Primary cutaneous aspergillosis in a patient with idiopathic aplastic anemia: a case report

¹University of Medicine Ibn El Jazzar, Mohamed Karoui street, 4002, Sousse, Tunisia, ²Department of Infectious Diseases, Farhat Hached Hospital, Ibn El Jazzar Street, 4000, Sousse, Tunisia, ³University of Medicine of Monastir, Avicenne street, 5019, Monastir, Tunisia, ⁴Department of Dermatology, Fattouma Bourguiba Hospital, Farhat Hached Avenue, 5000, Monastir, Tunisia, ⁵Department of Pathology, Farhat Hached Hospital, Ibn El Jazzar Street, 4000, Sousse, Tunisia, ⁶Laboratory of Parasitology-Mycology, Farhat Hached Hospital, Ibn El Jazzar Street, 4000, Sousse, Tunisia, ⁷Department of Medical Imaging, Fattouma Bourguiba Hospital, Farhat Hached Avenue, 5000, Monastir, Tunisia, ⁸Department of Hematology, Farhat Hached Hospital, Ibn El Jazzar Street, 4000, Sousse, Tunisia

^&Corresponding author
Mariem Ben Ticha, Department of Infectious Diseases, Faculty of Medicine of Sousse, Farhat Hached University Hospital, Sousse, Tunisia

Introduction    

Aspergillus spp. is the second most common cause of opportunistic fungal infection in humans after Candida [1,2]. This infection is often localized in the lungs, central nervous system (CNS), paranasal sinuses [3]. Cutaneous aspergillosis, both primary (PCA) and secondary (SCA), due to hematogenous dissemination of Aspergillus spp. is a relatively rare but life-threatening clinical manifestation and affects mostly immunocompromised patients [3]. Here we present a clinical case of an isolated PCA in a 23-year-old man with idiopathic aplastic anemia.

Patient and observation     

Patient information: a 23-year-old man with severe idiopathic aplastic anemia diagnosed in February 2019. He was treated with cyclosporine and transfusions. No relevant family or psychosocial history was reported.

Clinical findings: on admission, the patient presented with febrile neutropenia (temperature 39°C, absolute neutrophil count: 20/mm³) associated with chills and altered general condition. Cutaneous examination revealed a single circular erythematous and violaceous lesion located on the lateral aspect of the leg, with a central necrotic area (Figure 1). The lesion was painful, rapidly progressive, and initially described by the patient as a pustule. No other skin lesions were observed. There were no clinical signs suggestive of systemic involvement, particularly no pulmonary, neurological, or mucosal abnormalities.

Timeline: the patient was diagnosed with severe idiopathic aplastic anemia in February 2019 and started on immunosuppressive therapy with ciclosporin along with transfusion support. Two weeks later, he developed febrile neutropenia and was admitted to the hospital. At the same time, a skin lesion appeared on the leg and rapidly progressed to necrosis over a period of 10 days despite empirical broad-spectrum antibiotic therapy. A skin biopsy was performed, leading to the diagnosis of primary cutaneous aspergillosis. Surgical excision of the lesion was carried out, followed by initiation of antifungal therapy with voriconazole. Although local improvement was observed, the patient subsequently developed bacterial septic shock and died.

Diagnostic assessment: initial clinical suspicion was ecthyma gangrenosum; however, microbiological investigations were negative. Blood and urine cultures remained sterile, with no evidence of systemic bacterial infection. Mycological culture on Sabouraud dextrose agar showed characteristic macroscopic features with dark reverse pigmentation (Figure 2). Microscopic examination using the lamina technique confirmed the identification of Aspergillus flavus. Histopathological examination of the skin biopsy revealed abundant necrotic tissue containing numerous fungal elements (Figure 3A). Grocott staining demonstrated septate hyphae with acute-angle branching, highly suggestive of Aspergillus species (Figure 3B). Serum galactomannan antigenemia was positive, supporting the diagnosis of invasive aspergillosis. Cranial and whole-body computed tomography scans showed no evidence of pulmonary or systemic dissemination. The main differential diagnoses included ecthyma gangrenosum, bacterial skin infection, and pyoderma gangrenosum. Based on clinical, histopathological, and mycological findings, the final diagnosis of primary cutaneous aspergillosis was established. The prognosis was considered poor due to profound neutropenia and the underlying aplastic anemia.

