Case Letter

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

Nephrogenic systemic fibrosis (NSF) is an emerging medical entity in patients with renal disease, which results in progressive cutaneous and systemic fibrosis. It is a rare disorder that has been recognized in patients with renal impairment since 2000.¹ Patients with NSF demonstrate symmetric dermal and subcutaneous fibrosis evidenced by increasing skin induration on clinical examination. Nephrogenic systemic fibrosis most commonly involves the lower extremities, and after extending to the upper extremities and trunk, it sporadically involves the head and neck.

The clinical manifestation of NSF begins with edema, followed by marked dermal induration, sclerotic plaques, and joint contractures that can lead to considerable disability. Pathogenesis remains to be elucidated; it has been hypothesized that it could be related to gadolinium (Gd). Currently, there is no treatment of this unremitting disease.^1-3 We report the case of a patient affected by NSF after administration of Gd for magnetic resonance angiography.

A 56-year-old woman was referred to the department of dermatology at the University of Maryland (Baltimore, Maryland) with persistent swelling of the lower legs, forearms, and trunk of 5 months’ duration. She had end-stage renal disease of nonspecific origin. Five months prior to presentation, she had magnetic resonance angiography, during which 10 mmol of Gd was administered. After, she developed a persistent rash and swelling of the lower legs. On presentation, physical examination revealed symmetric, shiny, pigmented papules and plaques on the forearms, buttocks, thighs, and legs, with no facial involvement (Figure).

Symmetric pigmented papules and plaques on the right shoulder.

A skin biopsy of thigh lesions showed a diffuse dermal proliferation of bland spindle cells associated with dermal fibrosis. A CD4⁺ cellular infiltrate showed extension into the subcutaneous tissue. Deposition of Gd also was noted in the skin. She was treated with corticosteroid therapy, and after 2 months she reported softening of the affected skin. On 6-month follow-up, her skin lesions did not progress and there was no evidence of systemic involvement. Additionally, renal function had improved.

Nephrogenic systemic fibrosis, also known as nephrogenic fibrosing dermopathy, was first described by Cowper et al¹ in 2000. Since then, more than 215 cases have been reported in the literature. Clinically, it is characterized by acute onset of cutaneous hardening and thickening of the extremities and the trunk, often resulting in flexion contractures. There may be varying surface changes such as pigmentation, peau d’orange texture, and shiny sclerosis. Patients often experience unpleasant symptoms such as pain, pruritus, stiffness, and paresthesia. Systemic involvement has been documented in the heart, lung, tendons, muscle, testes, and lamina dura.^1-4

Histologic findings of NSF are diffuse dermal fibrosis with increased cellular infiltrates comprised of bland spindled fibrocytes. These fibrocytes express CD34 and type I procollagen. Collagen bundles are thickened but retain clefting, and elastic fibers often are prominent. This fibrotic pattern typically extends to the subcutaneous fat septa, which are widened and collagenous. The epidermis generally is uninvolved. Other findings include dermal mucin deposition, calcification of collagen and vessels, increased CD68⁺ histiocytes, increased factor XIIIa and dendritic cells, and neoangiogenesis. Rarely, multinucleated giant cells and Miescher radial granulomas with lymphocytic aggregates mimicking erythema nodosum have been described.^2-4

Dermatologic entities with similar clinical and histopathologic features, including scleroderma, scleromyxedema, lipodermatosclerosis, erythema nodosum, eosinophilic fasciitis, and spindle cell neoplasms, should be excluded.^1-4 The exact pathogenetic mechanisms of NSF have yet to be determined, but there is strong evidence that Gd plays an important causative role.¹ In fact, almost all patients with NSF have been exposed to Gd. Gadolinium has been documented in affected skin of patients with NSF and has been shown to induce NSF-like changes in rat models.

Other clinical factors that have been associated with NSF include erythropoietin, elevated serum calcium and phosphate levels, vascular injury or surgery, iron metabolic abnormalities, and metabolic acidosis. It is likely that many factors in the unique physiologic state of patients with renal failure contribute to the abnormal fibrotic reaction to Gd-containing contrast agents in NSF. Gadolinium is a member of a group of 15 elemental metals termed lanthanoids and has been used extensively worldwide in magnetic resonance imaging as a component of intravenously administered contrast agents. Currently, 6 such agents are approved for use in the United States: gadopentetate dimeglumine, gadoteridol, gadodiamide, gadoversetamide, gadobenate dimeglumine, and gadoxetate sodium. All are chelated Gd products, with the chelate serving to prevent toxicity from free Gd ions.

In patients with no renal function abnormalities, the biologic half-life of Gd-based magnetic resonance contrast agents (GBCAs) is 1.5 to 2.0 hours. However, in patients with abnormal kidney function, this half-life is inversely prolonged, proportional to the glomerular filtration rate.^5-7 The link between GBCA administration and NSF is compelling, though other etiologic associations have been reported. Surgical or vascular procedures, history of a hypercoagulable state, erythropoietin administration, and immune suppression have been proposed as triggering factors in NSF. The proposed mechanisms responsible for fibrosis in NSF have centered on a collagen-producing cell in the peripheral blood termed the circulating fibrocyte. These cells express CD34 and CD45RO antigens and are capable of producing type I collagen.

Circulating fibrocytes traffic to areas of chronic antigenic stimulation promoting wound repair and fibrotic reactions. Some authors have proposed that materials deposited in the skin might serve as targets for circulating fibrocytes.⁸ Circulating fibrocytes also are known to produce inflammatory cytokines including IL-1 and chemokines such as platelet-derived growth factor, transforming growth factor b, and others capable of propagating fibrotic responses. Increased expression of transforming growth factor has been reported in dendritic cells in NSF lesions and Parsons et al⁹ postulated that transglutaminase-2 activation of this protein may be responsible for inciting fibrosis in NSF. Transglutaminases also are known to be directly activated by Gd.^10,11

Transmetalation has been proposed as a possible operative phenomenon responsible for NSF. Several cations including zinc, copper, iron, and carbon are known to compete with Gd and may displace it from the ligand, with anions such as OHe, PO4 3e, and CO3 2e binding the resultant free Gd. Some GBCAs contain excess ligand to diminish potential free Gd concentrations. In fact, substantial elevations of serum calcium and phosphorus in patients with NSF have been noted in a large series of patients with NSF. Calciphylaxis, an often catastrophic condition arising in patients with renal failure, has been described in association with NSF, and sodium thiosulfate has been used with success in treating both conditions.¹⁰ In addition, Sanyal et al¹² noted a substantially higher serum calcium in NSF cases compared with controls.

Gadolinium plays an important role in the pathology of NSF and is confirmed by the presence of Gd in skin biopsies.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

To the Editor:

A 68-year-old man with a history of myelodysplastic syndrome and recurrent Sweet syndrome presented with left leg lesions of 3 months’ duration. The lesions originated as a solitary nodule on the left calf and subsequently developed into multiple nonpainful, nonpruritic, erythematous plaques of varying sizes with violaceous coloration and overlying necrotic eschar, occupying the entire anterior aspect of the left lower leg and left popliteal fossa (Figure). The patient denied any trauma or associated symptoms but had a history of Sweet syndrome that manifested as lesions on the arms and legs for which he took 6 mg of prednisone daily to prevent recurrence.

Multiple erythematous to violaceous plaques with overlying necrotic eschar on the anterior aspect of the left lower leg.

Histologic examination revealed nodular and diffuse chronic granulomatous and acute inflammatory infiltrate. Stains for bacteria, fungi, and acid-fast bacilli were negative. Cultures subsequently grew Mycobacterium kansasii, and the patient was started on isoniazid 300 mg daily, rifampin 600 mg daily, ethambutol 800 mg daily, and pyridoxine 50 mg daily. Chest radiograph and computed tomography showed no evidence of pulmonary disease and 2 blood cultures were negative for growth. The patient subsequently developed weakness that he attributed to the antibiotics and he decided to discontinue all treatment.

At 11 months the lesions showed no change; however, magnetic resonance imaging of the leg was suggestive of osteomyelitis. The patient was started on clarithromycin 500 mg twice daily with planned addition of isoniazid. The patient refused any additional antibiotics but agreed to continue the clarithromycin treatment for one year. He was subsequently lost to dermatology follow-up.

