has several types of lesions, all of which tend to occur on exposed parts because the disease is transmitted by the sandfly. The resulting syndrome depends upon a complex interaction between a specific species of Leishmania and the genetic and immunologic status of the host. Ultimately, either the patient's immune response is able to eliminate the infection and effect a spontaneous cure, or the immune response fails and a chronic form of leishmaniasis develops. The lupoid type spreads peripherally on a common erythematous base and occurs most commonly with the urban type of disease, caused by Leishmania tropica.1,2 

Case Report
A 69-year-old woman was admitted with coalescent, erythematous, papulo-infiltrative, nodular and verrucous plaques on her whole face. The lesion on her nose started one year ago as a slowly growing, indurated, livid, indolent papule that gradually enlarged and spread peripherally to cover a large part of her face in a few months. There was no response to topical antibacterial therapy. Results of a dermatologic examination revealed extensive confluent erythematous papules and infiltrative nodular and verrucous plaques with ulceration that were crusted over. The papules and plaques were localized on the patient's forehead, glabella, eyelids, nose, cheeks, and upper lip (Figure 1). The chin and lower lip were spared. Results of a complete clinical evaluation showed obesity and hypertension. There was no evidence of systemic involvement.

The results of the routine laboratory tests, including complete blood counts and serum biochemistry, were within reference range except for the erythrocyte sedimentation rate, which was 70 mm/h. Staphylococcus aureus was isolated from the bacterial culture of the lesion. Amastigotes of Leishmania species were seen both in monocytes and extracellularly in cutaneous scrapings from the center of the ulcer (Figure 2). A punch biopsy (4 mm in diameter) was performed at the edge of the plaque. Results of a histologic examination revealed a heavy infiltrate of histiocytes, lymphocytes, polymorphonuclear leukocytes, and a few plasma cells under the epithelium. Numerous organisms were present (mostly in histiocytes), which were nonencapsulated and contained a nucleus and a paranucleus (Figure 3). Absence of parasites in the smear prepared from the bone marrow biopsy eliminated the diagnosis of visceral leishmaniasis.

The patient's history, together with the clinical and histopathologic findings and the parasites in the smear obtained from the lesion, supported the diagnosis of lupoid leishmaniasis (LL). Systemic meglumine antimoniate treatment was started with 20 mg/kg per day intramuscularly and continued for 20 days. In addition to this therapy, an oral systemic antibiotic (ampicillin and sulbactam), 375 mg twice daily for 10 days, a topical antiseptic dressing, and an antibacterial ointment were used for secondary bacterial infection. During the treatment, transient elevations were detected in s e rum aminotransferase levels. After 20 days of therapy, lesions became less indurated and smooth (Figure 4), and no parasites were found in the smear obtained from the lesion. The patient was followed for one year after completion of treatment, and no relapse was observed.

Comment Leishmania infection following a bite from an infected sandfly may remain subclinical or may develop after an incubation period of 1 to 12 weeks. During the course of the disease, all classical stages of the development of leishmaniasis from small erythematous papules to nodules to ulcerative lesions can be seen. Secondary bacterial infection is common, which can lead to pain.2 Although LL has been used as a synonym for leishmaniasis recidivans, Oliveira-Neto et al1 stated that there is a clear difference between leishmaniasis recidivans and LL. This difference can be defined as LL being the initial clinical presentation, and leishmaniasis recidivans being a recurrent lesion. Therefore, it is not appropriate to use these 2 names synonymously. LL is a chronic condition that typically follows an acute cutaneous leishmaniasis infection. While the acute lesion heals with scarring, papules and nodules become apparent. The papules have a granulomatous, lupoid appearance and are often associated with ulceration and crusting, as in our case. The papules characteristically are present at the edge of the scarred area. Reported cases are associated predominantly with Old World rather than New World strains of leishmaniasis, with L tropica being the causative agent in most cases.3 Incidences reported for LL, following simple acute cutaneous leishmaniasis, range from 0.5% to 6.2% and are most prevalent in endemic areas of leishmaniasis, particularly in the Middle East.3,4 The clinical differential diagnosis of cutaneous leishmaniasis includes lupus vulgaris, verrucous skin tuberculosis, chronic leishmaniasis, discoid lupus erythematosus, and basal cell carcinoma. The histopathologic changes include epidermal atrophy or sometimes hyperkeratosis and acanthosis, follicular plugging, and a diffuse dermal granulomatous infiltrate composed of histiocytes, lymphocytes, giant cells, and plasma cells. The recurrent lesions generally resemble lupus vulgaris, with tuberculoid granulomas surrounded by a rim of lymphocytes and histiocytes and some giant cells. However, caseation necrosis is generally absent.1,5 Cutaneous leishmaniasis can become disseminated especially in immunosuppressed persons. There is still some question about the pathogenesis of this form of leishmaniasis, though factors such as the specific species involved, the host's immune response, the hormonal changes encountered with increasing age, and the changes in skin barrier with aging can be considered important points in causing such an unusual presentation.6,7 Indeed, parasites cause a defect in T-lymphocyte activation that the macrophages cannot kill.1,8 We think that the lesion became disseminated because our patient was elderly and obese. LL should be considered in all patients from endemic areas (like our country) of leishmaniasis who present with cutaneous large nodulo-plaques. There is no standardized treatment for this condition and thus multiple treatments have been reported with varying degrees of success.2,9 The pentavalent antimony derivatives sodium stibogluconate and meglumine antimoniate remain the mainstay of systemic treatment. Their mode of action is not known, though they inhibit glycolysis and fatty acid oxidation in Leishmania. Their efficacy is well established provided they are given for an adequate length of time.3 This case was treated with daily intramuscular injections of meglumine antimoniate for 20 days with marked improvement of clinical features.

