Contact Dermatitis

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Mycobacterium marinum is a nontuberculous mycobacteria that is often acquired via contact with contaminated salt or fresh water. We present a case of a 67-year-old man who developed several solitary nontender nodules on his hands and forearm after working on the underside of his boat. In addition, we provide a review of the literature and discuss how this infection is acquired, the underlying pathogenesis, the cutaneous and histologic findings, the differential diagnosis, the diagnostic methods, and the various treatment options.

Case Report
An otherwise healthy 67-year-old white man presented to the dermatology clinic with a 10-day history of multiple red scaly lesions on his hands and forearm. The patient recalled that the lesions appeared one week after he had scraped his hands on barnacles while cleaning the underside of his boat. On physical examination, the patient had multiple well-circumscribed, nontender, erythematous subcutaneous nodules with central crusting and scaling located on the dorsal aspect of both hands and his left forearm (Figure 1). There was no lymphadenopathy, and the patient denied fever, painful joints, or any other systemic symptoms.

Results from a punch biopsy of one of the lesions on the right dorsal hand were characterized as a mixed dense acute, chronic, and granulomatous infiltrate (Figure 2). Numerous acid-fast bacteria were seen on both Ziehl-Neelsen and Fite stains (Figure 3). In addition, a direct smear fluorochrome stain for acid-fast bacilli was positive. The patient was empirically treated with clarithromycin and ethambutol hydrochloride. Two weeks later, the acid-fast bacilli culture grew out Mycobacterium marinum sensitive to clarithromycin, ethambutol hydrochloride, and rifampin. After 2 months of treatment, his lesions had completely resolved.

Comment
M marinum is a nontuberculous atypical Mycobacterium that can cause cutaneous infection of sites of prior wounds exposed to contaminated fresh or salt water. Known originally as swimming pool granuloma, this infection was first described in 1951 after large outbreaks of cases involving swimming pools.1,2 After widespread pool chlorination in the 1960s, most reported cases were in fishermen and aquarium owners, giving rise to the term fish tank granuloma.3 Ornamental fish such as the Siamese fighting fish Betta splendens and the snakehead Channa striata are common hosts of the mycobacteria.4 With improper chlorination and emergence of chlorine-resistant organisms, swimming pool—associated infections have reemerged.3 After entering through an open wound, M marinum usually causes a tender erythematous nodule or pustule at the site of inoculation. Although the infection typically occurs on the dominant hand, any extremity may be affected. The average incubation period is approximately 2 to 4 weeks but can last as long as 9 months.3,5 With time, the lesion can evolve into a crusted ulcer with an underlying suppurative abscess or a verrucous nodule or plaque. As the infection spreads, multiple nodules can appear following the course of the draining lymphatics. This pattern is commonly known as sporotrichoid spread (Table) because of its resemblance to the ascending lymphangitis of sporotrichosis.2,6 With deeper infections, tenosynovitis may occur and can progress to septic arthritis and osteomyelitis.7 As with other atypical mycobacterial infections, the disease can disseminate and become fatal in immunocompromised patients.

The histopathology findings in patients with M marinum infections can range from acute and chronic inflammation to ill-defined suppurative granulomas, which is similar to findings seen with other types of mycobacterial infections. The granulomas are characterized by surviving organisms contained within a mixture of surrounding histiocytes and lymphocytes. In addition, suppurative granulomas are formed in response to the presence of multiple reactive neutrophils. The organisms rarely are seen on routine hematoxylin and eosin stain but may become positive on acid-fast stains such as Ziehl-Neelsen or Fite.2,8 Epidermal changes, including ulceration and pseudoepitheliomatous hyperplasia, can be seen in chronic lesions.2 Strain characteristics may play a critical role in the pathogenicity of M marinum.9 Several virulence factors now have been identified by using a research model for the pathogenesis in Mycobacterium tuberculosis infection. Factors that are required for intracellular survival of the mycobacteria in macrophages include the exported repetitive protein and the protein encoded by the macrophage-activated gene 24-1.10,11 In addition, the invasion and intracellular persistence protein A is essential for initial invasion of M marinum into macrophages and also allows for the intracellular survival of these organisms.10-12 Results from a purified protein derivative test can be positive in some cases but is not a reliable test for M marinum. Cultures grown at 30°C to 33°C may take at least 2 to 4 weeks and are positive in only 70% to 80% of cases.⁶ Polymerase chain reaction (PCR) may be used to confirm the diagnosis in culture-negative cases.13 Confirmatory tests such as culture and PCR help rule out other diseases that may present with similar clinical and histologic findings (ie, other atypical mycobacterial infections, sporotrichosis, deep fungal infections, leishmaniasis, catscratch disease, and tuberculosis verrucosa cutis). Most recently, via PCR, Cai et al14 has detected that heat shock protein 65 kD gene was present in all lesions containing M marinum. This important finding could lead to an earlier detection of this infection. With time, single lesions often can remit spontaneously, but it may take up to 3 years. During that time, the patient remains at high risk of developing tenosynovitis, septic arthritis that may mimic rheumatoid arthritis,15 osteomyelitis, and dissemination in immunocompromised patients, all of which prompt immediate treatment.2,7 No clinical trials exist for the treatment of M marinum infections because of the small number of patients with this disease. However, trimethoprim-sulfamethoxazole, minocycline, and clarithromycin all are effective treatments.5 Success with minocycline is particularly well-documented in the dermatology literature, even in cases complicated by delayed diagnosis and systemic immunosuppression.16 Anecdotal reports suggest that, despite the similarity in the mechanism and sensitivities of different second-generation tetracyclines, minocycline may be the most effective treatment option.13 On the other hand, clarithromycin is favored as a first-line treatment in the infectious diseases literature.6 Ethambutol hydrochloride and rifampin may be added to treat resistant strains. This combination has been proven to be more effective against M marinum than any single antibiotic regimen.5 Unfortunately, determining antibiotic sensitivity of M marinum is difficult because the organism often responds differently in vivo than in vitro.13 Refractory cases may require surgical debridement.2 The disease can be prevented by wearing gloves while working in fish tanks and immediately cleaning any abrasions or injuries that occur while working in contaminated water.6 Immunocompromised individuals should avoid aquariums completely. 