Therapeutic intervention: the patient initially received empirical intravenous antibiotic therapy with piperacillin-tazobactam and vancomycin for seven days, which was later escalated to imipenem and ciprofloxacin due to lack of clinical improvement. Following diagnostic confirmation, surgical resection of the necrotic lesion was performed (Figure 4). Antifungal therapy with voriconazole (200 mg twice daily) was initiated. The modification of treatment was justified by the absence of response to antibacterial therapy and confirmation of fungal infection.

Follow-up and outcomes: after initiation of voriconazole and surgical management, local clinical improvement was observed with no further extension of the lesion. The antifungal treatment was well tolerated without reported adverse effects. No evidence of fungal dissemination was detected during follow-up. However, the patient subsequently developed bacterial septic shock and died, despite appropriate management, without evidence of secondary invasive aspergillosis.

Informed consent: it could not be obtained as the patient was deceased and no next of kin could be contacted. Patient anonymity has been strictly preserved in accordance with the Declaration of Helsinki.

Discussion     

Cutaneous invasive aspergillosis (CIA) is classified into primary and secondary forms. Primary cutaneous aspergillosis (PCA) results from direct inoculation of the fungus into the skin generally associated with a lesion or local injury, and the second from the blood spreading of hyphae where the lung is usually the portal of entry, from which the pathogen may disseminate to almost any organ, often the brain and skin [1,4]. Primary cutaneous aspergillosis (PCA) is rare; few case reports and series have been published [1]. Cases have been described in neonates, in HIV/AIDS patients, cancer, especially hematological diseases, solid organ transplantation, etc. [1,3]. Primary cutaneous aspergillosis (PCA) may manifest with a nodule, pustule, papule, erythematous plaque, which may progress to central necrosis, or hemorrhagic bullae [5,6]. The microorganisms most often involved are Aspergillus flavus and Aspergillus fumigatus [1,7].

Several conditions can be confused with a CIA, such as pyoderma gangrenosum, ecthyma gangrenosum, malignant or inflammatory dermatoses [8]. Diagnosis relies on histopathological identification of septate hyphae with acute-angle branching and confirmation by fungal culture [1]. Although serum galactomannan may support the diagnosis of invasive aspergillosis, it does not reliably distinguish between primary and secondary cutaneous forms [7]. Cranial computed tomography scan, fundus examination of the eyes, whole body computed tomography scan, and lumbar puncture are important to rule out an secondary cutaneous aspergillosis (SCA) [1]. Combined surgical debridement and systemic antifungal therapy-particularly voriconazole, which is recommended as first-line therapy-are associated with improved outcomes [7,9]. Prognosis depends largely on immune status, degree of neutropenia, and early initiation of antifungal therapy [1]. In our case, despite appropriate antifungal treatment and local improvement, the patient died after developing septic shock following a bacterial infection with a multidrug-resistant organism.

Conclusion     

Primary cutaneous aspergillosis should be suspected in immunocompromised patients presenting with necrotic skin lesions unresponsive to antibacterial therapy. Early biopsy and mycological investigation are crucial to establish the diagnosis and initiate prompt antifungal treatment, which may improve prognosis.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All the authors have read and approved the final version of this manuscript.

Figures     

Figure 1: erythematous-violaceous skin lesion with central necrosis

Figure 2: macroscopic appearance of Aspergillus flavus culture on Sabouraud agar

Figure 3: A) histopathological examination showing necrotic tissue with fungal elements (H&E, x100); B) grocott staining showing septate hyphae with acute-angle branching (x100)

Figure 4: skin lesion after surgical excision

References