Nontuberculous mycobacteria (NTM) infection is a rare sequela of hematologic malignancy, seen in only 1.5% of patients.¹ The NTM most commonly seen in hematologic malignancy are generally the fast-growing species Mycobacterium abscessus, Mycobacterium chelonae, Mycobacterium fortuitum, or Mycobacterium phlei, rather than slow growers Mycobacterium avium, Mycobacterium intracellulare, Mycobacterium kansasii, Mycobacterium marinum, and Mycobacterium xenopi. Mycobacterium kansasii infection, such as seen in our patient, accounts for only 18% of cases.¹ This case is further distinguished by the fact that cutaneous infections with NTM also are generally caused by fast-growing organisms such as Mycobacterium abscessus-chelonae complex and M fortuitum, rather than the slow-growing M kansasii.^2,3

Mycobacterium kansasii is a slow-growing, acid-fast bacillus found in local water reservoirs, swimming pools, sewers, and tap water where it can live for up to 12 months.^2,4,5Mycobacterium kansasii is traditionally considered the most virulent NTM.^3,6 It most frequently causes a pulmonary infection in the immunosuppressed and patients with chronic bronchopulmonary disease.^6,7 Disseminated disease is less common and is primarily seen in immunocompromised patients, particularly in human immunodeficiency virus–positive patients, transplant recipients, and patients with hematologic malignancies.^1,6,8 Disseminated disease rarely has been seen in patients with normal immune function.^2,3

Cutaneous M kansasii infection has only infrequently been described. Most patients tend to be middle-aged men, with a median affected age of 43 years.^2,7,9,10 One review of cutaneous cases found that 72% had some form of altered immunity and more than 50% of those patients were on chronic steroids. The same review found that of the cases of cutaneous M kansasii in patients with altered immunity, only 30% had disseminated disease.¹⁰ Our patient was immunocompromised but showed no evidence of disseminated disease, as displayed by negative chest radiograph and computed tomography, lack of pulmonary symptoms, and negative blood cultures. As a 68-year-old man with myelodysplastic syndrome on chronic steroids with no disseminated disease, our patient fits well into these demographics, aside from his advanced age.

Cutaneous M kansasii infection has a variable presentation, manifesting as solitary lesions, nodules, pustules, seromas, erythematous plaques, verrucous lesions, ulcers, and as cellulitis.^5,7,9-12 Immune competent individuals were more likely to present with raised lesions or ulcers, whereas immune compromised individuals had a more diffuse presentation of cellulitis or seromas with variable histology.^6,8 Our patient, though immune compromised, presented with multiple erythematous plaques with eschars, which further endorses having a high clinical suspicion, as the lesions display marked heterogeneity.

Treatment of M kansasii infection consists of at least 1 year of isoniazid 300 mg daily, rifampin 600 mg daily, and ethambutol 15 mg/kg daily, with possible addition of streptomycin.^8,13Mycobacterium kansasii infection necessitates multidrug treatment due to the broad range of resistance exhibited by different isolated strains.¹⁴

Response to treatment in cutaneous M kansasii greatly depends on the underlying disease state of the individual. Generally, immune competent individuals do very well, while the course in immune compromised patients depends on their degree of illness. Patients with disseminated disease generally do poorly.^4,7,10 In at least one case of cutaneous disease, dissemination developed as a sequela, thus suggesting treatment is needed even in stable lesions.² Dissemination was a concern with our patient given the magnetic resonance imaging findings suggestive of osteomyelitis. Although treatment generally consists of triple therapy with isoniazid, rifampin, and ethambutol, given the high frequency of adverse effects due to isoniazid or rifampin, as was seen in our patient, the drug regimen might have to be altered to suit the patient. Susceptibility testing is desirable to aid in tailoring the treatment.^8,13 Furthermore, as the duration of treatment is at least 1 year, diligent follow-up must be maintained to avoid incomplete treatment.

The unpredictable presentation of cutaneous M kansasii infection coupled with the variable history necessitates a high level of clinical suspicion and a low threshold for culturing lesions. Furthermore, the long duration and complexity of the antibiotic regimen and the high incidence of adverse reactions demands strict follow-up, especially given the risk for progression to disseminated disease.

To the Editor:

Progressive cribriform and zosteriform hyperpigmentation (PCZH) was first described by Rower et al¹ in 1978. The diagnostic criteria included the following: (1) uniformly tan cribriform macular pigmentation in a zosteriform distribution; (2) a histologic pattern that consisted of a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells; (3) no history of rash, injury, or inflammation to suggest postinflammatory hyperpigmentation; (4) onset occurring well after birth with gradual extension; and (5) lack of other associated cutaneous or internal abnormalities.¹

Many pigmentary disorders occurring along the Blaschko lines are included in differential diagnosis of PCZH such as incontinentia pigmenti (IP), progressive zosteriform macular pigmented lesion (PZMPL), and linear and whorled nevoid hypermelanosis (LWNH). However, PCZH is considered to be the localized variant (the late onset) of LWNH.² We report a case of PCZH, a segmented and delayed form of LWNH.

A 25-year-old woman presented with asymptomatic progressive multiple brownish macular eruptions arranged in a zosteriform pattern on the left arm and thigh of 3 months’ duration. There was no history of injury or any prior cutaneous changes. There was no personal or family history of similar eruptions and she was otherwise in good health. She was not taking any medications. Physical examination showed linear, uniformly tanned, cribriform hyperpigmentation along the Blaschko lines on the left arm and thigh (Figure 1). Routine laboratory tests, including complete blood cell count with differential, were normal. Assuming a diagnosis of PCZH or PZMPL, we performed a punch biopsy on the left upper arm. The histopathologic findings showed increased pigmentation of the basal layer. There were a few dermal melanophages and no nevus cells present (Figure 2A). Fontana-Masson stain showed an increase in melanin in the basal layer (Figure 2B). On the basis of these clinical and histological findings, a diagnosis of PCZH was made. She was observed without treatment for 6 months showing no change.

Figure 1. Asymptomatic linear, uniformly tanned, cribriform hyperpigmentation along the Blaschko lines on the left arm (A) and thigh (B).

Progressive cribriform and zosteriform hyperpigmentation is a disorder of pigmentation along the Blaschko lines. The trunk is the most common site of involvement.³ In the differential diagnosis, other pigmentary disorders along the Blaschko lines must be excluded, including the pigmentary stage of IP, PZMPL, and LWNH. In IP, characteristic inflammatory vesicular and verrucous stages usually precede the whorled pigmentation.⁴ In approximately 80% of cases, IP is associated with various congenital abnormalities, particularly of the central nervous system, eyes, and teeth.⁵ Progressive zosteriform macular pigmented lesion is a chronic pigmentary dermatosis similar to PCZH but is characteristically accompanied by pruritus as a prodromal symptom. It is usually preceded by multiple pruritic macular pigmentation in part of the dermatome for a period of time. Then the size and number of the pigmented macules abruptly increases and coalesces into patches.⁶ Linear and whorled nevoid hypermelanosis was first described by Kalter et al⁷ in 1988. It is characterized by swirls and whorls of hyperpigmented macules without preceding bullae or verrucae along Blaschko lines, usually occurring within the first 2 years of life. The lesions are stable in some patients but can spread in others, stabilizing by 2 to 3 years of age.^7-10 It has been referred to as zosteriform lentiginous nevus, zebralike hyperpigmentation, and reticulate hyperpigmentation distributed in a zosteriform fashion.^2,9

Linear and whorled nevoid hypermelanosis can be distinguished from PCZH by a diffuse or localized pattern and an association of congenital anomalies.³ However, neurologic and skeletal anomalies also can be observed in PCZH.¹¹ Additionally, not all LWNH cases show a diffuse type.² Therefore, LWNH has been used to encompass a wide spectrum of clinical entities, ranging from the congenital or perinatal form described by Kalter et al⁷ to the segmented and delayed form described by Rower et al¹ for which there is a tendency to use the term progressive cribriform and zosteriform hyperpigmentation.^2,10,11 There are no clinical and histologic differences between PCZH and LWNH, other than a later onset.² Although some authors reported that PCZH and LWNH have increased hyperpigmentation of the basal layer and prominent melanocytes without incontinence of pigment on histopathology,^2,7,8 other reports have demonstrated that both could show pigment incontinence,^3,10,12-14 such as in our case.

Figure 2. Histopathologic findings showed increased pigmentation of the basal layer with a few dermal melanophages. No nevus cells were present (A)(H&E, original magnification ×100). Fontana-Masson stain showed an increase in melanin in the basal layer (B)(original magnification ×100).

Progressive cribriform and zosteriform hyperpigmentation is considered to be the localized variant as well as the late onset of LWNH.² We report a case of PCZH, a segmented and delayed form of LWNH without systemic abnormalities.

To the Editor:

Progressive cribriform and zosteriform hyperpigmentation (PCZH) was first described by Rower et al¹ in 1978. The diagnostic criteria included the following: (1) uniformly tan cribriform macular pigmentation in a zosteriform distribution; (2) a histologic pattern that consisted of a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells; (3) no history of rash, injury, or inflammation to suggest postinflammatory hyperpigmentation; (4) onset occurring well after birth with gradual extension; and (5) lack of other associated cutaneous or internal abnormalities.¹

Many pigmentary disorders occurring along the Blaschko lines are included in differential diagnosis of PCZH such as incontinentia pigmenti (IP), progressive zosteriform macular pigmented lesion (PZMPL), and linear and whorled nevoid hypermelanosis (LWNH). However, PCZH is considered to be the localized variant (the late onset) of LWNH.² We report a case of PCZH, a segmented and delayed form of LWNH.