Conclusion
M marinum is present in both salt and fresh water environments. Infection with the organism usually presents on an extremity as a painful cutaneous nodule with various secondary skin changes and can spread in a sporotrichoid pattern. Because the orga- nism can take several weeks to culture, patients with a presumptive diagnosis of M marinum infection should be initially treated with the appropriate antibiotics. Complications can range from tenosynovitis, septic arthritis, and osteomyelitis to disseminated disease in immunocompromised patients. 

Localized argyria is a rare disorder that occurs less frequently than generalized argyria. The pathogenesis involves direct implantation of silver in the skin or, more rarely, percutaneous absorption of silver salts via the eccrine glands. The silver salts are released into the surrounding tissues. Occupational exposure is the most common cause of localized argyria and occurs most frequently in miners, photographic laboratory workers, and jewelers. Round or oval well-demarcated blue-gray macules typically are seen. Generalized argyria most often results from systemic treatment with drugs that contain silver salts or from inhalation of silver particulates in the workplace.1 Generalized argyria usually presents with blue-gray discoloration of the skin, including non—sun-exposed skin, the lips, tongue, mucous membranes, lunulae, and sclera. Permanent diffuse blue-gray pigmentary change of the skin is observed with generalized argyria.

Case Report
A 58-year-old man presented with an ashen color to his face that had progressed over several years. The patient denied taking any medications and had no significant past medical history. The results of a complete blood count, chemistry panel, liver function test, and hepatitis panel were within reference range. His serum silver level also was within reference range at 11 ng/mL (reference range, 0—14 ng/mL). The results of a physical examination revealed diffuse blue-gray pigmentation distributed over the face and neck with a sharp line of demarcation at the collar (Figure 1). There was no photoaccentuation and no involvement of the nails, mucous membrane, or sclera. For the past 20 years, the patient worked as an electronics technician soldering silver-containing wire in the construction of electronic devices. He wore gloves, long-sleeved shirts, and pants but no protective mask.

The biopsy specimen revealed small, black, refractile granules within the membrane propria of the eccrine glands (Figure 2). Additional biopsy specimens were taken from the healthy skin of the right upper back and revealed no silver granules. These histologic features were consistent with argyria.

