Miller JL

Case Report

A 64-year-old woman presented to the Vanderbilt University Medical Center, Nashville, Tennessee, with right-sided abdominal pain, nausea, and dysuria of several days' duration 3 months after a cadaveric renal transplant and administration of cyclosporine and methylprednisolone. Pyelonephritis and acute tubular necrosis were diagnosed. Urine and blood cultures grew Escherichia coli and ultrasound imaging revealed ureteral obstruction of the transplanted kidney. Piperacillin/tazobactam and vancomycin were administered, and a right-sided nephrostomy tube was placed. One month later, the nephrostomy tube was removed and the ureter was reimplanted. The surgical wound, however, failed to close. Intravenous antibiotic administration was continued and wet-to-dry dressings were applied twice daily. In 3 days, the wound rapidly enlarged, became severely painful, and developed a black eschar. Despite repeated debridement, the black eschar would re-form within 24 hours after the procedure. Blood cultures were negative for fungus or bacteria but positive for cytomegalovirus. Piperacillin/tazobactam and vancomycin were continued, ganciclovir was added to the therapeutic regimen, and the dermatology department was consulted.

A large ulceration measuring 20X17 cm with a depth of 5.2 cm developed in the lower right quadrant of the abdomen (Figure 1). The ulcer base was pink, friable, and covered with a fragile black eschar. Histologic evaluation of the ulcer base revealed full-thickness epidermal necrosis, numerous neutrophils, and dermal edema (Figure 2). A superficial layer of hyphae and fungal fruiting bodies was noted (Figures 3 and 4). Tissue culture from the wound grew Aspergillus niger and a diagnosis of primary cutaneous aspergillosis was made.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

The patient underwent wide debridement of the abdominal wound and administration of maximal doses of liposomal amphotericin Β. Despite aggressive treatment, she rapidly deteriorated and died 14 days later. 

Comment

Aspergillus is a ubiquitous saprophytic mold that belongs to the class Ascomycetes and is commonly found in soil, water, and decaying vegetation.¹ Although rarely a pathogen in immunocompetent individuals, it commonly affects immunocompromised individuals and is second in incidence in this population (Candida infection is most prevalent).² The name Aspergillus was proposed in 1729 when Pietro Antonio Micheli, an Italian priest and biologist, noted that the organism resembled the aspergillum used to sprinkle holy water.³ To date, more than 900 species of Aspergillus have been defined. The most prevalent human pathogens include Aspergillus flavus, Aspergillus fumigatus, A niger, Aspergillus terreus, and Aspergillus ustus.^3-5

Risk factors for Aspergillus infection include inherited immunodeficiency disorders, organ transplantation, chronic corticosteroid and/or broad-spectrum antibiotic administration, cytotoxic chemotherapy, prolonged granulocytopenia, cirrhosis, diabetes mellitus, uremia, local tissue injury (ie, burn, surgical manipulation), underlying malignancy, chronic alcoholism, neonatal status, and cytomegalovirus infection.⁶ Risk factors specific to solid organ transplant recipients include prolonged surgeries; laparotomies, excluding those at transplantation; uremia; neutropenia; cytomegalovirus infection; and administration of high-dose corticosteroids, tacrolimus, or cyclosporine.⁷