A 25-year-old woman presented with asymptomatic progressive multiple brownish macular eruptions arranged in a zosteriform pattern on the left arm and thigh of 3 months’ duration. There was no history of injury or any prior cutaneous changes. There was no personal or family history of similar eruptions and she was otherwise in good health. She was not taking any medications. Physical examination showed linear, uniformly tanned, cribriform hyperpigmentation along the Blaschko lines on the left arm and thigh (Figure 1). Routine laboratory tests, including complete blood cell count with differential, were normal. Assuming a diagnosis of PCZH or PZMPL, we performed a punch biopsy on the left upper arm. The histopathologic findings showed increased pigmentation of the basal layer. There were a few dermal melanophages and no nevus cells present (Figure 2A). Fontana-Masson stain showed an increase in melanin in the basal layer (Figure 2B). On the basis of these clinical and histological findings, a diagnosis of PCZH was made. She was observed without treatment for 6 months showing no change.

Figure 1. Asymptomatic linear, uniformly tanned, cribriform hyperpigmentation along the Blaschko lines on the left arm (A) and thigh (B).

Progressive cribriform and zosteriform hyperpigmentation is a disorder of pigmentation along the Blaschko lines. The trunk is the most common site of involvement.³ In the differential diagnosis, other pigmentary disorders along the Blaschko lines must be excluded, including the pigmentary stage of IP, PZMPL, and LWNH. In IP, characteristic inflammatory vesicular and verrucous stages usually precede the whorled pigmentation.⁴ In approximately 80% of cases, IP is associated with various congenital abnormalities, particularly of the central nervous system, eyes, and teeth.⁵ Progressive zosteriform macular pigmented lesion is a chronic pigmentary dermatosis similar to PCZH but is characteristically accompanied by pruritus as a prodromal symptom. It is usually preceded by multiple pruritic macular pigmentation in part of the dermatome for a period of time. Then the size and number of the pigmented macules abruptly increases and coalesces into patches.⁶ Linear and whorled nevoid hypermelanosis was first described by Kalter et al⁷ in 1988. It is characterized by swirls and whorls of hyperpigmented macules without preceding bullae or verrucae along Blaschko lines, usually occurring within the first 2 years of life. The lesions are stable in some patients but can spread in others, stabilizing by 2 to 3 years of age.^7-10 It has been referred to as zosteriform lentiginous nevus, zebralike hyperpigmentation, and reticulate hyperpigmentation distributed in a zosteriform fashion.^2,9

Linear and whorled nevoid hypermelanosis can be distinguished from PCZH by a diffuse or localized pattern and an association of congenital anomalies.³ However, neurologic and skeletal anomalies also can be observed in PCZH.¹¹ Additionally, not all LWNH cases show a diffuse type.² Therefore, LWNH has been used to encompass a wide spectrum of clinical entities, ranging from the congenital or perinatal form described by Kalter et al⁷ to the segmented and delayed form described by Rower et al¹ for which there is a tendency to use the term progressive cribriform and zosteriform hyperpigmentation.^2,10,11 There are no clinical and histologic differences between PCZH and LWNH, other than a later onset.² Although some authors reported that PCZH and LWNH have increased hyperpigmentation of the basal layer and prominent melanocytes without incontinence of pigment on histopathology,^2,7,8 other reports have demonstrated that both could show pigment incontinence,^3,10,12-14 such as in our case.

Figure 2. Histopathologic findings showed increased pigmentation of the basal layer with a few dermal melanophages. No nevus cells were present (A)(H&E, original magnification ×100). Fontana-Masson stain showed an increase in melanin in the basal layer (B)(original magnification ×100).

Progressive cribriform and zosteriform hyperpigmentation is considered to be the localized variant as well as the late onset of LWNH.² We report a case of PCZH, a segmented and delayed form of LWNH without systemic abnormalities.

To the Editor:

Progressive cribriform and zosteriform hyperpigmentation (PCZH) was first described by Rower et al¹ in 1978. The diagnostic criteria included the following: (1) uniformly tan cribriform macular pigmentation in a zosteriform distribution; (2) a histologic pattern that consisted of a mild increase in melanin pigment in the basal cell layer and complete absence of nevus cells; (3) no history of rash, injury, or inflammation to suggest postinflammatory hyperpigmentation; (4) onset occurring well after birth with gradual extension; and (5) lack of other associated cutaneous or internal abnormalities.¹

Many pigmentary disorders occurring along the Blaschko lines are included in differential diagnosis of PCZH such as incontinentia pigmenti (IP), progressive zosteriform macular pigmented lesion (PZMPL), and linear and whorled nevoid hypermelanosis (LWNH). However, PCZH is considered to be the localized variant (the late onset) of LWNH.² We report a case of PCZH, a segmented and delayed form of LWNH.

A 25-year-old woman presented with asymptomatic progressive multiple brownish macular eruptions arranged in a zosteriform pattern on the left arm and thigh of 3 months’ duration. There was no history of injury or any prior cutaneous changes. There was no personal or family history of similar eruptions and she was otherwise in good health. She was not taking any medications. Physical examination showed linear, uniformly tanned, cribriform hyperpigmentation along the Blaschko lines on the left arm and thigh (Figure 1). Routine laboratory tests, including complete blood cell count with differential, were normal. Assuming a diagnosis of PCZH or PZMPL, we performed a punch biopsy on the left upper arm. The histopathologic findings showed increased pigmentation of the basal layer. There were a few dermal melanophages and no nevus cells present (Figure 2A). Fontana-Masson stain showed an increase in melanin in the basal layer (Figure 2B). On the basis of these clinical and histological findings, a diagnosis of PCZH was made. She was observed without treatment for 6 months showing no change.

Figure 1. Asymptomatic linear, uniformly tanned, cribriform hyperpigmentation along the Blaschko lines on the left arm (A) and thigh (B).

Progressive cribriform and zosteriform hyperpigmentation is a disorder of pigmentation along the Blaschko lines. The trunk is the most common site of involvement.³ In the differential diagnosis, other pigmentary disorders along the Blaschko lines must be excluded, including the pigmentary stage of IP, PZMPL, and LWNH. In IP, characteristic inflammatory vesicular and verrucous stages usually precede the whorled pigmentation.⁴ In approximately 80% of cases, IP is associated with various congenital abnormalities, particularly of the central nervous system, eyes, and teeth.⁵ Progressive zosteriform macular pigmented lesion is a chronic pigmentary dermatosis similar to PCZH but is characteristically accompanied by pruritus as a prodromal symptom. It is usually preceded by multiple pruritic macular pigmentation in part of the dermatome for a period of time. Then the size and number of the pigmented macules abruptly increases and coalesces into patches.⁶ Linear and whorled nevoid hypermelanosis was first described by Kalter et al⁷ in 1988. It is characterized by swirls and whorls of hyperpigmented macules without preceding bullae or verrucae along Blaschko lines, usually occurring within the first 2 years of life. The lesions are stable in some patients but can spread in others, stabilizing by 2 to 3 years of age.^7-10 It has been referred to as zosteriform lentiginous nevus, zebralike hyperpigmentation, and reticulate hyperpigmentation distributed in a zosteriform fashion.^2,9

Linear and whorled nevoid hypermelanosis can be distinguished from PCZH by a diffuse or localized pattern and an association of congenital anomalies.³ However, neurologic and skeletal anomalies also can be observed in PCZH.¹¹ Additionally, not all LWNH cases show a diffuse type.² Therefore, LWNH has been used to encompass a wide spectrum of clinical entities, ranging from the congenital or perinatal form described by Kalter et al⁷ to the segmented and delayed form described by Rower et al¹ for which there is a tendency to use the term progressive cribriform and zosteriform hyperpigmentation.^2,10,11 There are no clinical and histologic differences between PCZH and LWNH, other than a later onset.² Although some authors reported that PCZH and LWNH have increased hyperpigmentation of the basal layer and prominent melanocytes without incontinence of pigment on histopathology,^2,7,8 other reports have demonstrated that both could show pigment incontinence,^3,10,12-14 such as in our case.

Figure 2. Histopathologic findings showed increased pigmentation of the basal layer with a few dermal melanophages. No nevus cells were present (A)(H&E, original magnification ×100). Fontana-Masson stain showed an increase in melanin in the basal layer (B)(original magnification ×100).

Progressive cribriform and zosteriform hyperpigmentation is considered to be the localized variant as well as the late onset of LWNH.² We report a case of PCZH, a segmented and delayed form of LWNH without systemic abnormalities.

To the Editor:

Numerous drugs have been implicated as possible causes of lichenoid drug eruptions (LDEs). We describe a case of an LDE secondary to placement of a levonorgestrel-releasing intrauterine system (IUS).