Comment
Localized argyria is a rare disorder that presents with asymptomatic blue-gray macules.2 The lesions may be large and ill defined or sharply demarcated, resembling blue nevi.1 The most common cause of localized argyria is occupational exposure; small silver particles enter the skin by mechanical impregnation of workers involved in silver mining, silver refining, silverware and metal alloy manufacturing, and photographic processing.3 Localized argyria also has been attributed to surgical and dental procedures, silver earrings, and acupuncture needles.4-6 Additionally, localized argyria may be caused by percutaneous absorption of silver salts via the eccrine glands, which most likely occurred in this case. Generalized argyria most commonly results from long-term systemic use of silver-containing nose drops or colloidal silver—containing dietary supplements,7 homemade silver solution,8 and ingested or topical silver nitrate.9 Inhalation of silver-bearing dust in industries such as silver refining or metal grinding also may cause generalized argyria. Corneal argyrosis associated with silver soldering has been previously reported10,11; full cutaneous examination was not described in these patients. The presentation of generalized argyria typically begins with gray-brown staining of the gums that progresses to involve the skin diffusely. The mucocutaneous findings in argyria are the results of elevated serum silver levels, which lead to dermal and mucosal deposition of the metal. Histopathology evaluations reveal black-silver granules around the eccrine glands, in the walls of blood vessels, and along elastic fibers. The granules occasionally are found in the arrector pili muscles, perineural tissue, and around collagen fibrils. The slate gray, metallic, or blue-gray pigmentation seen in argyria may be clinically apparent after a few months but usually takes years to develop and depends on the degree of exposure.12,13 In some patients, the entire skin may acquire a slate blue—gray color. Hyperpigmentation is most apparent in sun-exposed areas of the skin, especially the forehead, nose, and hands. Although pigmentary changes occur primarily in sun-exposed sites, the granules are deposited evenly throughout the skin. Light causes silver-containing compounds complexed with proteins in the skin to be reduced to elemental silver, similar to the process of developing photographs.14 In addition, the silver stimulates melanocyte tyrosinase activity, which results in an increase in melanin production.15 The sclerae, nail beds, and mucous membranes also may become hyperpigmented. Viscera, including the spleen, liver, and gut, tend to show a blue discoloration that is evident during abdominal surgery or at postmortem examination. Our patient is unique because he presented with the diffuse pigmentary changes that would be seen with generalized argyria, but the pigmentary changes were limited to his face and neck. Other features suggestive of generalized argyria, such as sclerae and nail changes or silver impregnation in non—sun-exposed skin, were not present. The presence of silver granules in the eccrine glands of only exposed skin favors a diagnosis of localized argyria because of percutaneous silver absorption via the eccrine glands. A careful history is necessary in the diagnosis of argyria, with inquiries about possible occupational and environmental exposure and the use of dietary supplements containing colloidal silver protein. Habitual use of silver-based nose drops may produce pigmentation that is most apparent on the nose and nail lunulae. Scar-localized argyria may occur secondary to the use of silver sulfadiazine cream.16 Other causes of diffuse blue-gray pigmentation include medications (eg, phenothiazines, antimalarials, amiodarone, minocycline), heavy metal exposure (eg, mercury, bismuth, arsenic, gold, lead), hemochromatosis, ochronosis, cyanosis, polycythemia vera, and diffuse melanosis in metastatic melanoma.17 The average human body contains approximately 1 mg of silver.18 Serum silver has a reference range of 0 to 14 ng/mL. The smallest amount of silver reported to produce generalized argyria in humans ranges from 5 to 40 g.19 Although the amount of silver in argyria usually results in no serious effects on human health, a few cases of notable clinical symptoms and signs have been documented. Some of the complications of systemic toxic effects of silver include gastrointestinal tract catarrh, tissue wasting, uremia, albuminuria, fatty degeneration of the liver, hemorrhage, and idiopathic thrombocytopenia.20 The treatment of both localized and generalized argyria is difficult. Hydroquinone, depigmenting creams, and dermabrasion are not successful.9 Selenium and sulfur have been shown to have favorable modifying effects on the metabolism and toxicity of silver by forming complexes with the silver. The Q-switched double-frequency Nd:YAG laser, which has been used in the treatment of tattoos, also may be effective in the treatment of localized argyria.21 Unfortunately, no completely satisfactory treatment modality exists and some pigmentation remains permanent. However, sunscreens and opaque cosmetics may be helpful in masking discoloration and preventing further pigmentary darkening.17 To our knowledge, this is the first presented case of localized argyria secondary to aerosolized silver. This case emphasizes the need for skin protection in individuals with occupational exposure to aerosolized solder. 

Localized argyria is a rare disorder that occurs less frequently than generalized argyria. The pathogenesis involves direct implantation of silver in the skin or, more rarely, percutaneous absorption of silver salts via the eccrine glands. The silver salts are released into the surrounding tissues. Occupational exposure is the most common cause of localized argyria and occurs most frequently in miners, photographic laboratory workers, and jewelers. Round or oval well-demarcated blue-gray macules typically are seen. Generalized argyria most often results from systemic treatment with drugs that contain silver salts or from inhalation of silver particulates in the workplace.1 Generalized argyria usually presents with blue-gray discoloration of the skin, including non—sun-exposed skin, the lips, tongue, mucous membranes, lunulae, and sclera. Permanent diffuse blue-gray pigmentary change of the skin is observed with generalized argyria.