Cutaneous leishmaniasis has several types of lesions, all of which tend to occur on exposed parts because the disease is transmitted by the sandfly. The resulting syndrome depends upon a complex interaction between a specific species of Leishmania and the genetic and immunologic status of the host. Ultimately, either the patient's immune response is able to eliminate the infection and effect a spontaneous cure, or the immune response fails and a chronic form of leishmaniasis develops. The lupoid type spreads peripherally on a common erythematous base and occurs most commonly with the urban type of disease, caused by Leishmania tropica.1,2 

Case Report
A 69-year-old woman was admitted with coalescent, erythematous, papulo-infiltrative, nodular and verrucous plaques on her whole face. The lesion on her nose started one year ago as a slowly growing, indurated, livid, indolent papule that gradually enlarged and spread peripherally to cover a large part of her face in a few months. There was no response to topical antibacterial therapy. Results of a dermatologic examination revealed extensive confluent erythematous papules and infiltrative nodular and verrucous plaques with ulceration that were crusted over. The papules and plaques were localized on the patient's forehead, glabella, eyelids, nose, cheeks, and upper lip (Figure 1). The chin and lower lip were spared. Results of a complete clinical evaluation showed obesity and hypertension. There was no evidence of systemic involvement.

The results of the routine laboratory tests, including complete blood counts and serum biochemistry, were within reference range except for the erythrocyte sedimentation rate, which was 70 mm/h. Staphylococcus aureus was isolated from the bacterial culture of the lesion. Amastigotes of Leishmania species were seen both in monocytes and extracellularly in cutaneous scrapings from the center of the ulcer (Figure 2). A punch biopsy (4 mm in diameter) was performed at the edge of the plaque. Results of a histologic examination revealed a heavy infiltrate of histiocytes, lymphocytes, polymorphonuclear leukocytes, and a few plasma cells under the epithelium. Numerous organisms were present (mostly in histiocytes), which were nonencapsulated and contained a nucleus and a paranucleus (Figure 3). Absence of parasites in the smear prepared from the bone marrow biopsy eliminated the diagnosis of visceral leishmaniasis.

The patient's history, together with the clinical and histopathologic findings and the parasites in the smear obtained from the lesion, supported the diagnosis of lupoid leishmaniasis (LL). Systemic meglumine antimoniate treatment was started with 20 mg/kg per day intramuscularly and continued for 20 days. In addition to this therapy, an oral systemic antibiotic (ampicillin and sulbactam), 375 mg twice daily for 10 days, a topical antiseptic dressing, and an antibacterial ointment were used for secondary bacterial infection. During the treatment, transient elevations were detected in s e rum aminotransferase levels. After 20 days of therapy, lesions became less indurated and smooth (Figure 4), and no parasites were found in the smear obtained from the lesion. The patient was followed for one year after completion of treatment, and no relapse was observed.