A 28-year-old woman presented with an extensive pruritic rash of 2 months’ duration. She reported that it began on the wrists; progressed inward to involve the trunk; and then became generalized over the trunk, back, wrists, and legs. A levonorgestrel-releasing IUS had been placed 6 weeks prior to the onset of the rash. She was otherwise healthy and took loratadine and pseudoephedrine on occasion for environmental allergies. On examination there were violaceous, lichenified, flat-topped, polygonal papules scattered over the arms, legs, and trunk (Figure 1). Some papules demonstrated a Köbner phenomenon. No Wickham striae or mucosal involvement was noted. Rapid plasma reagin and hepatitis panel were negative. The patient was treated empirically with fluocinonide ointment 0.05% twice daily.

Figure 1. Violaceous, lichenified, flat-topped, polygonal papules on the back of a 28-year-old woman associated with use of a levonorgestrel-releasing intrauterine system. Figure 2. Classic lichenoid reaction pattern including irregular acanthosis lying above a dense bandlike infiltrate of lymphocytes with liquefaction degeneration of the basal layer, rare Civatte bodies in the epidermis, and melanophages in the dermis (A and B)(H&E, original magnifications ×100 and ×200).

A shave biopsy was taken at the initial visit prior to steroid treatment. Histology revealed a classic lichenoid reaction pattern (Figure 2) and irregular acanthosis lying above the dense bandlike infiltrate of lymphocytes with liquefaction degeneration of the basal layer, rare Civatte bodies in the epidermis, and melanophages in the dermis.

At 5-week follow-up, the patient showed some improvement but not complete control of the lesions with topical steroids. Because the patient was on no other regular medications, we recommended a 3-month trial removal of the IUS. The patient decided to have the IUS removed and noted complete clearance of the skin lesions within 1 month. Challenge with oral or intradermal levonorgestrel was not conducted after clearance of the rash, which is a weakness in this report. Accordingly, the possibility that this patient’s condition was caused by idiopathic lichen planus, which may resolve spontaneously, cannot be ruled out. However, because the patient noted substantial improvement following removal of the device and remained symptom free 2 years after removal, we concluded that the cutaneous lesions were secondary to an LDE in response to the IUS.

It should be noted that as-needed use of pseudoephedrine and loratadine continued during this 2-year follow-up period and again the patient experienced no return of symptoms, which is particularly important because both of these agents have been associated with drug eruption patterns akin to lichenoid tissue reaction/interface dermatitis patterns. Pseudoephedrine is particularly notorious for causing nonpigmenting fixed drug eruptions such as those that heal without hyperpigmentation, while antihistamines such as loratadine have been associated with lichenoid and subacute lupus erythematosus–pattern drug reactions.^1,2

Lichenoid drug reactions fall into the category of lymphocyte-rich lichenoid tissue reaction/interface dermatitis skin disorders.³ There are currently 202 different drugs reported to cause lichen planus or lichenoid eruptions as collected in Litt’s Drug Eruption & Reaction Database.⁴ Some of the more common causes of an LDE include angiotensin-converting enzyme inhibitors, antimalarials, calcium channel blockers, gold salts, and nonsteroidal anti-inflammatory drugs.^3,4 Lichenoid eruptions typically are attributed to oral hormonal contraceptives only.^5,6 An eruption in response to intrauterine levonorgestrel treatment is rare. One case report of a lichenoid eruption in response to a copper IUS was hypothesized to be due to presence of nickel salts as a manufacturing contaminant; however, the manufacturer denied the presence of the contaminant.⁷

The manufacturer’s information for health care professionals prescribing levonorgestrel-releasing IUS describes rashes as an adverse reaction present in less than 5% of individuals.⁸ Levonorgestrel-releasing IUS consists of a polyethylene frame compounded with barium sulfate, 52 mg of levonorgestrel, silicone (polydimethylsiloxane), and a monofilament brown polyethylene removal thread. The device initially releases 20 μg levonorgestrel daily, with a stable levonorgestrel plasma level of 150 to 200 pg/mL reached after the first few weeks following insertion of the device.⁸ Levonorgestrel is an agonist at the progesterone and androgen receptors.⁹ In clinical trials, levonorgestrel was implicated as the cause of increased acne, hair loss, and hirsutism as cutaneous side effects from use of levonorgestrel implants.¹⁰ However, to our knowledge, none of the other components of the levonorgestrel-releasing IUS have previously been reported to cause lichen planus or LDE.

The levonorgestrel-releasing IUS has been implicated as the cause of biopsy-proven Sweet disease,¹¹ exacerbation of preexisting seborrheic dermatitis,¹² rosacea,¹³ and autoimmune progesterone dermatitis.¹⁴ The skin findings in these cases resolved after removal of the IUS and appropriate treatment.

Identification of the causative drug can be difficult in LDE, as timing of the eruption can vary. The latent period has been reported to range from a few months to 1 to 2 years.¹⁵ Additionally, the clinical picture is often complicated in patients with a history of different drug dosages or multiple medications. When present, the histologic features of parakeratosis and eosinophils can be clues that a lichen planus–like eruption is drug related rather than idiopathic. However, the absence of these features does not rule out a medication or environmental trigger. In this case, the time-event relationship likely indicates that the eruption was related to the levonorgestrel-releasing IUS and not triggered by other medications or not idiopathic in nature. Lichenoid drug eruptions can resolve within a few weeks or up to 2 years after drug cessation and can occasionally be complicated by partial or complete resolution and recurrence even when the drug has not been discontinued.^16,17 Lichenoid drug eruptions or idiopathic lichen planus generally are treated with topical immunomodulators or corticosteroids.³

Based on the time-event relationship, morphology, distribution, and histopathologic findings, we conclude that our patient developed LDE in response to the placement of a levonorgestrel-releasing IUS. Clinicians should be aware of the possibility of LDE occurring as a rare adverse effect of these devices.

To the Editor:

Numerous drugs have been implicated as possible causes of lichenoid drug eruptions (LDEs). We describe a case of an LDE secondary to placement of a levonorgestrel-releasing intrauterine system (IUS).

A 28-year-old woman presented with an extensive pruritic rash of 2 months’ duration. She reported that it began on the wrists; progressed inward to involve the trunk; and then became generalized over the trunk, back, wrists, and legs. A levonorgestrel-releasing IUS had been placed 6 weeks prior to the onset of the rash. She was otherwise healthy and took loratadine and pseudoephedrine on occasion for environmental allergies. On examination there were violaceous, lichenified, flat-topped, polygonal papules scattered over the arms, legs, and trunk (Figure 1). Some papules demonstrated a Köbner phenomenon. No Wickham striae or mucosal involvement was noted. Rapid plasma reagin and hepatitis panel were negative. The patient was treated empirically with fluocinonide ointment 0.05% twice daily.

Figure 1. Violaceous, lichenified, flat-topped, polygonal papules on the back of a 28-year-old woman associated with use of a levonorgestrel-releasing intrauterine system. Figure 2. Classic lichenoid reaction pattern including irregular acanthosis lying above a dense bandlike infiltrate of lymphocytes with liquefaction degeneration of the basal layer, rare Civatte bodies in the epidermis, and melanophages in the dermis (A and B)(H&E, original magnifications ×100 and ×200).

A shave biopsy was taken at the initial visit prior to steroid treatment. Histology revealed a classic lichenoid reaction pattern (Figure 2) and irregular acanthosis lying above the dense bandlike infiltrate of lymphocytes with liquefaction degeneration of the basal layer, rare Civatte bodies in the epidermis, and melanophages in the dermis.

At 5-week follow-up, the patient showed some improvement but not complete control of the lesions with topical steroids. Because the patient was on no other regular medications, we recommended a 3-month trial removal of the IUS. The patient decided to have the IUS removed and noted complete clearance of the skin lesions within 1 month. Challenge with oral or intradermal levonorgestrel was not conducted after clearance of the rash, which is a weakness in this report. Accordingly, the possibility that this patient’s condition was caused by idiopathic lichen planus, which may resolve spontaneously, cannot be ruled out. However, because the patient noted substantial improvement following removal of the device and remained symptom free 2 years after removal, we concluded that the cutaneous lesions were secondary to an LDE in response to the IUS.

