What Was Behind this Patient’s Eruption?

PATIENT PRESENTATION

A 57-year-old Caucasian female presented to our office as a referral from a local emergency room. She had lived in Arizona for 15 years. She complained of a pruritic eruption on her scalp, trunk, arms and legs that had begun suddenly 7 days earlier. She also reported fever, fatigue, joint aches and a mild cough during the previous week. She lacked any significant past medical history and denied the use of any new medications. She denied any recent travel or contact with anyone sick. On physical examination, the patient appeared fatigued and had a low-grade fever of 99 degrees Fahrenheit. We noted multiple firm, erythematous, deep-set plaques scattered on the scalp, arms and legs. She also had smaller, more faint patches of similar appearance on the lower back and abdomen. Her ocular and oral mucosal surfaces were clear of injection and erythema. Initial laboratory results in the emergency room revealed a white blood cell count of 13,100/mm3 and a normal metabolic panel 20. The patient’s preliminary chest X-ray was negative. Biopsies were obtained and results are pending.

Diagnosis: Interstitial Granulomatous Dermatitis Secondary to Pulmonary Coccidioidomycosis

Interstitial granulomatous dermatitis has recently been described as another reactive manifestation of primary pulmonary coccidioidomycosis.¹ Biopsy of skin lesions histologically demonstrates interstitial granulomatous dermatitis with neutrophils, eosinophils and leukocytoclasis. Degeneration of collagen is also observed within the granulomatous foci, along with increased dermal mucin. No fungal organisms are identifiable on biopsy. Serum IgM antibodies to Coccidioides immitis were positive by enzyme immunoassay in all previously reported cases.¹ Histopathologic review of skin biopsies from our patient was consistent with interstitial granulomatous dermatitis. Papillary dermal edema was evident, with abundant mucin deposition confirmed by a colloidal iron stain. A Gomori methenamine-silver stain for fungi was negative, as was direct immunofluorescence for IgG, IgA and C3. Subsequent laboratory studies revealed a negative ANA screen and a negative Mycoplasma pneumoniae IgM titer. Enzyme immunoassay demonstrated serum IgM antibodies to C. immitis. After evaluation of the patient’s history, physical exam and laboratory findings, we concluded that her cutaneous lesions developed secondary to pulmonary coccidioidomycosis. Initial diagnostic considerations also included bullous pemphigoid, erythema multiforme, lupus, granuloma annulare and possible drug eruption. The absence of identifiable organisms in her lesions may represent a reactive immunological manifestation of her primary lung infection, as opposed to fungal dissemination to the skin. The histologic pattern observed on biopsy was consistent with a newly described reactive form of the disease.¹

More about Coccidioidomycosis

Coccidioidomycosis is endemic in the hot, dry areas of southern California, Arizona and New Mexico, and is acquired through inhalation of airborne arthroconidia.² Hematogenous dissemination of the fungus from the lungs occurs in <1% of all infections, and has been shown to result in lesions of various organs, primarily skin and subcutaneous tissue, as well as bone, meninges, spleen, liver and kidney.³ Factors contributing to increased risk of dissemination include immunosuppression, male gender, African-American and Filipino ethnicity and pregnancy.² Roughly 60% of primary pulmonary infections do not produce the characteristic acute symptoms, which include fever, cough, weight loss, myalgias, anorexia, chest pain and respiratory distress. However, about 50% of all symptomatic infections produce cutaneous findings.² Skin lesions may develop via dissemination from an infected lung, in which case the fungus can be identified with fungal stains and culture, or they may evolve due to a reactive immunologic mechanism in which case no organisms are identifiable on biopsy.¹ Rarely, C. immitis may be acquired percutaneously and cause a primary skin infection. This form of coccidioidomycosis can be differentiated from disseminated disease using coccidioidin skin sensitivity tests and latex agglutination and precipitin tests.⁴

Reviewing Cutaneous Findings in Coccidioidomycosis

During the initial pulmonary infection, patients may develop toxic erythema, erythema nodosum or erythema multiforme in the setting of transient flu-like symptoms. These cutaneous manifestations are observed in patients demonstrating the reactive form of the disease.² Toxic erythema may occur during the first several days of infection, producing a fine, diffuse pruritic rash that may be erythematous, urticarial, maculopapular or morbilliform. Erythema nodosum is the most common reactive pattern overall, and is most commonly observed in adult Caucasian women, while erythema multiforme may present more commonly in children.² C. immitis is not identifiable with biopsy or fungal staining in these cases. However, serum IgM antibodies to coccidioidal antigens are present in 80% of patients after 2 weeks,² and positive serology is diagnostic.¹ It has been postulated that circulating immune complexes, which are characteristic of pulmonary coccidioidomycosis, may be responsible for the erythema nodosum, as well as the interstitial granulomatous dermatitis observed in these patients.^1,5 In cases of disseminated disease, the most commonly observed skin lesions include granulomatous papules, nodules or plaques appearing primarily on the head,³ typically involving the central face and nasolabial fold.^2,4 Dissemination may occur soon after infection or may take place months to years later.³ Lesions produced by C. immitis can also mimic contact dermatitis, actinic keratosis, squamous cell carcinoma, bullous pemphigoid, warts, rosacea, tuberculosis, sarcoid and other etiologies. The diagnosis of disseminated disease is made by biopsy with fungal staining or tissue culture.²

