Revised

[version 2; peer review: 2 approved, 1 approved with reservations]

Yasmine KALBOUSSI

https://orcid.org/0009-0004-3616-2164

https://orcid.org/0000-0002-6152-0988

https://orcid.org/0000-0002-4613-6689

Yasmine KALBOUSSI

https://orcid.org/0009-0004-3616-2164

https://orcid.org/0000-0002-6152-0988

https://orcid.org/0000-0002-4613-6689

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Invasive aspergillosis is a severe infection that usually affects immunocompromised patients. Primary cutaneous involvement is a rare presentation and presents a challenge for early diagnosis. We report a case of primary cutaneous aspergillosis (PCA) in an immunocompromised patient with no evident prior skin trauma and with pulmonary dissemination.

We report the case of primary cutaneous aspergillosis involving the left ankle in a 5-year-old girl with no history of preceding trauma. The patient was undergoing chemotherapy for lymphoblastic leukemia. Aspergillus hyphae were identified on skin biopsy. Cultures grew Aspergillus flavus. The diagnosis of cutaneous aspergillosis enabled the diagnosis of probable pulmonary aspergillosis, although there was no mycopathological proof of lung infection. The patient was treated with initial Amphotericin B followed by Voriconazole with complete skin and respiratory response.

This case underscores the critical need to consider cutaneous aspergillosis in immunocompromised patients with necrotic skin lesions— even in the absence of obvious trauma—as prompt diagnosis and treatment are vital to prevent dissemination and and improve outcomes.

Invasive aspergillosis is a severe and potentially fatal infection usually affecting immunocompromised patients.^1,2 Pulmonary involvement is the predominant presentation, whereas cutaneous localization is much less frequent. This can develop as a primary infection, usually arising from direct inoculation of the skin³ or occur as part of a disseminated infection from the lung.¹ The true incidence of primary cutaneous aspergillosis (PCA) among immunocompromised patients is not well established but seems to be rising, possibly as a result of better recognition and the increasing number of immunocompromised individuals.^4,5 The major limitation in the management of these infections is the challenge of early diagnosis. We report a rare case of primary cutaneous aspergillosis (PCA) caused by Aspergillus flavus in a neutropenic and immunocompromised 5 year- old patient with no evident prior skin trauma. PCA is typically associated with breaches in skin integrity caused by catheters, dressings, or trauma, making the present case particularly unusual.

A 5-year-old girl was admitted to the Haematology department of Farhat-Hached hospital (Sousse, Tunisia) in September 2024 for acute lymphoblastic leukemia. The patient was treated according to EORTC protocole (Very High Risk aka VHR group) and received Chemotherapy VANDA consisting of : anthracyclines, L-asparginase, cyclophosphamide, methotrexate and corticosteroids (12mg of dexamethasone per day during 5 days). She had a cytological remission: 3% Blastic cells but a positive minimal residual disease (MRD) on the Last Bone Marrow assessement. In April 2025, she was admitted to receive consolidation chemotherapy. Seven days after the last dose, she developed high-grade fever (40 °C), concomitantly with the appearance of a small 5-mm black spot on her left ankle ( Figure 1), with no evidence of intravenous catheterization, local trauma, dressing, or other identifiable predisposing skin condition at the lesion site. The patient was neutropenic, with an absolute neutrophil count <500/mm³ for 5 days. Biological investigations demonstrated elevated inflammatory markers, including C-reactive protein (CRP), and bacterial and viral microbiological workup was negative. She was started on broad-spectrum antibiotics made of Piperacillin-Tazobactam and Vancomycin. Three days later, the patient still febrile and the skin lesion grew larger about 1.5 cm, becoming swollen with a crusted center and red surrounding skin. Antibiotics were switched to Imipenem and Ciprofloxacin with no improvement.