It should be noted that as-needed use of pseudoephedrine and loratadine continued during this 2-year follow-up period and again the patient experienced no return of symptoms, which is particularly important because both of these agents have been associated with drug eruption patterns akin to lichenoid tissue reaction/interface dermatitis patterns. Pseudoephedrine is particularly notorious for causing nonpigmenting fixed drug eruptions such as those that heal without hyperpigmentation, while antihistamines such as loratadine have been associated with lichenoid and subacute lupus erythematosus–pattern drug reactions.^1,2

Lichenoid drug reactions fall into the category of lymphocyte-rich lichenoid tissue reaction/interface dermatitis skin disorders.³ There are currently 202 different drugs reported to cause lichen planus or lichenoid eruptions as collected in Litt’s Drug Eruption & Reaction Database.⁴ Some of the more common causes of an LDE include angiotensin-converting enzyme inhibitors, antimalarials, calcium channel blockers, gold salts, and nonsteroidal anti-inflammatory drugs.^3,4 Lichenoid eruptions typically are attributed to oral hormonal contraceptives only.^5,6 An eruption in response to intrauterine levonorgestrel treatment is rare. One case report of a lichenoid eruption in response to a copper IUS was hypothesized to be due to presence of nickel salts as a manufacturing contaminant; however, the manufacturer denied the presence of the contaminant.⁷

The manufacturer’s information for health care professionals prescribing levonorgestrel-releasing IUS describes rashes as an adverse reaction present in less than 5% of individuals.⁸ Levonorgestrel-releasing IUS consists of a polyethylene frame compounded with barium sulfate, 52 mg of levonorgestrel, silicone (polydimethylsiloxane), and a monofilament brown polyethylene removal thread. The device initially releases 20 μg levonorgestrel daily, with a stable levonorgestrel plasma level of 150 to 200 pg/mL reached after the first few weeks following insertion of the device.⁸ Levonorgestrel is an agonist at the progesterone and androgen receptors.⁹ In clinical trials, levonorgestrel was implicated as the cause of increased acne, hair loss, and hirsutism as cutaneous side effects from use of levonorgestrel implants.¹⁰ However, to our knowledge, none of the other components of the levonorgestrel-releasing IUS have previously been reported to cause lichen planus or LDE.

The levonorgestrel-releasing IUS has been implicated as the cause of biopsy-proven Sweet disease,¹¹ exacerbation of preexisting seborrheic dermatitis,¹² rosacea,¹³ and autoimmune progesterone dermatitis.¹⁴ The skin findings in these cases resolved after removal of the IUS and appropriate treatment.

Identification of the causative drug can be difficult in LDE, as timing of the eruption can vary. The latent period has been reported to range from a few months to 1 to 2 years.¹⁵ Additionally, the clinical picture is often complicated in patients with a history of different drug dosages or multiple medications. When present, the histologic features of parakeratosis and eosinophils can be clues that a lichen planus–like eruption is drug related rather than idiopathic. However, the absence of these features does not rule out a medication or environmental trigger. In this case, the time-event relationship likely indicates that the eruption was related to the levonorgestrel-releasing IUS and not triggered by other medications or not idiopathic in nature. Lichenoid drug eruptions can resolve within a few weeks or up to 2 years after drug cessation and can occasionally be complicated by partial or complete resolution and recurrence even when the drug has not been discontinued.^16,17 Lichenoid drug eruptions or idiopathic lichen planus generally are treated with topical immunomodulators or corticosteroids.³

Based on the time-event relationship, morphology, distribution, and histopathologic findings, we conclude that our patient developed LDE in response to the placement of a levonorgestrel-releasing IUS. Clinicians should be aware of the possibility of LDE occurring as a rare adverse effect of these devices.

To the Editor:

Numerous drugs have been implicated as possible causes of lichenoid drug eruptions (LDEs). We describe a case of an LDE secondary to placement of a levonorgestrel-releasing intrauterine system (IUS).

A 28-year-old woman presented with an extensive pruritic rash of 2 months’ duration. She reported that it began on the wrists; progressed inward to involve the trunk; and then became generalized over the trunk, back, wrists, and legs. A levonorgestrel-releasing IUS had been placed 6 weeks prior to the onset of the rash. She was otherwise healthy and took loratadine and pseudoephedrine on occasion for environmental allergies. On examination there were violaceous, lichenified, flat-topped, polygonal papules scattered over the arms, legs, and trunk (Figure 1). Some papules demonstrated a Köbner phenomenon. No Wickham striae or mucosal involvement was noted. Rapid plasma reagin and hepatitis panel were negative. The patient was treated empirically with fluocinonide ointment 0.05% twice daily.

Figure 1. Violaceous, lichenified, flat-topped, polygonal papules on the back of a 28-year-old woman associated with use of a levonorgestrel-releasing intrauterine system. Figure 2. Classic lichenoid reaction pattern including irregular acanthosis lying above a dense bandlike infiltrate of lymphocytes with liquefaction degeneration of the basal layer, rare Civatte bodies in the epidermis, and melanophages in the dermis (A and B)(H&E, original magnifications ×100 and ×200).

A shave biopsy was taken at the initial visit prior to steroid treatment. Histology revealed a classic lichenoid reaction pattern (Figure 2) and irregular acanthosis lying above the dense bandlike infiltrate of lymphocytes with liquefaction degeneration of the basal layer, rare Civatte bodies in the epidermis, and melanophages in the dermis.

At 5-week follow-up, the patient showed some improvement but not complete control of the lesions with topical steroids. Because the patient was on no other regular medications, we recommended a 3-month trial removal of the IUS. The patient decided to have the IUS removed and noted complete clearance of the skin lesions within 1 month. Challenge with oral or intradermal levonorgestrel was not conducted after clearance of the rash, which is a weakness in this report. Accordingly, the possibility that this patient’s condition was caused by idiopathic lichen planus, which may resolve spontaneously, cannot be ruled out. However, because the patient noted substantial improvement following removal of the device and remained symptom free 2 years after removal, we concluded that the cutaneous lesions were secondary to an LDE in response to the IUS.

It should be noted that as-needed use of pseudoephedrine and loratadine continued during this 2-year follow-up period and again the patient experienced no return of symptoms, which is particularly important because both of these agents have been associated with drug eruption patterns akin to lichenoid tissue reaction/interface dermatitis patterns. Pseudoephedrine is particularly notorious for causing nonpigmenting fixed drug eruptions such as those that heal without hyperpigmentation, while antihistamines such as loratadine have been associated with lichenoid and subacute lupus erythematosus–pattern drug reactions.^1,2

Lichenoid drug reactions fall into the category of lymphocyte-rich lichenoid tissue reaction/interface dermatitis skin disorders.³ There are currently 202 different drugs reported to cause lichen planus or lichenoid eruptions as collected in Litt’s Drug Eruption & Reaction Database.⁴ Some of the more common causes of an LDE include angiotensin-converting enzyme inhibitors, antimalarials, calcium channel blockers, gold salts, and nonsteroidal anti-inflammatory drugs.^3,4 Lichenoid eruptions typically are attributed to oral hormonal contraceptives only.^5,6 An eruption in response to intrauterine levonorgestrel treatment is rare. One case report of a lichenoid eruption in response to a copper IUS was hypothesized to be due to presence of nickel salts as a manufacturing contaminant; however, the manufacturer denied the presence of the contaminant.⁷

The manufacturer’s information for health care professionals prescribing levonorgestrel-releasing IUS describes rashes as an adverse reaction present in less than 5% of individuals.⁸ Levonorgestrel-releasing IUS consists of a polyethylene frame compounded with barium sulfate, 52 mg of levonorgestrel, silicone (polydimethylsiloxane), and a monofilament brown polyethylene removal thread. The device initially releases 20 μg levonorgestrel daily, with a stable levonorgestrel plasma level of 150 to 200 pg/mL reached after the first few weeks following insertion of the device.⁸ Levonorgestrel is an agonist at the progesterone and androgen receptors.⁹ In clinical trials, levonorgestrel was implicated as the cause of increased acne, hair loss, and hirsutism as cutaneous side effects from use of levonorgestrel implants.¹⁰ However, to our knowledge, none of the other components of the levonorgestrel-releasing IUS have previously been reported to cause lichen planus or LDE.

The levonorgestrel-releasing IUS has been implicated as the cause of biopsy-proven Sweet disease,¹¹ exacerbation of preexisting seborrheic dermatitis,¹² rosacea,¹³ and autoimmune progesterone dermatitis.¹⁴ The skin findings in these cases resolved after removal of the IUS and appropriate treatment.

Identification of the causative drug can be difficult in LDE, as timing of the eruption can vary. The latent period has been reported to range from a few months to 1 to 2 years.¹⁵ Additionally, the clinical picture is often complicated in patients with a history of different drug dosages or multiple medications. When present, the histologic features of parakeratosis and eosinophils can be clues that a lichen planus–like eruption is drug related rather than idiopathic. However, the absence of these features does not rule out a medication or environmental trigger. In this case, the time-event relationship likely indicates that the eruption was related to the levonorgestrel-releasing IUS and not triggered by other medications or not idiopathic in nature. Lichenoid drug eruptions can resolve within a few weeks or up to 2 years after drug cessation and can occasionally be complicated by partial or complete resolution and recurrence even when the drug has not been discontinued.^16,17 Lichenoid drug eruptions or idiopathic lichen planus generally are treated with topical immunomodulators or corticosteroids.³

Based on the time-event relationship, morphology, distribution, and histopathologic findings, we conclude that our patient developed LDE in response to the placement of a levonorgestrel-releasing IUS. Clinicians should be aware of the possibility of LDE occurring as a rare adverse effect of these devices.