Case Report
A 58-year-old man presented with an ashen color to his face that had progressed over several years. The patient denied taking any medications and had no significant past medical history. The results of a complete blood count, chemistry panel, liver function test, and hepatitis panel were within reference range. His serum silver level also was within reference range at 11 ng/mL (reference range, 0—14 ng/mL). The results of a physical examination revealed diffuse blue-gray pigmentation distributed over the face and neck with a sharp line of demarcation at the collar (Figure 1). There was no photoaccentuation and no involvement of the nails, mucous membrane, or sclera. For the past 20 years, the patient worked as an electronics technician soldering silver-containing wire in the construction of electronic devices. He wore gloves, long-sleeved shirts, and pants but no protective mask.

The biopsy specimen revealed small, black, refractile granules within the membrane propria of the eccrine glands (Figure 2). Additional biopsy specimens were taken from the healthy skin of the right upper back and revealed no silver granules. These histologic features were consistent with argyria.

Comment
Localized argyria is a rare disorder that presents with asymptomatic blue-gray macules.2 The lesions may be large and ill defined or sharply demarcated, resembling blue nevi.1 The most common cause of localized argyria is occupational exposure; small silver particles enter the skin by mechanical impregnation of workers involved in silver mining, silver refining, silverware and metal alloy manufacturing, and photographic processing.3 Localized argyria also has been attributed to surgical and dental procedures, silver earrings, and acupuncture needles.4-6 Additionally, localized argyria may be caused by percutaneous absorption of silver salts via the eccrine glands, which most likely occurred in this case. Generalized argyria most commonly results from long-term systemic use of silver-containing nose drops or colloidal silver—containing dietary supplements,7 homemade silver solution,8 and ingested or topical silver nitrate.9 Inhalation of silver-bearing dust in industries such as silver refining or metal grinding also may cause generalized argyria. Corneal argyrosis associated with silver soldering has been previously reported10,11; full cutaneous examination was not described in these patients. The presentation of generalized argyria typically begins with gray-brown staining of the gums that progresses to involve the skin diffusely. The mucocutaneous findings in argyria are the results of elevated serum silver levels, which lead to dermal and mucosal deposition of the metal. Histopathology evaluations reveal black-silver granules around the eccrine glands, in the walls of blood vessels, and along elastic fibers. The granules occasionally are found in the arrector pili muscles, perineural tissue, and around collagen fibrils. The slate gray, metallic, or blue-gray pigmentation seen in argyria may be clinically apparent after a few months but usually takes years to develop and depends on the degree of exposure.12,13 In some patients, the entire skin may acquire a slate blue—gray color. Hyperpigmentation is most apparent in sun-exposed areas of the skin, especially the forehead, nose, and hands. Although pigmentary changes occur primarily in sun-exposed sites, the granules are deposited evenly throughout the skin. Light causes silver-containing compounds complexed with proteins in the skin to be reduced to elemental silver, similar to the process of developing photographs.14 In addition, the silver stimulates melanocyte tyrosinase activity, which results in an increase in melanin production.15 The sclerae, nail beds, and mucous membranes also may become hyperpigmented. Viscera, including the spleen, liver, and gut, tend to show a blue discoloration that is evident during abdominal surgery or at postmortem examination. Our patient is unique because he presented with the diffuse pigmentary changes that would be seen with generalized argyria, but the pigmentary changes were limited to his face and neck. Other features suggestive of generalized argyria, such as sclerae and nail changes or silver impregnation in non—sun-exposed skin, were not present. The presence of silver granules in the eccrine glands of only exposed skin favors a diagnosis of localized argyria because of percutaneous silver absorption via the eccrine glands. A careful history is necessary in the diagnosis of argyria, with inquiries about possible occupational and environmental exposure and the use of dietary supplements containing colloidal silver protein. Habitual use of silver-based nose drops may produce pigmentation that is most apparent on the nose and nail lunulae. Scar-localized argyria may occur secondary to the use of silver sulfadiazine cream.16 Other causes of diffuse blue-gray pigmentation include medications (eg, phenothiazines, antimalarials, amiodarone, minocycline), heavy metal exposure (eg, mercury, bismuth, arsenic, gold, lead), hemochromatosis, ochronosis, cyanosis, polycythemia vera, and diffuse melanosis in metastatic melanoma.17 The average human body contains approximately 1 mg of silver.18 Serum silver has a reference range of 0 to 14 ng/mL. The smallest amount of silver reported to produce generalized argyria in humans ranges from 5 to 40 g.19 Although the amount of silver in argyria usually results in no serious effects on human health, a few cases of notable clinical symptoms and signs have been documented. Some of the complications of systemic toxic effects of silver include gastrointestinal tract catarrh, tissue wasting, uremia, albuminuria, fatty degeneration of the liver, hemorrhage, and idiopathic thrombocytopenia.20 The treatment of both localized and generalized argyria is difficult. Hydroquinone, depigmenting creams, and dermabrasion are not successful.9 Selenium and sulfur have been shown to have favorable modifying effects on the metabolism and toxicity of silver by forming complexes with the silver. The Q-switched double-frequency Nd:YAG laser, which has been used in the treatment of tattoos, also may be effective in the treatment of localized argyria.21 Unfortunately, no completely satisfactory treatment modality exists and some pigmentation remains permanent. However, sunscreens and opaque cosmetics may be helpful in masking discoloration and preventing further pigmentary darkening.17 To our knowledge, this is the first presented case of localized argyria secondary to aerosolized silver. This case emphasizes the need for skin protection in individuals with occupational exposure to aerosolized solder. 