When a mild cough appeared seven after the onset of the cutaneous lesion, a full-body CT scan was done. It showed nodules and lung infiltrates with a halo sign highly suggestive of angio-invasive pulmonary aspergillosis. Respiratory sampling was not performed due to the patient’s thrombocytopenia and clinical fragility and Intravenous amphotericin was started immediately. Within 12 hours, she became afebrile for the first time. The skin lesion on her ankle evolved: it became itchy, developed a necrotic center with a purplish halo, and later the center dried out, with a hemorrhagic edge and ulceration. Eventually, the necrotic center detached from the lesion. This necrotic tissue was sent to the mycology laboratory for analysis.

Microscopic examination revealed large, septate, and irregular hyphae with acute-angle branching, suggestive of Aspergillus ( Figures 2). The specimen was cultured on Sabouraud dextrose agar supplemented with chloramphenicol (SC) and incubated at 30 °C. Fungal growth, 4 days after incubation, was consistent with Aspergillus. Identification using the Vitek MS PRIME (bioMérieux, France), yielded Aspergillus flavus. Antifungal susceptibility testing was carried out using the MIC Test Strip method (Liofilchem, Roseto degli Abruzzi, Italy). The minimum inhibitory concentrations (MICs) were as follows: 0.75 mg/L for Amphotericin B and 0,38 mg/L for Voriconazole. No respiratory specimens were submitted for mycological examination. Concurrently, the serum galactomannan index was measured using the Platelia Aspergillus enzyme immunoassay (Bio-Rad, France), yielding a positive result with an index value of 0.57, using the manufacturer-recommended positivity cut-off of 0.5.

Diagnosis of PCA with probable pulmonary dissemination was confirmed. Based on these findings, antifungal therapy was switched to Voriconazole, leading to complete resolution of the cutaneous lesions. The patient was subsequently discharged with a favorable outcome. With regular follow-up and local wound care, she achieved full recovery, and no relapse was observed at 6-month follow-up.

We report a rare case of primary cutaneous aspergillosis (PCA) due to Aspergillus flavus in a neutropenic patient with acute lymphoblastic leukemia, which subsequently progressed to invasive pulmonary aspergillosis. This case demonstrates the rapid progression of an initially inconspicuous cutaneous lesion to a severe necrotizing infection. It underscores the importance of careful clinical evaluation, as seemingly minor skin findings may represent an entry point for invasive fungal disease. Clinicians should maintain a high index of suspicion for primary cutaneous aspergillosis in neutropenic patients. Therefore, even a localized skin lesion requires aggressive systemic antifungal therapy to prevent dissemination.

Pediatric patients undergoing chemotherapy for hematological malignancies as illustrated by this 5-year-old girl, represent a high-risk cohort for invasive fungal infections.^1,2 The population-based incidence of invasive aspergillosis (IA) in children remains unknown and is likely to vary between healthcare settings and countries. However, data from the Kids’ Inpatient Database, a large representative dataset of hospitalizations in the United States, reported an annual incidence of 437 cases per 100,000 (0.4%) hospitalized immunocompromised children in 2000 (new reference). The most associated disorders in children are leukemias and lymphomas.³ However, some cases have been reported with immunocompetent patients.⁴ Intensive regimens, including anthracyclines and cyclophosphamide, induce profound and prolonged neutropenia, which is the major risk factor for invasive aspergillosis.⁵ Corticosteroids, a key component of leukemia protocols, further impair immune defenses by suppressing macrophage and neutrophil function, crippling the host’s ability to contain fungal invasion. Consequently, this immunocompromised state, defined by cytotoxic and steroid-induced deficits, creates a perfect environment for invasive fungal diseases.