Cutaneous aspergillosis is classically described as primary or secondary. Secondary disease occurs via hematogenous dissemination, often from a pulmonary focus, or by extension from a contiguous anatomic site.2 In primary cutaneous aspergillosis, breaks in the skin are directly inoculated by airborne spores or contaminated materials.⁸ The use of adhesive tape is a common risk factor. Intermittent stripping of the stratum corneum with dressing changes presumably induces sufficient mechanical trauma to permit infection following contact with contaminated arm boards, intravenous catheters, tape, or gauze.^8-14 Ongoing construction/renovation or air circulation systems harboring Aspergillus species may contribute to aerial dissemination of spores.^3,15 Potted plants in a hematology ward have been reported as a source of A terreus infection, and certain foods, especially pepper (ground black pepper) and tea (regular and herbal tea), have high rates of contamination with Aspergillus species.^16,17 Primary cutaneous aspergillosis begins as an erythematous fluctuant nodule that undergoes rapid ulceration, which produces a central black eschar.⁸A flavus is the most common pathogen in primary cutaneous aspergillosis, but infection with Aspergillus glaucus, A niger, A terreus, and A ustus also have been described.² Primary cutaneous aspergillosis in solid organ transplant recipients is uncommon, and to our knowledge, this is the first reported case caused by A niger. In this population, cutaneous aspergillosis can occur as a primary infection directly in the surgical wound or as nodules near a site of a break in the epidermis that is different than the primary surgical wound.⁹ Patients present with fever, changes in the wound surface, swelling, induration, and tenderness. Interestingly, primary cutaneous aspergillosis in solid organ transplant recipients generally occurs despite a neutrophil count within reference range.⁹ Rapid diagnosis can be made by potassium hydroxide examination of the wound as well as skin biopsy and tissue culture.¹⁵ Because Aspergillus tends to invade blood vessels of the dermis and subcutaneous tissues, biopsy specimens should be taken from the center of the lesion and should include subcutaneous fat. Mycelial forms of the organism may be found within the epidermis and dermis. Aspergillus is a dichotomous branching fungus with septate hyphae measuring 3 µm in diameter and branching at a 45º angle. The fruiting body rarely is observed in tissue samples unless an overwhelming number of organisms are present.^5,9,18 The fungal elements may be visualized with hematoxylin and eosin stain but are highlighted by Gomori methenamine-silver or periodic acid-Schiff stains. Tissue cultures should be grown in Sabouraud dextrose agar. The diagnosis of primary cutaneous aspergillosis can be made only after excluding other sites of infection.

Successful treatment of primary cutaneous aspergillosis requires a high index of suspicion, with early diagnosis and aggressive management. Primary cutaneous aspergillosis should be considered in the differential diagnosis of necrotizing skin lesions and nonhealing surgical wounds in immunosuppressed patients. Maximized immunosurveillance is critical and immunosuppressive medications should be decreased or discontinued if possible. Necrotic tissue requires debridement. However, as demonstrated in our patient, debridement alone may be insufficient for eradication of the infection, especially in immunocompromised patients. Antifungal antibiotics should be administered as soon as possible. The classic antimicrobial drug of choice is intravenous ampho- tericin Β.^2,3,19,20 This drug is fungicidal both in vitro and in vivo, with a low incidence of resistance.^21,22 However, studies have shown better survival rates with voriconazole compared with amphotericin Β as initial therapy for invasive aspergillosis.^23,24 Caspofungin combined with voriconazole also has been shown to be particularly effective as initial treatment of invasive aspergillosis in solid organ transplant recipients with renal dysfunction or A fumigatus infections.²⁵

Case Report

A 64-year-old woman presented to the Vanderbilt University Medical Center, Nashville, Tennessee, with right-sided abdominal pain, nausea, and dysuria of several days' duration 3 months after a cadaveric renal transplant and administration of cyclosporine and methylprednisolone. Pyelonephritis and acute tubular necrosis were diagnosed. Urine and blood cultures grew Escherichia coli and ultrasound imaging revealed ureteral obstruction of the transplanted kidney. Piperacillin/tazobactam and vancomycin were administered, and a right-sided nephrostomy tube was placed. One month later, the nephrostomy tube was removed and the ureter was reimplanted. The surgical wound, however, failed to close. Intravenous antibiotic administration was continued and wet-to-dry dressings were applied twice daily. In 3 days, the wound rapidly enlarged, became severely painful, and developed a black eschar. Despite repeated debridement, the black eschar would re-form within 24 hours after the procedure. Blood cultures were negative for fungus or bacteria but positive for cytomegalovirus. Piperacillin/tazobactam and vancomycin were continued, ganciclovir was added to the therapeutic regimen, and the dermatology department was consulted.