Localized argyria is a rare disorder that occurs less frequently than generalized argyria. The pathogenesis involves direct implantation of silver in the skin or, more rarely, percutaneous absorption of silver salts via the eccrine glands. The silver salts are released into the surrounding tissues. Occupational exposure is the most common cause of localized argyria and occurs most frequently in miners, photographic laboratory workers, and jewelers. Round or oval well-demarcated blue-gray macules typically are seen. Generalized argyria most often results from systemic treatment with drugs that contain silver salts or from inhalation of silver particulates in the workplace.1 Generalized argyria usually presents with blue-gray discoloration of the skin, including non—sun-exposed skin, the lips, tongue, mucous membranes, lunulae, and sclera. Permanent diffuse blue-gray pigmentary change of the skin is observed with generalized argyria.

Case Report
A 58-year-old man presented with an ashen color to his face that had progressed over several years. The patient denied taking any medications and had no significant past medical history. The results of a complete blood count, chemistry panel, liver function test, and hepatitis panel were within reference range. His serum silver level also was within reference range at 11 ng/mL (reference range, 0—14 ng/mL). The results of a physical examination revealed diffuse blue-gray pigmentation distributed over the face and neck with a sharp line of demarcation at the collar (Figure 1). There was no photoaccentuation and no involvement of the nails, mucous membrane, or sclera. For the past 20 years, the patient worked as an electronics technician soldering silver-containing wire in the construction of electronic devices. He wore gloves, long-sleeved shirts, and pants but no protective mask.

The biopsy specimen revealed small, black, refractile granules within the membrane propria of the eccrine glands (Figure 2). Additional biopsy specimens were taken from the healthy skin of the right upper back and revealed no silver granules. These histologic features were consistent with argyria.