Comment Leishmania infection following a bite from an infected sandfly may remain subclinical or may develop after an incubation period of 1 to 12 weeks. During the course of the disease, all classical stages of the development of leishmaniasis from small erythematous papules to nodules to ulcerative lesions can be seen. Secondary bacterial infection is common, which can lead to pain.2 Although LL has been used as a synonym for leishmaniasis recidivans, Oliveira-Neto et al1 stated that there is a clear difference between leishmaniasis recidivans and LL. This difference can be defined as LL being the initial clinical presentation, and leishmaniasis recidivans being a recurrent lesion. Therefore, it is not appropriate to use these 2 names synonymously. LL is a chronic condition that typically follows an acute cutaneous leishmaniasis infection. While the acute lesion heals with scarring, papules and nodules become apparent. The papules have a granulomatous, lupoid appearance and are often associated with ulceration and crusting, as in our case. The papules characteristically are present at the edge of the scarred area. Reported cases are associated predominantly with Old World rather than New World strains of leishmaniasis, with L tropica being the causative agent in most cases.3 Incidences reported for LL, following simple acute cutaneous leishmaniasis, range from 0.5% to 6.2% and are most prevalent in endemic areas of leishmaniasis, particularly in the Middle East.3,4 The clinical differential diagnosis of cutaneous leishmaniasis includes lupus vulgaris, verrucous skin tuberculosis, chronic leishmaniasis, discoid lupus erythematosus, and basal cell carcinoma. The histopathologic changes include epidermal atrophy or sometimes hyperkeratosis and acanthosis, follicular plugging, and a diffuse dermal granulomatous infiltrate composed of histiocytes, lymphocytes, giant cells, and plasma cells. The recurrent lesions generally resemble lupus vulgaris, with tuberculoid granulomas surrounded by a rim of lymphocytes and histiocytes and some giant cells. However, caseation necrosis is generally absent.1,5 Cutaneous leishmaniasis can become disseminated especially in immunosuppressed persons. There is still some question about the pathogenesis of this form of leishmaniasis, though factors such as the specific species involved, the host's immune response, the hormonal changes encountered with increasing age, and the changes in skin barrier with aging can be considered important points in causing such an unusual presentation.6,7 Indeed, parasites cause a defect in T-lymphocyte activation that the macrophages cannot kill.1,8 We think that the lesion became disseminated because our patient was elderly and obese. LL should be considered in all patients from endemic areas (like our country) of leishmaniasis who present with cutaneous large nodulo-plaques. There is no standardized treatment for this condition and thus multiple treatments have been reported with varying degrees of success.2,9 The pentavalent antimony derivatives sodium stibogluconate and meglumine antimoniate remain the mainstay of systemic treatment. Their mode of action is not known, though they inhibit glycolysis and fatty acid oxidation in Leishmania. Their efficacy is well established provided they are given for an adequate length of time.3 This case was treated with daily intramuscular injections of meglumine antimoniate for 20 days with marked improvement of clinical features.

Cutaneous leishmaniasis has several types of lesions, all of which tend to occur on exposed parts because the disease is transmitted by the sandfly. The resulting syndrome depends upon a complex interaction between a specific species of Leishmania and the genetic and immunologic status of the host. Ultimately, either the patient's immune response is able to eliminate the infection and effect a spontaneous cure, or the immune response fails and a chronic form of leishmaniasis develops. The lupoid type spreads peripherally on a common erythematous base and occurs most commonly with the urban type of disease, caused by Leishmania tropica.1,2 

Case Report
A 69-year-old woman was admitted with coalescent, erythematous, papulo-infiltrative, nodular and verrucous plaques on her whole face. The lesion on her nose started one year ago as a slowly growing, indurated, livid, indolent papule that gradually enlarged and spread peripherally to cover a large part of her face in a few months. There was no response to topical antibacterial therapy. Results of a dermatologic examination revealed extensive confluent erythematous papules and infiltrative nodular and verrucous plaques with ulceration that were crusted over. The papules and plaques were localized on the patient's forehead, glabella, eyelids, nose, cheeks, and upper lip (Figure 1). The chin and lower lip were spared. Results of a complete clinical evaluation showed obesity and hypertension. There was no evidence of systemic involvement.