Cutaneous aspergillosis can occur either as a primary infection or as a secondary manifestation.^6,7 Primary cutaneous aspergillosis (PCA) typically results from the direct inoculation of spores into the skin via breaches in barrier integrity, such as at catheter insertion sites, trauma wounds, or beneath occlusive dressings. In contrast, secondary cutaneous involvement occurs almost exclusively through hematogenous dissemination^7,8 from a deep-seated focus, most commonly the lung. This form is associated with the angioinvasive behavior of Aspergillus species. Determining whether the infection is primary or secondary to a primary site, such as the lungs, is crucial for guiding treatment.⁹ In our case, the initial isolated cutaneous lesion, which appeared concomitantly with the onset of fever, and the absence of radiological lung abnormalities at presentation, strongly supports the diagnosis of primary cutaneous aspergillosis with subsequent pulmonary dissemination. However, we acknowledge the limitation that a secondary cutaneous involvement in the context of systemic disease cannot be completely excluded. This cutaneous aspergillosis occurred in the absence of any clinically apparent skin injury, which, to our knowledge, appears to be exceptional. However, a minor or unnoticed breach in the skin barrier cannot be excluded. This case highlights that primary cutaneous aspergillosis should be considered even in the absence of evident skin trauma.

PCA can have different presentations: erythematous macules and papules with pain and itching, necrotizing skin lesions, hemorragic bullas, ulcerations with central necrosis or violaceous nodules.¹⁰ The variety of presentations and the non-typical form of lesions lead to an underdiagnosis of PCA and emphasize on the importance of mycological examination in order to start antifungal treatment and avoid the dissemination.

The definitive diagnosis of cutaneous aspergillosis relies on examination and culture of a deep tissue biopsy, as superficial samples are often inadequate¹¹ direct examination typically reveals septate hyphae with acute-angle branching, suggestive of Aspergillus, though not pathognomonic, as similar hyaline molds like Fusarium must be excluded.⁸ While A. fumigatus predominates in invasive aspergillosis overall, accounting for approximately 53% of pediatric cases in the largest multicenter study,¹ A. flavus is notably prevalent in primary cutaneous infections (PCA), accounting for a significant proportion of cases.^6,12 Our case aligns with this epidemiological profile for PCA. Serological biomarkers, such as serum galactomannan (GM), provide valuable adjunctive evidence. In pediatric patients, GM assay offers good sensitivity and specificity, and a positive result in a high-risk clinical context strongly supports the diagnosis of invasive disease.⁸ In this case, the galactomannan antigenemia (index 0.57) was borderline and not sufficient on its own to confirm disseminated infection.

According to the EORTC/MSGERC criteria,¹³ our patient fulfilled the definition of proven invasive cutaneous aspergillosis, based on the demonstration of septate hyphae in direct examination from a deep skin biopsy and confirmatory culture yielding Aspergillus. However, imaging alone is insufficiently specific for diagnosing pulmonary aspergillosis, as current guidelines require microbiological evidence for a probable infection.

The antifungal susceptibility testingc onfirmed a fully susceptible profile, with a notably low Voriconazole MIC of 0.38 mg/L, strongly justifying its use as primary therapy according to EUCAST guidelines. The patient’s sequential antifungal regimen—initial Amphotericin B followed by Voriconazole—is a common clinical strategy for managing suspected invasive fungal infections.^14,15 Most patients treated with one or the other had full recovery.¹⁶ However, this approach requires careful consideration due to on going debates about potential antagonistic interactions between the two drug classes.¹⁷ Surgical debridementand oral Itraconazole are also therapeutic options with extended lesions.¹⁸

This clinical case highlights the importance of considering cutaneous aspergillosis in immunocompromised patients presenting with skin lesions that progress to necrosis, even in the absence of trauma history. Particular attention must be paid to such lesions, as prompt diagnosis and treatment are crucial to prevent dissemination and reduce infection-related mortality.

A written consent was provided and signed by the patient’s parent, including the authorization for publishing clinical details and/or clinical images.

Grant information

The author(s) declared that no grants were involved in supporting this work.

Copyright

© 2026 KALBOUSSI Y et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Version 2

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VERSION 2 PUBLISHED 30 Mar 2026

Comment

Alongside their report, reviewers assign a status to the article:

Approved

The paper is scientifically sound in its current form and only minor, if any, improvements are suggested

Approved with reservations

A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit.

Not approved

Fundamental flaws in the paper seriously undermine the findings and conclusions

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