Comment
Localized argyria is a rare disorder that presents with asymptomatic blue-gray macules.2 The lesions may be large and ill defined or sharply demarcated, resembling blue nevi.1 The most common cause of localized argyria is occupational exposure; small silver particles enter the skin by mechanical impregnation of workers involved in silver mining, silver refining, silverware and metal alloy manufacturing, and photographic processing.3 Localized argyria also has been attributed to surgical and dental procedures, silver earrings, and acupuncture needles.4-6 Additionally, localized argyria may be caused by percutaneous absorption of silver salts via the eccrine glands, which most likely occurred in this case. Generalized argyria most commonly results from long-term systemic use of silver-containing nose drops or colloidal silver—containing dietary supplements,7 homemade silver solution,8 and ingested or topical silver nitrate.9 Inhalation of silver-bearing dust in industries such as silver refining or metal grinding also may cause generalized argyria. Corneal argyrosis associated with silver soldering has been previously reported10,11; full cutaneous examination was not described in these patients. The presentation of generalized argyria typically begins with gray-brown staining of the gums that progresses to involve the skin diffusely. The mucocutaneous findings in argyria are the results of elevated serum silver levels, which lead to dermal and mucosal deposition of the metal. Histopathology evaluations reveal black-silver granules around the eccrine glands, in the walls of blood vessels, and along elastic fibers. The granules occasionally are found in the arrector pili muscles, perineural tissue, and around collagen fibrils. The slate gray, metallic, or blue-gray pigmentation seen in argyria may be clinically apparent after a few months but usually takes years to develop and depends on the degree of exposure.12,13 In some patients, the entire skin may acquire a slate blue—gray color. Hyperpigmentation is most apparent in sun-exposed areas of the skin, especially the forehead, nose, and hands. Although pigmentary changes occur primarily in sun-exposed sites, the granules are deposited evenly throughout the skin. Light causes silver-containing compounds complexed with proteins in the skin to be reduced to elemental silver, similar to the process of developing photographs.14 In addition, the silver stimulates melanocyte tyrosinase activity, which results in an increase in melanin production.15 The sclerae, nail beds, and mucous membranes also may become hyperpigmented. Viscera, including the spleen, liver, and gut, tend to show a blue discoloration that is evident during abdominal surgery or at postmortem examination. Our patient is unique because he presented with the diffuse pigmentary changes that would be seen with generalized argyria, but the pigmentary changes were limited to his face and neck. Other features suggestive of generalized argyria, such as sclerae and nail changes or silver impregnation in non—sun-exposed skin, were not present. The presence of silver granules in the eccrine glands of only exposed skin favors a diagnosis of localized argyria because of percutaneous silver absorption via the eccrine glands. A careful history is necessary in the diagnosis of argyria, with inquiries about possible occupational and environmental exposure and the use of dietary supplements containing colloidal silver protein. Habitual use of silver-based nose drops may produce pigmentation that is most apparent on the nose and nail lunulae. Scar-localized argyria may occur secondary to the use of silver sulfadiazine cream.16 Other causes of diffuse blue-gray pigmentation include medications (eg, phenothiazines, antimalarials, amiodarone, minocycline), heavy metal exposure (eg, mercury, bismuth, arsenic, gold, lead), hemochromatosis, ochronosis, cyanosis, polycythemia vera, and diffuse melanosis in metastatic melanoma.17 The average human body contains approximately 1 mg of silver.18 Serum silver has a reference range of 0 to 14 ng/mL. The smallest amount of silver reported to produce generalized argyria in humans ranges from 5 to 40 g.19 Although the amount of silver in argyria usually results in no serious effects on human health, a few cases of notable clinical symptoms and signs have been documented. Some of the complications of systemic toxic effects of silver include gastrointestinal tract catarrh, tissue wasting, uremia, albuminuria, fatty degeneration of the liver, hemorrhage, and idiopathic thrombocytopenia.20 The treatment of both localized and generalized argyria is difficult. Hydroquinone, depigmenting creams, and dermabrasion are not successful.9 Selenium and sulfur have been shown to have favorable modifying effects on the metabolism and toxicity of silver by forming complexes with the silver. The Q-switched double-frequency Nd:YAG laser, which has been used in the treatment of tattoos, also may be effective in the treatment of localized argyria.21 Unfortunately, no completely satisfactory treatment modality exists and some pigmentation remains permanent. However, sunscreens and opaque cosmetics may be helpful in masking discoloration and preventing further pigmentary darkening.17 To our knowledge, this is the first presented case of localized argyria secondary to aerosolized silver. This case emphasizes the need for skin protection in individuals with occupational exposure to aerosolized solder. 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49 

Pemphigus describes a group of autoimmune chronic bullous diseases, originally named in 1791.1 The term pemphigus stems from the Greek pemphix meaning blister or bubble.2 Pemphigus is usually divided into 2 major forms depending on blister location: pemphigus vulgaris (PV) and pemphigus foliaceus (PF). Pemphigus vegetans is a variant of PV, and pemphigus erythematosus (PE) and fogo selvagem are variants of PF. During the past 3 decades, uncommon forms of pemphigus have been described, including pemphigus herpetiformis, immunoglobulin A (IgA) pemphigus, and paraneoplastic pemphigus.3 The incidence of pemphigus ranges from 0.76 to 5 new cases per million per year.2 In a recent analysis of 1209 patients with pemphigus in Iran, the PV to PF ratio was found to be 12:1. However, this ratio varies widely in different parts of the world.4 In one report, 73% of cases of pemphigus in France were PV.5 PV also is the most common clinical type of pemphigus in Kuwait, Israel, and Singapore.6-8 In a report on pemphigus in South Africa, the most common clinical variant was PF, and 80% of these patients were black.9 Of note, in the Indian population in this region, PV was more common. A high percentage of PF is endemic in rural Brazil, Tunisia, and Columbia.9 

Case Report
A 58-year-old white woman presented with a 6-month history of superficial erosions on the chest, upper back, hairline, and retroauricular areas. She denied any photosensitivity, and there was no mucosal involvement. The patient's medical history was otherwise unremarkable. Superficial erosions with a positive Nikolsky sign were present on the chest (Figure), upper back, and frontal hairline, as well as in the retroauricular areas bilaterally. Two punch biopsies (one lesional and one perilesional) were performed. Routine histology results showed intraepidermal vesicles in the upper granular layer containing acantholytic cells. Results of direct immunofluorescence demonstrated IgG and complement 3 (C3) in the intercellular spaces in the epidermal cell surface. Of note, antinuclear antibody and anti–double-stranded DNA were negative. These findings were consistent with our clinical diagnosis of PF.