A large ulceration measuring 20X17 cm with a depth of 5.2 cm developed in the lower right quadrant of the abdomen (Figure 1). The ulcer base was pink, friable, and covered with a fragile black eschar. Histologic evaluation of the ulcer base revealed full-thickness epidermal necrosis, numerous neutrophils, and dermal edema (Figure 2). A superficial layer of hyphae and fungal fruiting bodies was noted (Figures 3 and 4). Tissue culture from the wound grew Aspergillus niger and a diagnosis of primary cutaneous aspergillosis was made.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

The patient underwent wide debridement of the abdominal wound and administration of maximal doses of liposomal amphotericin Β. Despite aggressive treatment, she rapidly deteriorated and died 14 days later. 

Comment

Aspergillus is a ubiquitous saprophytic mold that belongs to the class Ascomycetes and is commonly found in soil, water, and decaying vegetation.¹ Although rarely a pathogen in immunocompetent individuals, it commonly affects immunocompromised individuals and is second in incidence in this population (Candida infection is most prevalent).² The name Aspergillus was proposed in 1729 when Pietro Antonio Micheli, an Italian priest and biologist, noted that the organism resembled the aspergillum used to sprinkle holy water.³ To date, more than 900 species of Aspergillus have been defined. The most prevalent human pathogens include Aspergillus flavus, Aspergillus fumigatus, A niger, Aspergillus terreus, and Aspergillus ustus.^3-5

Risk factors for Aspergillus infection include inherited immunodeficiency disorders, organ transplantation, chronic corticosteroid and/or broad-spectrum antibiotic administration, cytotoxic chemotherapy, prolonged granulocytopenia, cirrhosis, diabetes mellitus, uremia, local tissue injury (ie, burn, surgical manipulation), underlying malignancy, chronic alcoholism, neonatal status, and cytomegalovirus infection.⁶ Risk factors specific to solid organ transplant recipients include prolonged surgeries; laparotomies, excluding those at transplantation; uremia; neutropenia; cytomegalovirus infection; and administration of high-dose corticosteroids, tacrolimus, or cyclosporine.⁷

Cutaneous aspergillosis is classically described as primary or secondary. Secondary disease occurs via hematogenous dissemination, often from a pulmonary focus, or by extension from a contiguous anatomic site.2 In primary cutaneous aspergillosis, breaks in the skin are directly inoculated by airborne spores or contaminated materials.⁸ The use of adhesive tape is a common risk factor. Intermittent stripping of the stratum corneum with dressing changes presumably induces sufficient mechanical trauma to permit infection following contact with contaminated arm boards, intravenous catheters, tape, or gauze.^8-14 Ongoing construction/renovation or air circulation systems harboring Aspergillus species may contribute to aerial dissemination of spores.^3,15 Potted plants in a hematology ward have been reported as a source of A terreus infection, and certain foods, especially pepper (ground black pepper) and tea (regular and herbal tea), have high rates of contamination with Aspergillus species.^16,17 Primary cutaneous aspergillosis begins as an erythematous fluctuant nodule that undergoes rapid ulceration, which produces a central black eschar.⁸A flavus is the most common pathogen in primary cutaneous aspergillosis, but infection with Aspergillus glaucus, A niger, A terreus, and A ustus also have been described.² Primary cutaneous aspergillosis in solid organ transplant recipients is uncommon, and to our knowledge, this is the first reported case caused by A niger. In this population, cutaneous aspergillosis can occur as a primary infection directly in the surgical wound or as nodules near a site of a break in the epidermis that is different than the primary surgical wound.⁹ Patients present with fever, changes in the wound surface, swelling, induration, and tenderness. Interestingly, primary cutaneous aspergillosis in solid organ transplant recipients generally occurs despite a neutrophil count within reference range.⁹ Rapid diagnosis can be made by potassium hydroxide examination of the wound as well as skin biopsy and tissue culture.¹⁵ Because Aspergillus tends to invade blood vessels of the dermis and subcutaneous tissues, biopsy specimens should be taken from the center of the lesion and should include subcutaneous fat. Mycelial forms of the organism may be found within the epidermis and dermis. Aspergillus is a dichotomous branching fungus with septate hyphae measuring 3 µm in diameter and branching at a 45º angle. The fruiting body rarely is observed in tissue samples unless an overwhelming number of organisms are present.^5,9,18 The fungal elements may be visualized with hematoxylin and eosin stain but are highlighted by Gomori methenamine-silver or periodic acid-Schiff stains. Tissue cultures should be grown in Sabouraud dextrose agar. The diagnosis of primary cutaneous aspergillosis can be made only after excluding other sites of infection.