To the Editor:

Mycoplasma pneumoniae has been implicated as a cause of acute urticaria (AU) in children,¹ but its role in adults with AU is unknown. The aim of this retrospective study was to compare the incidence of acute M pneumoniae infection in adults with AU and chronic urticaria (CU).

A chart review was performed on adult patients with AU and CU who presented at a private dermatology practice in Singapore. Acute M pneumoniae infection was diagnosed on the basis of a single indirect microparticle agglutinin assay (MAA) titer of 1:320 or higher. All statistical tests were performed using SPSS version 13.0. P=.05 was regarded as significant. Data from 49 adults with AU and 44 adults with CU were analyzed. The distribution of MAA titers in adults with AU and CU are shown in the Figure. Microparticle agglutinin assay was negative in 10 (20.4%) of 49 adults with AU. Fifteen (30.6%) of 49 adults with AU had evidence of acute M pneumoniae infection, as indicated by an MAA titer of 1:320 or higher. The remaining 24 (49.0%) had evidence of prior infection as indicated by titers above the manufacturer’s cutoff of 1:40² and below our cutoff for acute infection of 1:320 or higher. Microparticle agglutinin assay was negative in 11 (25%) of 44 adults with CU. Three (6.8%) adults with CU were diagnosed with acute M pneumoniae infection and 30 (68.2%) were diagnosed with prior infection. The incidence of acute M pneumoniae infection was 30.6% in adults with AU compared to 6.8% in adults with CU, and the difference was statistically significant (P=.004).

Mycoplasma pneumoniae antibody titer in patients with acute urticaria (n=49) and chronic urticaria (n=44).

Extrapulmonary complications of M pneumoniae involving practically every organ system have been described and 25% of patients develop cutaneous symptoms³ including AU. In 2007, Kano et al⁴ reported M pneumoniae infection-induced erythema nodosum, anaphylactoid purpura, and AU in a family of 3. This report was interesting because it showed that M pneumoniae had the ability to elicit different cutaneous reactions depending on the maturity of the adaptive immunity of a host, even among individuals of a common genetic background. A Taiwanese study found that 21 (32%) of 65 children with AU had M pneumoniae infection as determined by a positive Mycoplasma IgM test or an equivocal Mycoplasma IgM coupled with positive cold agglutinin test results.¹

In our study, we found serological evidence of acute M pneumoniae infection in 15 (30.6%) of 49 adults with AU compared to 3 (6.8%) of 44 adults with CU (P=.004), suggesting that M pneumoniae also may play a role in the etiology of adult AU. Diagnosis of acute M pneumoniae infection is challenging, as it is often impossible to obtain convalescent serum that will show the 4-fold rise in titer. Single MAA titers of 1:160 or higher have been recommended for diagnosis of acute infection,⁵ but because of higher background activity in Singapore, we used a higher titer (>1:320). However, in doing so, we could be underestimating the true incidence of acute M pneumoniae infections.

The role of M pneumoniae in CU is uncertain. A Thai study reported that 55% of 38 children with CU had elevated M pneumoniae titers but did not provide details of actual titers or define what they meant by elevated titers.⁶ The incidence of acute and prior infection in our patients with CU was 6.8% and 68.2%, respectively. Unfortunately, we cannot determine the significance of the 68.2% incidence rate of prior infection in the absence of a normal control population of patients without urticaria. Another limitation of this study is that we compared M pneumoniae infection rate in AU with CU on the assumption that infection is not likely to play a significant role in CU, which may not necessarily be the case. Tests for other etiologic agents, including viruses, also were not performed. Not withstanding these limitations, this study suggests that acute M pneumoniae infection is significantly more common in adults with AU than in adults with CU.

This study showed that M pneumoniae might play a role in the etiology of AU in adults and our findings need to be confirmed by prospective studies. Several more questions must be answered before deciding whether the current practice of treating AU symptomatically without investigation needs to be changed. First, does treatment of M pneumoniae infection have any influence on the course of AU? The fact that AU usually is self-limiting suggests that treatment may not influence the disease course. Second, does treatment of underlying M pneumoniae infection shorten the course of AU? Third, do AU patients with untreated M pneumoniae infection face a higher risk for developing CU? This question is intriguing for the following reasons: (1) 30% to 50% of CU cases are autoimmune in etiology⁷; (2) antibodies to galactocerebroside that cross-react with glycolipids on M pneumoniae have been detected in patients with M pneumoniae–associated Guillain-Barré syndrome, suggesting a form of molecular mimicry⁸; and (3) antinuclear antibody also has occasionally been detected in sera of patients with M pneumoniae.⁹ It would be interesting to test patients with autoimmune and nonautoimmune CU for evidence of M pneumoniae serology infection.

We hope that prospective studies will be conducted in the future to confirm our findings and answer some of the questions raised.

To the Editor:

Mycoplasma pneumoniae has been implicated as a cause of acute urticaria (AU) in children,¹ but its role in adults with AU is unknown. The aim of this retrospective study was to compare the incidence of acute M pneumoniae infection in adults with AU and chronic urticaria (CU).

A chart review was performed on adult patients with AU and CU who presented at a private dermatology practice in Singapore. Acute M pneumoniae infection was diagnosed on the basis of a single indirect microparticle agglutinin assay (MAA) titer of 1:320 or higher. All statistical tests were performed using SPSS version 13.0. P=.05 was regarded as significant. Data from 49 adults with AU and 44 adults with CU were analyzed. The distribution of MAA titers in adults with AU and CU are shown in the Figure. Microparticle agglutinin assay was negative in 10 (20.4%) of 49 adults with AU. Fifteen (30.6%) of 49 adults with AU had evidence of acute M pneumoniae infection, as indicated by an MAA titer of 1:320 or higher. The remaining 24 (49.0%) had evidence of prior infection as indicated by titers above the manufacturer’s cutoff of 1:40² and below our cutoff for acute infection of 1:320 or higher. Microparticle agglutinin assay was negative in 11 (25%) of 44 adults with CU. Three (6.8%) adults with CU were diagnosed with acute M pneumoniae infection and 30 (68.2%) were diagnosed with prior infection. The incidence of acute M pneumoniae infection was 30.6% in adults with AU compared to 6.8% in adults with CU, and the difference was statistically significant (P=.004).

Mycoplasma pneumoniae antibody titer in patients with acute urticaria (n=49) and chronic urticaria (n=44).

Extrapulmonary complications of M pneumoniae involving practically every organ system have been described and 25% of patients develop cutaneous symptoms³ including AU. In 2007, Kano et al⁴ reported M pneumoniae infection-induced erythema nodosum, anaphylactoid purpura, and AU in a family of 3. This report was interesting because it showed that M pneumoniae had the ability to elicit different cutaneous reactions depending on the maturity of the adaptive immunity of a host, even among individuals of a common genetic background. A Taiwanese study found that 21 (32%) of 65 children with AU had M pneumoniae infection as determined by a positive Mycoplasma IgM test or an equivocal Mycoplasma IgM coupled with positive cold agglutinin test results.¹

In our study, we found serological evidence of acute M pneumoniae infection in 15 (30.6%) of 49 adults with AU compared to 3 (6.8%) of 44 adults with CU (P=.004), suggesting that M pneumoniae also may play a role in the etiology of adult AU. Diagnosis of acute M pneumoniae infection is challenging, as it is often impossible to obtain convalescent serum that will show the 4-fold rise in titer. Single MAA titers of 1:160 or higher have been recommended for diagnosis of acute infection,⁵ but because of higher background activity in Singapore, we used a higher titer (>1:320). However, in doing so, we could be underestimating the true incidence of acute M pneumoniae infections.

The role of M pneumoniae in CU is uncertain. A Thai study reported that 55% of 38 children with CU had elevated M pneumoniae titers but did not provide details of actual titers or define what they meant by elevated titers.⁶ The incidence of acute and prior infection in our patients with CU was 6.8% and 68.2%, respectively. Unfortunately, we cannot determine the significance of the 68.2% incidence rate of prior infection in the absence of a normal control population of patients without urticaria. Another limitation of this study is that we compared M pneumoniae infection rate in AU with CU on the assumption that infection is not likely to play a significant role in CU, which may not necessarily be the case. Tests for other etiologic agents, including viruses, also were not performed. Not withstanding these limitations, this study suggests that acute M pneumoniae infection is significantly more common in adults with AU than in adults with CU.