Managing This Condition

Data from prospective controlled trials regarding treatment of primary pulmonary coccidioidomycosis infections is lacking, but historically more than 95% of infections resolved spontaneously.⁶ Indications for treatment with antifungal agents include:

• weight loss of more than 10%
• infiltrates involving more than one-half of one lung or portions of both lungs • persistent hilar adenopathy or pulmonary involvement
• titers of complement fixation (CF) antibodies to C. immitis >1:16
• failure to develop dermal hypersensitivity to coccidioidal antigens
• symptoms persisting for more than 6 weeks
• African-American, Filipino or Mexican race
• pregnancy and immunosuppressed states.^2,6

The antifungal agent of choice depends on the severity of disease. Amphotericin B (Abelcet, AmBisome, Amphotec, Fungizone) is utilized in more severe infections, as well as during pregnancy, and requires weekly monitoring of renal function, hematocrit and electrolytes.² Azole agents are employed more commonly in maintenance therapy of patients with chronic disease, but are less efficacious and more hepatotoxic than Amphotericin B.⁷ Disseminated coccidioidomycosis requires definite medicinal therapy and may require surgical intervention, including debridement and drainage of infected sites.² After treatment is completed, CF titers should be monitored to ensure disease resolution.⁶ Our patient was referred to the infectious diseases clinic for further work-up and treatment, and was found by sputum smear to have a mild pulmonary infection with C. immitis. She was prescribed oral fluconazole (Diflucan) 400 mg/d for 2 months and was also started on a 3-week slow taper of oral methylprednisolone (Medrol, Methylpred), which started at 40 mg/d. Approximately 6 weeks later she reported a complete resolution of her eruption and associated symptoms, and denied experiencing any negative side effects while taking fluconazole.

PATIENT PRESENTATION

A 57-year-old Caucasian female presented to our office as a referral from a local emergency room. She had lived in Arizona for 15 years. She complained of a pruritic eruption on her scalp, trunk, arms and legs that had begun suddenly 7 days earlier. She also reported fever, fatigue, joint aches and a mild cough during the previous week. She lacked any significant past medical history and denied the use of any new medications. She denied any recent travel or contact with anyone sick. On physical examination, the patient appeared fatigued and had a low-grade fever of 99 degrees Fahrenheit. We noted multiple firm, erythematous, deep-set plaques scattered on the scalp, arms and legs. She also had smaller, more faint patches of similar appearance on the lower back and abdomen. Her ocular and oral mucosal surfaces were clear of injection and erythema. Initial laboratory results in the emergency room revealed a white blood cell count of 13,100/mm3 and a normal metabolic panel 20. The patient’s preliminary chest X-ray was negative. Biopsies were obtained and results are pending.

Diagnosis: Interstitial Granulomatous Dermatitis Secondary to Pulmonary Coccidioidomycosis

Interstitial granulomatous dermatitis has recently been described as another reactive manifestation of primary pulmonary coccidioidomycosis.¹ Biopsy of skin lesions histologically demonstrates interstitial granulomatous dermatitis with neutrophils, eosinophils and leukocytoclasis. Degeneration of collagen is also observed within the granulomatous foci, along with increased dermal mucin. No fungal organisms are identifiable on biopsy. Serum IgM antibodies to Coccidioides immitis were positive by enzyme immunoassay in all previously reported cases.¹ Histopathologic review of skin biopsies from our patient was consistent with interstitial granulomatous dermatitis. Papillary dermal edema was evident, with abundant mucin deposition confirmed by a colloidal iron stain. A Gomori methenamine-silver stain for fungi was negative, as was direct immunofluorescence for IgG, IgA and C3. Subsequent laboratory studies revealed a negative ANA screen and a negative Mycoplasma pneumoniae IgM titer. Enzyme immunoassay demonstrated serum IgM antibodies to C. immitis. After evaluation of the patient’s history, physical exam and laboratory findings, we concluded that her cutaneous lesions developed secondary to pulmonary coccidioidomycosis. Initial diagnostic considerations also included bullous pemphigoid, erythema multiforme, lupus, granuloma annulare and possible drug eruption. The absence of identifiable organisms in her lesions may represent a reactive immunological manifestation of her primary lung infection, as opposed to fungal dissemination to the skin. The histologic pattern observed on biopsy was consistent with a newly described reactive form of the disease.¹