Successful treatment of primary cutaneous aspergillosis requires a high index of suspicion, with early diagnosis and aggressive management. Primary cutaneous aspergillosis should be considered in the differential diagnosis of necrotizing skin lesions and nonhealing surgical wounds in immunosuppressed patients. Maximized immunosurveillance is critical and immunosuppressive medications should be decreased or discontinued if possible. Necrotic tissue requires debridement. However, as demonstrated in our patient, debridement alone may be insufficient for eradication of the infection, especially in immunocompromised patients. Antifungal antibiotics should be administered as soon as possible. The classic antimicrobial drug of choice is intravenous ampho- tericin Β.^2,3,19,20 This drug is fungicidal both in vitro and in vivo, with a low incidence of resistance.^21,22 However, studies have shown better survival rates with voriconazole compared with amphotericin Β as initial therapy for invasive aspergillosis.^23,24 Caspofungin combined with voriconazole also has been shown to be particularly effective as initial treatment of invasive aspergillosis in solid organ transplant recipients with renal dysfunction or A fumigatus infections.²⁵

Case Report

A 64-year-old woman presented to the Vanderbilt University Medical Center, Nashville, Tennessee, with right-sided abdominal pain, nausea, and dysuria of several days' duration 3 months after a cadaveric renal transplant and administration of cyclosporine and methylprednisolone. Pyelonephritis and acute tubular necrosis were diagnosed. Urine and blood cultures grew Escherichia coli and ultrasound imaging revealed ureteral obstruction of the transplanted kidney. Piperacillin/tazobactam and vancomycin were administered, and a right-sided nephrostomy tube was placed. One month later, the nephrostomy tube was removed and the ureter was reimplanted. The surgical wound, however, failed to close. Intravenous antibiotic administration was continued and wet-to-dry dressings were applied twice daily. In 3 days, the wound rapidly enlarged, became severely painful, and developed a black eschar. Despite repeated debridement, the black eschar would re-form within 24 hours after the procedure. Blood cultures were negative for fungus or bacteria but positive for cytomegalovirus. Piperacillin/tazobactam and vancomycin were continued, ganciclovir was added to the therapeutic regimen, and the dermatology department was consulted.

A large ulceration measuring 20X17 cm with a depth of 5.2 cm developed in the lower right quadrant of the abdomen (Figure 1). The ulcer base was pink, friable, and covered with a fragile black eschar. Histologic evaluation of the ulcer base revealed full-thickness epidermal necrosis, numerous neutrophils, and dermal edema (Figure 2). A superficial layer of hyphae and fungal fruiting bodies was noted (Figures 3 and 4). Tissue culture from the wound grew Aspergillus niger and a diagnosis of primary cutaneous aspergillosis was made.

PLEASE REFER TO THE PDF TO VIEW THE FIGURES

The patient underwent wide debridement of the abdominal wound and administration of maximal doses of liposomal amphotericin Β. Despite aggressive treatment, she rapidly deteriorated and died 14 days later. 

Comment

Aspergillus is a ubiquitous saprophytic mold that belongs to the class Ascomycetes and is commonly found in soil, water, and decaying vegetation.¹ Although rarely a pathogen in immunocompetent individuals, it commonly affects immunocompromised individuals and is second in incidence in this population (Candida infection is most prevalent).² The name Aspergillus was proposed in 1729 when Pietro Antonio Micheli, an Italian priest and biologist, noted that the organism resembled the aspergillum used to sprinkle holy water.³ To date, more than 900 species of Aspergillus have been defined. The most prevalent human pathogens include Aspergillus flavus, Aspergillus fumigatus, A niger, Aspergillus terreus, and Aspergillus ustus.^3-5