This study showed that M pneumoniae might play a role in the etiology of AU in adults and our findings need to be confirmed by prospective studies. Several more questions must be answered before deciding whether the current practice of treating AU symptomatically without investigation needs to be changed. First, does treatment of M pneumoniae infection have any influence on the course of AU? The fact that AU usually is self-limiting suggests that treatment may not influence the disease course. Second, does treatment of underlying M pneumoniae infection shorten the course of AU? Third, do AU patients with untreated M pneumoniae infection face a higher risk for developing CU? This question is intriguing for the following reasons: (1) 30% to 50% of CU cases are autoimmune in etiology⁷; (2) antibodies to galactocerebroside that cross-react with glycolipids on M pneumoniae have been detected in patients with M pneumoniae–associated Guillain-Barré syndrome, suggesting a form of molecular mimicry⁸; and (3) antinuclear antibody also has occasionally been detected in sera of patients with M pneumoniae.⁹ It would be interesting to test patients with autoimmune and nonautoimmune CU for evidence of M pneumoniae serology infection.

We hope that prospective studies will be conducted in the future to confirm our findings and answer some of the questions raised.

To the Editor:

Mycoplasma pneumoniae has been implicated as a cause of acute urticaria (AU) in children,¹ but its role in adults with AU is unknown. The aim of this retrospective study was to compare the incidence of acute M pneumoniae infection in adults with AU and chronic urticaria (CU).

A chart review was performed on adult patients with AU and CU who presented at a private dermatology practice in Singapore. Acute M pneumoniae infection was diagnosed on the basis of a single indirect microparticle agglutinin assay (MAA) titer of 1:320 or higher. All statistical tests were performed using SPSS version 13.0. P=.05 was regarded as significant. Data from 49 adults with AU and 44 adults with CU were analyzed. The distribution of MAA titers in adults with AU and CU are shown in the Figure. Microparticle agglutinin assay was negative in 10 (20.4%) of 49 adults with AU. Fifteen (30.6%) of 49 adults with AU had evidence of acute M pneumoniae infection, as indicated by an MAA titer of 1:320 or higher. The remaining 24 (49.0%) had evidence of prior infection as indicated by titers above the manufacturer’s cutoff of 1:40² and below our cutoff for acute infection of 1:320 or higher. Microparticle agglutinin assay was negative in 11 (25%) of 44 adults with CU. Three (6.8%) adults with CU were diagnosed with acute M pneumoniae infection and 30 (68.2%) were diagnosed with prior infection. The incidence of acute M pneumoniae infection was 30.6% in adults with AU compared to 6.8% in adults with CU, and the difference was statistically significant (P=.004).

Mycoplasma pneumoniae antibody titer in patients with acute urticaria (n=49) and chronic urticaria (n=44).

Extrapulmonary complications of M pneumoniae involving practically every organ system have been described and 25% of patients develop cutaneous symptoms³ including AU. In 2007, Kano et al⁴ reported M pneumoniae infection-induced erythema nodosum, anaphylactoid purpura, and AU in a family of 3. This report was interesting because it showed that M pneumoniae had the ability to elicit different cutaneous reactions depending on the maturity of the adaptive immunity of a host, even among individuals of a common genetic background. A Taiwanese study found that 21 (32%) of 65 children with AU had M pneumoniae infection as determined by a positive Mycoplasma IgM test or an equivocal Mycoplasma IgM coupled with positive cold agglutinin test results.¹

In our study, we found serological evidence of acute M pneumoniae infection in 15 (30.6%) of 49 adults with AU compared to 3 (6.8%) of 44 adults with CU (P=.004), suggesting that M pneumoniae also may play a role in the etiology of adult AU. Diagnosis of acute M pneumoniae infection is challenging, as it is often impossible to obtain convalescent serum that will show the 4-fold rise in titer. Single MAA titers of 1:160 or higher have been recommended for diagnosis of acute infection,⁵ but because of higher background activity in Singapore, we used a higher titer (>1:320). However, in doing so, we could be underestimating the true incidence of acute M pneumoniae infections.

The role of M pneumoniae in CU is uncertain. A Thai study reported that 55% of 38 children with CU had elevated M pneumoniae titers but did not provide details of actual titers or define what they meant by elevated titers.⁶ The incidence of acute and prior infection in our patients with CU was 6.8% and 68.2%, respectively. Unfortunately, we cannot determine the significance of the 68.2% incidence rate of prior infection in the absence of a normal control population of patients without urticaria. Another limitation of this study is that we compared M pneumoniae infection rate in AU with CU on the assumption that infection is not likely to play a significant role in CU, which may not necessarily be the case. Tests for other etiologic agents, including viruses, also were not performed. Not withstanding these limitations, this study suggests that acute M pneumoniae infection is significantly more common in adults with AU than in adults with CU.

This study showed that M pneumoniae might play a role in the etiology of AU in adults and our findings need to be confirmed by prospective studies. Several more questions must be answered before deciding whether the current practice of treating AU symptomatically without investigation needs to be changed. First, does treatment of M pneumoniae infection have any influence on the course of AU? The fact that AU usually is self-limiting suggests that treatment may not influence the disease course. Second, does treatment of underlying M pneumoniae infection shorten the course of AU? Third, do AU patients with untreated M pneumoniae infection face a higher risk for developing CU? This question is intriguing for the following reasons: (1) 30% to 50% of CU cases are autoimmune in etiology⁷; (2) antibodies to galactocerebroside that cross-react with glycolipids on M pneumoniae have been detected in patients with M pneumoniae–associated Guillain-Barré syndrome, suggesting a form of molecular mimicry⁸; and (3) antinuclear antibody also has occasionally been detected in sera of patients with M pneumoniae.⁹ It would be interesting to test patients with autoimmune and nonautoimmune CU for evidence of M pneumoniae serology infection.

We hope that prospective studies will be conducted in the future to confirm our findings and answer some of the questions raised.

To the Editor:

The shiitake mushroom (Lentinula edodes) is a popular Asian food and represents the second most consumed mushroom in the world. It is known for having a range of strong health benefits including antihypertensive, anti-inflammatory, and immunomodulatory effects. Especially in Asia, this mushroom has been used in patients with cancers of the gastrointestinal tract and also may be helpful in the treatment of human immunodeficiency virus.^1,2 The source of these effects is lentinan, a polysaccharide in the mushroom. However, lentinan also can cause a toxic reaction of the skin when the mushrooms are eaten raw or undercooked. These reactions are mainly reported in Asia, but more cases have been published in the last decade in Europe and the United States, evidence that the incidence of this adverse effect has increased in the Western world.

A 65-year-old woman with no notable medical history presented to our outpatient practice with sudden onset of a pruritic, erythematous, papular eruption on the neck. The eruption began that morning. The diagnosis of eczematous dermatitis was made and hydrocortisone cream 2.5% was started. Three days later, she returned with spread of the rash to the trunk, arms, and legs despite the topical treatment. She denied fevers, chills, or constitutional symptoms. The patient also denied recent travel or bug bites. However, she reported that she recently had started using raw shiitake mushrooms in her salad; the first time was 3 days before the symptoms appeared. Physical examination revealed erythematous skin with long flagellate streaks composed of petechiae, papules, and vesicles involving the trunk, arms, and legs (Figure). Oral and nasal mucosae were uninvolved. Dermatographism was negative. The diagnosis of flagellate dermatitis from shiitake mushrooms was made given the patient’s history and the unique clinical findings of the skin. Blood work and a biopsy were not performed. Instead, the patient was advised to avoid shiitake mushrooms and use clobetasol propionate cream 0.05% twice daily for 2 weeks on the affected areas. The symptoms resolved within 10 days.

Erythematous flagellate streaks composed of petechiae, papules, and vesicles localized on the patient’s back (A) and right upper arm (B) associated with shiitake mushroom consumption.

The first known case of toxicoderma to shiitake mushrooms was reported in Japan by Nakamura³ in 1977. Since this seminal report, numerous cases have followed. This disorder is mainly seen in Asia.

Patients usually present with linear groups of pruritic, papular, petechial, and vesicular lesions in a flagellate pattern, most commonly localized on the trunk, arms, and legs. Oral and nasal mucosae usually are not involved, and fever and malaise may be associated. All symptoms typically occur 1 to 2 days after ingestion of the mushrooms. The patient’s history and typical clinical findings lead to a diagnosis; however, blood tests may show inflammation with leukocytosis and elevated C-reactive protein levels. Biopsy of the skin shows lymphocytic dermal infiltrates with spongiosis and necrotic cells within the epidermis.⁴

Differential diagnoses include flagellate dermatitis associated with bleomycin, a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Because it causes breaks in the DNA, bleomycin is commonly used as a chemotherapeutic agent in treating Hodgkin lymphoma and other malignancies. It presents with linear postinflammatory hyperpigmentation of the skin. However, unlike shiitake dermatitis, there is a lack of papules. Another differential diagnosis includes herpes zoster virus, which should be ruled out clinically.

All symptoms in shiitake dermatitis usually resolve within 1 to 8 weeks of avoidance of the culprit food. Topical steroids and antihistamines can be given.