The patient was initially started on a high potency topical corticosteroid (clobetasol propionate ointment) for 4 weeks with no improvement. She was then given prednisone 60 mg/d for approximately one month when new lesions ceased to appear; then the medication was slowly tapered off. Dapsone also was added to her regimen after an initial baseline level of glucose-6-phosphate dehydrogenase and a baseline complete blood count were obtained. Dapsone was initiated at 50 mg/d while prednisone was being slowly tapered. Cacit D3 in a single morning dose (1000 mg calcium and 880 IU vitamin D) also was added to the regimen. Of note, the patient was taking celecoxib for intermittent joint pain, but a literature search at that time did not reveal an association with similar eruptions; our patient was asked to discontinue the celecoxib at the initiation of oral prednisone. She was seen at regular follow-up visits every month. As the patient improved clinically, dapsone was reduced to 25 mg and finally discontinued after about 6 months. Oral prednisone taper continued slowly over a total of 18 months. No lesions were present for the last 3 monthly visits.

Comment
PF comprises 2 major categories: endemic and sporadic. The endemic form, also known as fogo selvagem, primarily affects children and young adults in rural Brazil. In contrast, the sporadic form of PF is generally a disease of middle-aged individuals and the elderly. Of note, there are several cases of nonendemic PF occurring in children,10 and 2 cases reported in the neonatal period.11 Many patients with PE show serologic findings suggestive of systemic lupus erythematosus (SLE), especially the presence of anti-nuclear antibodies.2,12 PF is an autoimmune blistering disease of unknown etiology with antibodies produced against desmoglein 1 (Dsg1).13 Dsg1 is an adhesive cadherin protein found in the desmosomal cell junction in the suprabasal layers of the epidermis.14,15 Binding of the antibody results in the loss of cell adhesion or acantholysis and formation of the clinical picture of PF.16 The blisters are subcorneal, occurring in and around the granular cell layer of the epidermis.13 Blister formation is superficial because the most differentiated layer of the epidermis is the only area in which Dsg1 is critically important to cell adhesion, and there is no protection redundancy of adhesion molecules by coexpression of Dsg3.17 Of interest, one study has demonstrated that the autoantibodies in up to 7% of patients with PF and up to 50% of patients with PV recognize both Dsg1 and Dsg3 isoforms.18 It also is reported that some patients can progress from PF to PV or vice versa, though the latter is less common.19 It has been shown that this transition correlates well with the qualitative and quantitative changes in the profile of Dsg1 and Dsg3 antibodies.20 Patients with PF have been reported to have a predominance of circulating IgG4 antiepidermal autoantibodies, followed by a lesser degree of IgG1, IgG2, and IgG3 subclasses.21 PF has shown a strong association with several HLA-DRB1 haplotypes.22,23 Most recently, an association with HLA-DRB1*0101 was found in the Mexican population.24 Sunlight exposure25 and several drugs such as penicillamine26,27 have been identified as possible triggering factors for the disease. In children, bacteria, cytomegalovirus, and otitis also have been implicated.10 Similarly, an unusual case of childhood PF apparently triggered by conjunctivitis was reported.28 PF manifests clinically as recurrent shallow erosions accompanied by erythema, scaling, and crusting.29 Lesions usually are found in a seborrheic distribution (central face, neck, chest, or upper back).30 Patients develop superficial fragile vesicles, which often are not seen. In contrast to PV, PF patients rarely have mucosal involvement.11 The onset of disease may be slow, starting with only a few transient scattered crusted lesions.2 The condition may then stay localized for years or progress into generalized involvement, sometimes resulting in an exfoliative erythroderma.31 In general, patients are not severely ill but often complain of burning and pain associated with the skin lesions.2 Fogo selvagem, formerly known as Brazilian PF, occurs in an endemic fashion in certain regions of Brazil.32 The condition has been described in certain regions of Brazil since the turn of the century.33 The prevalence in some rural areas of Brazil is as high as 3.4%.34 There also have been reports of other possible foci of endemic PF in Tunisia and Columbia.35,36 Endemic PF differs from sporadic PF in its geographic distribution, high familial incidence, and young age of onset.36 The clinical manifestations, histology, and immunopathologic features are indistinguishable from sporadic PF.29,32 The distinct epidemiology of the condition is suggestive of an environmental or infectious agent. Studies have identified that most patients are young peasants or children who live in close proximity to rivers, which exposes the children to the hematophagous insect belonging to the Simulium nigrimanum species, also known by its popular name borrachudo (blackfly).37,38 PE was first described by Senear and Usher39 in 1926. Originally, the term PE was introduced to describe patients with immunologic features of both SLE and pemphigus.2 Many patients with PE show serologic findings suggestive of SLE, especially the presence of antinuclear antibodies.12,40 However, there are only a few reports of PE occurring in patients who have clearly defined SLE.41,42 In most of these cases, the diagnosis of SLE had been