Risk factors for Aspergillus infection include inherited immunodeficiency disorders, organ transplantation, chronic corticosteroid and/or broad-spectrum antibiotic administration, cytotoxic chemotherapy, prolonged granulocytopenia, cirrhosis, diabetes mellitus, uremia, local tissue injury (ie, burn, surgical manipulation), underlying malignancy, chronic alcoholism, neonatal status, and cytomegalovirus infection.⁶ Risk factors specific to solid organ transplant recipients include prolonged surgeries; laparotomies, excluding those at transplantation; uremia; neutropenia; cytomegalovirus infection; and administration of high-dose corticosteroids, tacrolimus, or cyclosporine.⁷

Cutaneous aspergillosis is classically described as primary or secondary. Secondary disease occurs via hematogenous dissemination, often from a pulmonary focus, or by extension from a contiguous anatomic site.2 In primary cutaneous aspergillosis, breaks in the skin are directly inoculated by airborne spores or contaminated materials.⁸ The use of adhesive tape is a common risk factor. Intermittent stripping of the stratum corneum with dressing changes presumably induces sufficient mechanical trauma to permit infection following contact with contaminated arm boards, intravenous catheters, tape, or gauze.^8-14 Ongoing construction/renovation or air circulation systems harboring Aspergillus species may contribute to aerial dissemination of spores.^3,15 Potted plants in a hematology ward have been reported as a source of A terreus infection, and certain foods, especially pepper (ground black pepper) and tea (regular and herbal tea), have high rates of contamination with Aspergillus species.^16,17 Primary cutaneous aspergillosis begins as an erythematous fluctuant nodule that undergoes rapid ulceration, which produces a central black eschar.⁸A flavus is the most common pathogen in primary cutaneous aspergillosis, but infection with Aspergillus glaucus, A niger, A terreus, and A ustus also have been described.² Primary cutaneous aspergillosis in solid organ transplant recipients is uncommon, and to our knowledge, this is the first reported case caused by A niger. In this population, cutaneous aspergillosis can occur as a primary infection directly in the surgical wound or as nodules near a site of a break in the epidermis that is different than the primary surgical wound.⁹ Patients present with fever, changes in the wound surface, swelling, induration, and tenderness. Interestingly, primary cutaneous aspergillosis in solid organ transplant recipients generally occurs despite a neutrophil count within reference range.⁹ Rapid diagnosis can be made by potassium hydroxide examination of the wound as well as skin biopsy and tissue culture.¹⁵ Because Aspergillus tends to invade blood vessels of the dermis and subcutaneous tissues, biopsy specimens should be taken from the center of the lesion and should include subcutaneous fat. Mycelial forms of the organism may be found within the epidermis and dermis. Aspergillus is a dichotomous branching fungus with septate hyphae measuring 3 µm in diameter and branching at a 45º angle. The fruiting body rarely is observed in tissue samples unless an overwhelming number of organisms are present.^5,9,18 The fungal elements may be visualized with hematoxylin and eosin stain but are highlighted by Gomori methenamine-silver or periodic acid-Schiff stains. Tissue cultures should be grown in Sabouraud dextrose agar. The diagnosis of primary cutaneous aspergillosis can be made only after excluding other sites of infection.

Successful treatment of primary cutaneous aspergillosis requires a high index of suspicion, with early diagnosis and aggressive management. Primary cutaneous aspergillosis should be considered in the differential diagnosis of necrotizing skin lesions and nonhealing surgical wounds in immunosuppressed patients. Maximized immunosurveillance is critical and immunosuppressive medications should be decreased or discontinued if possible. Necrotic tissue requires debridement. However, as demonstrated in our patient, debridement alone may be insufficient for eradication of the infection, especially in immunocompromised patients. Antifungal antibiotics should be administered as soon as possible. The classic antimicrobial drug of choice is intravenous ampho- tericin Β.^2,3,19,20 This drug is fungicidal both in vitro and in vivo, with a low incidence of resistance.^21,22 However, studies have shown better survival rates with voriconazole compared with amphotericin Β as initial therapy for invasive aspergillosis.^23,24 Caspofungin combined with voriconazole also has been shown to be particularly effective as initial treatment of invasive aspergillosis in solid organ transplant recipients with renal dysfunction or A fumigatus infections.²⁵