More about Coccidioidomycosis

Coccidioidomycosis is endemic in the hot, dry areas of southern California, Arizona and New Mexico, and is acquired through inhalation of airborne arthroconidia.² Hematogenous dissemination of the fungus from the lungs occurs in <1% of all infections, and has been shown to result in lesions of various organs, primarily skin and subcutaneous tissue, as well as bone, meninges, spleen, liver and kidney.³ Factors contributing to increased risk of dissemination include immunosuppression, male gender, African-American and Filipino ethnicity and pregnancy.² Roughly 60% of primary pulmonary infections do not produce the characteristic acute symptoms, which include fever, cough, weight loss, myalgias, anorexia, chest pain and respiratory distress. However, about 50% of all symptomatic infections produce cutaneous findings.² Skin lesions may develop via dissemination from an infected lung, in which case the fungus can be identified with fungal stains and culture, or they may evolve due to a reactive immunologic mechanism in which case no organisms are identifiable on biopsy.¹ Rarely, C. immitis may be acquired percutaneously and cause a primary skin infection. This form of coccidioidomycosis can be differentiated from disseminated disease using coccidioidin skin sensitivity tests and latex agglutination and precipitin tests.⁴

Reviewing Cutaneous Findings in Coccidioidomycosis

During the initial pulmonary infection, patients may develop toxic erythema, erythema nodosum or erythema multiforme in the setting of transient flu-like symptoms. These cutaneous manifestations are observed in patients demonstrating the reactive form of the disease.² Toxic erythema may occur during the first several days of infection, producing a fine, diffuse pruritic rash that may be erythematous, urticarial, maculopapular or morbilliform. Erythema nodosum is the most common reactive pattern overall, and is most commonly observed in adult Caucasian women, while erythema multiforme may present more commonly in children.² C. immitis is not identifiable with biopsy or fungal staining in these cases. However, serum IgM antibodies to coccidioidal antigens are present in 80% of patients after 2 weeks,² and positive serology is diagnostic.¹ It has been postulated that circulating immune complexes, which are characteristic of pulmonary coccidioidomycosis, may be responsible for the erythema nodosum, as well as the interstitial granulomatous dermatitis observed in these patients.^1,5 In cases of disseminated disease, the most commonly observed skin lesions include granulomatous papules, nodules or plaques appearing primarily on the head,³ typically involving the central face and nasolabial fold.^2,4 Dissemination may occur soon after infection or may take place months to years later.³ Lesions produced by C. immitis can also mimic contact dermatitis, actinic keratosis, squamous cell carcinoma, bullous pemphigoid, warts, rosacea, tuberculosis, sarcoid and other etiologies. The diagnosis of disseminated disease is made by biopsy with fungal staining or tissue culture.²

Managing This Condition

Data from prospective controlled trials regarding treatment of primary pulmonary coccidioidomycosis infections is lacking, but historically more than 95% of infections resolved spontaneously.⁶ Indications for treatment with antifungal agents include:

• weight loss of more than 10%
• infiltrates involving more than one-half of one lung or portions of both lungs • persistent hilar adenopathy or pulmonary involvement
• titers of complement fixation (CF) antibodies to C. immitis >1:16
• failure to develop dermal hypersensitivity to coccidioidal antigens
• symptoms persisting for more than 6 weeks
• African-American, Filipino or Mexican race
• pregnancy and immunosuppressed states.^2,6

The antifungal agent of choice depends on the severity of disease. Amphotericin B (Abelcet, AmBisome, Amphotec, Fungizone) is utilized in more severe infections, as well as during pregnancy, and requires weekly monitoring of renal function, hematocrit and electrolytes.² Azole agents are employed more commonly in maintenance therapy of patients with chronic disease, but are less efficacious and more hepatotoxic than Amphotericin B.⁷ Disseminated coccidioidomycosis requires definite medicinal therapy and may require surgical intervention, including debridement and drainage of infected sites.² After treatment is completed, CF titers should be monitored to ensure disease resolution.⁶ Our patient was referred to the infectious diseases clinic for further work-up and treatment, and was found by sputum smear to have a mild pulmonary infection with C. immitis. She was prescribed oral fluconazole (Diflucan) 400 mg/d for 2 months and was also started on a 3-week slow taper of oral methylprednisolone (Medrol, Methylpred), which started at 40 mg/d. Approximately 6 weeks later she reported a complete resolution of her eruption and associated symptoms, and denied experiencing any negative side effects while taking fluconazole.