The underlying pathology is a toxic reaction to the polysaccharide lentinan in the mushrooms, which is known as a thermolabile agent.⁵ Therefore, it may only cause a toxic reaction when the mushrooms are consumed raw or undercooked. Prick testing is usually negative in these patients, which suggests a toxic and not an immunologic reaction of the human body.⁶ Other forms of reaction to shiitake mushrooms include contact dermatitis after skin contact and allergic alveolitis after occupational exposure to mushroom spores, mainly in individuals cultivating shiitake mushrooms (mushroom worker’s lung). In these forms of the disease, prick testing may be positive.^7,8

Flagellate dermatitis caused by shiitake mushrooms is still an uncommon dermatologic phenomenon in the Western world. Future studies and cases should be reported to increase the awareness of this disorder. Although the patients present with typical clinical findings, the diagnosis can be missed if history is not carefully considered.

To the Editor:

The shiitake mushroom (Lentinula edodes) is a popular Asian food and represents the second most consumed mushroom in the world. It is known for having a range of strong health benefits including antihypertensive, anti-inflammatory, and immunomodulatory effects. Especially in Asia, this mushroom has been used in patients with cancers of the gastrointestinal tract and also may be helpful in the treatment of human immunodeficiency virus.^1,2 The source of these effects is lentinan, a polysaccharide in the mushroom. However, lentinan also can cause a toxic reaction of the skin when the mushrooms are eaten raw or undercooked. These reactions are mainly reported in Asia, but more cases have been published in the last decade in Europe and the United States, evidence that the incidence of this adverse effect has increased in the Western world.

A 65-year-old woman with no notable medical history presented to our outpatient practice with sudden onset of a pruritic, erythematous, papular eruption on the neck. The eruption began that morning. The diagnosis of eczematous dermatitis was made and hydrocortisone cream 2.5% was started. Three days later, she returned with spread of the rash to the trunk, arms, and legs despite the topical treatment. She denied fevers, chills, or constitutional symptoms. The patient also denied recent travel or bug bites. However, she reported that she recently had started using raw shiitake mushrooms in her salad; the first time was 3 days before the symptoms appeared. Physical examination revealed erythematous skin with long flagellate streaks composed of petechiae, papules, and vesicles involving the trunk, arms, and legs (Figure). Oral and nasal mucosae were uninvolved. Dermatographism was negative. The diagnosis of flagellate dermatitis from shiitake mushrooms was made given the patient’s history and the unique clinical findings of the skin. Blood work and a biopsy were not performed. Instead, the patient was advised to avoid shiitake mushrooms and use clobetasol propionate cream 0.05% twice daily for 2 weeks on the affected areas. The symptoms resolved within 10 days.

Erythematous flagellate streaks composed of petechiae, papules, and vesicles localized on the patient’s back (A) and right upper arm (B) associated with shiitake mushroom consumption.

The first known case of toxicoderma to shiitake mushrooms was reported in Japan by Nakamura³ in 1977. Since this seminal report, numerous cases have followed. This disorder is mainly seen in Asia.

Patients usually present with linear groups of pruritic, papular, petechial, and vesicular lesions in a flagellate pattern, most commonly localized on the trunk, arms, and legs. Oral and nasal mucosae usually are not involved, and fever and malaise may be associated. All symptoms typically occur 1 to 2 days after ingestion of the mushrooms. The patient’s history and typical clinical findings lead to a diagnosis; however, blood tests may show inflammation with leukocytosis and elevated C-reactive protein levels. Biopsy of the skin shows lymphocytic dermal infiltrates with spongiosis and necrotic cells within the epidermis.⁴

Differential diagnoses include flagellate dermatitis associated with bleomycin, a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Because it causes breaks in the DNA, bleomycin is commonly used as a chemotherapeutic agent in treating Hodgkin lymphoma and other malignancies. It presents with linear postinflammatory hyperpigmentation of the skin. However, unlike shiitake dermatitis, there is a lack of papules. Another differential diagnosis includes herpes zoster virus, which should be ruled out clinically.

All symptoms in shiitake dermatitis usually resolve within 1 to 8 weeks of avoidance of the culprit food. Topical steroids and antihistamines can be given.

The underlying pathology is a toxic reaction to the polysaccharide lentinan in the mushrooms, which is known as a thermolabile agent.⁵ Therefore, it may only cause a toxic reaction when the mushrooms are consumed raw or undercooked. Prick testing is usually negative in these patients, which suggests a toxic and not an immunologic reaction of the human body.⁶ Other forms of reaction to shiitake mushrooms include contact dermatitis after skin contact and allergic alveolitis after occupational exposure to mushroom spores, mainly in individuals cultivating shiitake mushrooms (mushroom worker’s lung). In these forms of the disease, prick testing may be positive.^7,8

Flagellate dermatitis caused by shiitake mushrooms is still an uncommon dermatologic phenomenon in the Western world. Future studies and cases should be reported to increase the awareness of this disorder. Although the patients present with typical clinical findings, the diagnosis can be missed if history is not carefully considered.

To the Editor:

The shiitake mushroom (Lentinula edodes) is a popular Asian food and represents the second most consumed mushroom in the world. It is known for having a range of strong health benefits including antihypertensive, anti-inflammatory, and immunomodulatory effects. Especially in Asia, this mushroom has been used in patients with cancers of the gastrointestinal tract and also may be helpful in the treatment of human immunodeficiency virus.^1,2 The source of these effects is lentinan, a polysaccharide in the mushroom. However, lentinan also can cause a toxic reaction of the skin when the mushrooms are eaten raw or undercooked. These reactions are mainly reported in Asia, but more cases have been published in the last decade in Europe and the United States, evidence that the incidence of this adverse effect has increased in the Western world.

A 65-year-old woman with no notable medical history presented to our outpatient practice with sudden onset of a pruritic, erythematous, papular eruption on the neck. The eruption began that morning. The diagnosis of eczematous dermatitis was made and hydrocortisone cream 2.5% was started. Three days later, she returned with spread of the rash to the trunk, arms, and legs despite the topical treatment. She denied fevers, chills, or constitutional symptoms. The patient also denied recent travel or bug bites. However, she reported that she recently had started using raw shiitake mushrooms in her salad; the first time was 3 days before the symptoms appeared. Physical examination revealed erythematous skin with long flagellate streaks composed of petechiae, papules, and vesicles involving the trunk, arms, and legs (Figure). Oral and nasal mucosae were uninvolved. Dermatographism was negative. The diagnosis of flagellate dermatitis from shiitake mushrooms was made given the patient’s history and the unique clinical findings of the skin. Blood work and a biopsy were not performed. Instead, the patient was advised to avoid shiitake mushrooms and use clobetasol propionate cream 0.05% twice daily for 2 weeks on the affected areas. The symptoms resolved within 10 days.

Erythematous flagellate streaks composed of petechiae, papules, and vesicles localized on the patient’s back (A) and right upper arm (B) associated with shiitake mushroom consumption.

The first known case of toxicoderma to shiitake mushrooms was reported in Japan by Nakamura³ in 1977. Since this seminal report, numerous cases have followed. This disorder is mainly seen in Asia.

Patients usually present with linear groups of pruritic, papular, petechial, and vesicular lesions in a flagellate pattern, most commonly localized on the trunk, arms, and legs. Oral and nasal mucosae usually are not involved, and fever and malaise may be associated. All symptoms typically occur 1 to 2 days after ingestion of the mushrooms. The patient’s history and typical clinical findings lead to a diagnosis; however, blood tests may show inflammation with leukocytosis and elevated C-reactive protein levels. Biopsy of the skin shows lymphocytic dermal infiltrates with spongiosis and necrotic cells within the epidermis.⁴

Differential diagnoses include flagellate dermatitis associated with bleomycin, a glycopeptide antibiotic produced by the bacterium Streptomyces verticillus. Because it causes breaks in the DNA, bleomycin is commonly used as a chemotherapeutic agent in treating Hodgkin lymphoma and other malignancies. It presents with linear postinflammatory hyperpigmentation of the skin. However, unlike shiitake dermatitis, there is a lack of papules. Another differential diagnosis includes herpes zoster virus, which should be ruled out clinically.

All symptoms in shiitake dermatitis usually resolve within 1 to 8 weeks of avoidance of the culprit food. Topical steroids and antihistamines can be given.

The underlying pathology is a toxic reaction to the polysaccharide lentinan in the mushrooms, which is known as a thermolabile agent.⁵ Therefore, it may only cause a toxic reaction when the mushrooms are consumed raw or undercooked. Prick testing is usually negative in these patients, which suggests a toxic and not an immunologic reaction of the human body.⁶ Other forms of reaction to shiitake mushrooms include contact dermatitis after skin contact and allergic alveolitis after occupational exposure to mushroom spores, mainly in individuals cultivating shiitake mushrooms (mushroom worker’s lung). In these forms of the disease, prick testing may be positive.^7,8

Flagellate dermatitis caused by shiitake mushrooms is still an uncommon dermatologic phenomenon in the Western world. Future studies and cases should be reported to increase the awareness of this disorder. Although the patients present with typical clinical findings, the diagnosis can be missed if history is not carefully considered.