established months to years earlier.42 PE also may be associated with a variety of autoantibodies and may require extensive immunotherapy.43 PE has characteristic findings on direct immunofluorescence, usually IgG and C3 at the basement membrane zone of erythematous facial skin, in addition to the epidermal cell surface IgG.12,44 Clinically, the lesions of PE resemble those of PF but are most commonly restricted to the upper trunk, head, and neck.42 PE may remain localized for years, or it may evolve into more generalized PF.40 PE also has been associated with myasthenia gravis and thymomas.45 The histologic changes of PF, PE, and fogo selvagem are identical.2 Early blisters indicate acantholysis just below the stratum corneum and in the granular layer. The stratum corneum often is lost from the surface of these lesions. The deeper epidermis, below the granular layer, remains intact. Another frequent finding is subcorneal pustules, with neutrophils and acantholytic epidermal cells in the blister cavity.12 Immunofluorescence using both direct and indirect techniques is the most reliable method of diagnosing pemphigus.46 Most patients with pemphigus have IgG and C3 deposits at the epidermal cell surfaces and circulating IgG against the same components.47 However, the cell staining pattern of both direct and indirect immunofluorescence is virtually identical in PV and PF, making it difficult to distinguish between them.48 One innovation has been the introduction of an antigen-specific ELISA (enzyme-linked immunosorbent assay) test for the diagnosis of pemphigus: if a serum is positive against Dsg3, the test results indicate a diagnosis of PV, regardless of reactivity against Dsg1; if a serum is negative for Dsg3 and positive for Dsg1, the test results indicate a diagnosis of PF.48 The differential diagnosis of PF includes other forms of pemphigus, bullous impetigo, subcorneal pustular dermatosis, linear IgA dermatosis, and seborrheic dermatitis.2,30 Before the advent of glucocorticoid therapy, PF was fatal in about 60% of patients.12 The aim of current therapy is to suppress the production of pathogenic antibodies, stop the development of new lesions, and heal old lesions.49 The therapy of PF differs from that of PV only in that treatment can be less aggressive because morbidity and mortality are lower.26 In all patients, a complete review of medications should be done to exclude the possibility of drug-induced PF. The most commonly implicated medications are penicillamine,27 captopril,50 lisinopril,51 nifedipine,52 and topical imiquimod.53 Because PF may be localized for many years and the prognosis without systemic therapy may be good, patients do not necessarily require systemic therapy. This patient group may be treated successfully with topical corticosteroids.29,54 Patients with active and widespread disease require systemic therapy.16 An initial dose of prednisone at 1.0 mg/kg can usually be tapered down toward an alternate-day dosage within 1 to 3 months.29 One patient has been kept on a low dose of corticosteroids successfully as maintenance over an extended period.55 Patients with the most severe disease (ie, disease unresponsive to corticosteroids) should be considered for adjuvant immunosuppressive drugs as steroid-sparing agents.29,49 The goal of immunosuppressive therapy is to suppress the production of antibodies. One of the medications used is mycophenolate mofetil, which is shown to be an effective steroid-sparing agent.56,57 Oral cyclophosphamide, which also is an effective adjuvant alkylating agent in the treatment of severe and refractory PV and PF, can be combined with pulse intravenous corticosteroids. However, the use of alkylating agents should be done with care because of the risk of side effects such as hemorrhagic cystitis, susceptibility to infection, potential infertility, mutagenic potential, and lifetime risk for transitional cell carcinoma of the bladder and hematologic malignancies.58 Other immunosuppressive medications that have been used include azathioprine,59,60 methotrexate,61,62 and cyclosporine.63,64 In patients for whom conventional therapies have failed, alternative therapies such as intravenous immunoglobulin,65 plasmapheresis,⁶⁶ and extracorporeal photochemotherapy67,68 have been employed successfully. A single case of PF occurring after unrelated cord blood transplantation was reported to be successfully treated with rituximab, an anti-CD20 antibody.69 Dapsone has been used both as monotherapy and in combination regimens. In a study of 9 patients, 5 had at least 50% improvement.70 Only patients with low titers or undetectable circulating antibodies responded to monotherapy. The value of dapsone in the treatment of PF remains to be clearly established.71 There have been a few case reports indicating that a combination of tetracycline and niacinamide is an effective alternative to steroids in superficial pemphigus.72 Other agents reported in the literature include gold,43,73 chlorambucil,74 and hydroxychloroquine sulfate.75 It is commonly perceived that PF is more benign than PV. Although uncommon, there are several reports of death occurring in PF.65,76 Infection is often the cause of death, and therapy is frequently a contributing factor because it causes the immunosuppression necessary to treat active disease.77 The effective management of PF requires a knowledge of the pathophysiology and pharmacologic effects of the agents used, an ability to make an accurate diagnosis, and an understanding of the patient's expectations.49 

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.