The results of the routine laboratory tests, including complete blood counts and serum biochemistry, were within reference range except for the erythrocyte sedimentation rate, which was 70 mm/h. Staphylococcus aureus was isolated from the bacterial culture of the lesion. Amastigotes of Leishmania species were seen both in monocytes and extracellularly in cutaneous scrapings from the center of the ulcer (Figure 2). A punch biopsy (4 mm in diameter) was performed at the edge of the plaque. Results of a histologic examination revealed a heavy infiltrate of histiocytes, lymphocytes, polymorphonuclear leukocytes, and a few plasma cells under the epithelium. Numerous organisms were present (mostly in histiocytes), which were nonencapsulated and contained a nucleus and a paranucleus (Figure 3). Absence of parasites in the smear prepared from the bone marrow biopsy eliminated the diagnosis of visceral leishmaniasis.

The patient's history, together with the clinical and histopathologic findings and the parasites in the smear obtained from the lesion, supported the diagnosis of lupoid leishmaniasis (LL). Systemic meglumine antimoniate treatment was started with 20 mg/kg per day intramuscularly and continued for 20 days. In addition to this therapy, an oral systemic antibiotic (ampicillin and sulbactam), 375 mg twice daily for 10 days, a topical antiseptic dressing, and an antibacterial ointment were used for secondary bacterial infection. During the treatment, transient elevations were detected in s e rum aminotransferase levels. After 20 days of therapy, lesions became less indurated and smooth (Figure 4), and no parasites were found in the smear obtained from the lesion. The patient was followed for one year after completion of treatment, and no relapse was observed.

Comment Leishmania infection following a bite from an infected sandfly may remain subclinical or may develop after an incubation period of 1 to 12 weeks. During the course of the disease, all classical stages of the development of leishmaniasis from small erythematous papules to nodules to ulcerative lesions can be seen. Secondary bacterial infection is common, which can lead to pain.2 Although LL has been used as a synonym for leishmaniasis recidivans, Oliveira-Neto et al1 stated that there is a clear difference between leishmaniasis recidivans and LL. This difference can be defined as LL being the initial clinical presentation, and leishmaniasis recidivans being a recurrent lesion. Therefore, it is not appropriate to use these 2 names synonymously. LL is a chronic condition that typically follows an acute cutaneous leishmaniasis infection. While the acute lesion heals with scarring, papules and nodules become apparent. The papules have a granulomatous, lupoid appearance and are often associated with ulceration and crusting, as in our case. The papules characteristically are present at the edge of the scarred area. Reported cases are associated predominantly with Old World rather than New World strains of leishmaniasis, with L tropica being the causative agent in most cases.3 Incidences reported for LL, following simple acute cutaneous leishmaniasis, range from 0.5% to 6.2% and are most prevalent in endemic areas of leishmaniasis, particularly in the Middle East.3,4 The clinical differential diagnosis of cutaneous leishmaniasis includes lupus vulgaris, verrucous skin tuberculosis, chronic leishmaniasis, discoid lupus erythematosus, and basal cell carcinoma. The histopathologic changes include epidermal atrophy or sometimes hyperkeratosis and acanthosis, follicular plugging, and a diffuse dermal granulomatous infiltrate composed of histiocytes, lymphocytes, giant cells, and plasma cells. The recurrent lesions generally resemble lupus vulgaris, with tuberculoid granulomas surrounded by a rim of lymphocytes and histiocytes and some giant cells. However, caseation necrosis is generally absent.1,5 Cutaneous leishmaniasis can become disseminated especially in immunosuppressed persons. There is still some question about the pathogenesis of this form of leishmaniasis, though factors such as the specific species involved, the host's immune response, the hormonal changes encountered with increasing age, and the changes in skin barrier with aging can be considered important points in causing such an unusual presentation.6,7 Indeed, parasites cause a defect in T-lymphocyte activation that the macrophages cannot kill.1,8 We think that the lesion became disseminated because our patient was elderly and obese. LL should be considered in all patients from endemic areas (like our country) of leishmaniasis who present with cutaneous large nodulo-plaques. There is no standardized treatment for this condition and thus multiple treatments have been reported with varying degrees of success.2,9 The pentavalent antimony derivatives sodium stibogluconate and meglumine antimoniate remain the mainstay of systemic treatment. Their mode of action is not known, though they inhibit glycolysis and fatty acid oxidation in Leishmania. Their efficacy is well established provided they are given for an adequate length of time.3 This case was treated with daily intramuscular injections of meglumine antimoniate for 20 days with marked improvement of clinical features.