The patient, a 30-year-old female, had a long-standing history of UC since her initial diagnosis in January 2020. Even though she had been started early on a regimen of azathioprine and prednisolone, she has remained steroid-dependent, with repeated relapses during attempts to taper her dosage. During traveling to a Middle Eastern country, she experienced escalated symptoms, including mucous diarrhea up to sixteen times a day, fever, and occasional vomiting. She self-medicated with excessive amounts of metamizole (at least a 5 ml and a 10 ml bottle where used, adding up to 35 g of metamizole), leading to sporadic episodes of weakness and dizziness.

Upon her return to Germany, the patient was first admitted with dyspnea and fever to a regional hospital where she was initiated on empirical piperacillin/tazobactam, suspecting sepsis. Four days later, she was transferred to our facility with a provisional diagnosis of hemophagocytic lymphohistiocytosis (HLH). This diagnosis was confirmed on her meeting five of the eight diagnostic criteria: fever, splenomegaly, cytopenia affecting both platelets and neutrophils, elevated ferritin levels (peak 27.693 µg/l), and increased levels of soluble IL-2 receptor (peak > 750,000 U/ml). Treatment was started with 3 × 8 mg of dexamethasone. This initial diagnosis was later confirmed by a bone marrow examination.

At our facility, the patient presented with fever and tachycardia, accompanied by abdominal swelling and diminished bowel sounds. By initial microbiological work-up of bronchoalveolar lavage Aspergillus flavus was identified by culture and consecutive mass spectrometry and cytomegalovirus (CMV) of 6.7 × 105 copies/ml by PCR. A. flavus was later tested pan-sensitive using culture methods. Blood tests displayed a persistent cytopenia, a CRP level of 110 mg/dl, and a procalcitonin level of 2.8 ng/ml. A rectoscopy exposed severe UC (Mayo 3). Sequential CT scans of the lungs highlighted severe fungal pneumonia as illustrated in Fig. 1. Additional radiological evaluations of abdominal CT scans revealed pancolitis, pronounced mesenteric lymphadenopathy, hepatosplenomegaly, and significant edema of the bowel wall. The patient’s condition declined, culminating in acute renal failure and the necessity for dialysis. In management of her clinical complications, the patient’s Prednisolone dosage was methodically reduced from 70 mg at admission to 2.5 mg per day at 6 weeks after admission, as depicted in Fig. 1. This modification was intended to optimize the patient’s immune response to tackle the Aspergillus infection.

A timeline during the hospital stay displays Galactomannan (Aspergillus-Ag) levels indicating the extent of the fungal infection, and neutrophil granulocytes count (Neutr. Gran. in Gpt/l = gigaparticle per liter) reflecting immune recovery. Alongside neutrophil levels, select lung CT-Scan images highlight fungal progression and pneumothorax. The chart also illustrates the administration of glucocorticoids, depicted in terms of cortisol-equivalency or anti-inflammatory potency, with 400 being the therapeutic threshold for IRIS, and the administration of intra venous Immunoglobulin G and three antimycotic treatments targeting Aspergillus flavus. For the voriconazole dosage regimen, it is given in milligrams and administered twice daily, with therapeutic drug monitoring for serum levels. Isavuconazole is administered at 200 mg/day, and Amphotericin at 250 mg/day, both at consistent dosages

Six weeks after initial admission, multiple necrotic lesions manifested across various parts of her body (Fig. 2A, B). Histopathological evaluation of the skin lesions revealed pronounced necrosis of the fibrolipomatous tissue, with evidence of invasive mycosis and intermittent angioinvasive dissemination patterns (Fig. 2B, C). We interpret the presence of fungal elements in this context as probably non-viable pathogens remaining post effective antifungal treatment caused by the patient’s delayed immune clearance of fungal debris. However, it is important to consider, as highlighted by Donnelly et al. [1], that such an interpretation must be made cautiously, given the known limitations in the sensitivity of culture methods for detecting live fungal pathogens.

A and B Highlight granulomatous skin necroses. Pathological assessment of these areas using Grocott Gomori staining, revealed the mycelial network structures, depicted in microscopic views (C and D)

Along with these findings, the patient’s UC symptoms progressively intensified, making a subtotal colectomy with ileostomy essential by August’s end. This surgery was vital to address the continual bleeding, which was inducing recurrent anemia.

Two months after admission, despite the aggressive antifungal and antibiotic treatments in accordance with medical guidelines the patient’s infectious symptoms worsened, in contrast to the declining Aspergillus-antigen levels. As the patient’s bone marrow recovered, blood tests revealed an increase in neutrophil granulocytes count, as depicted in Fig. 1. This surge in immune response was concurrent with a decline in the patient’s overall health and the onset of a spontaneous pneumothorax, which became more severe in the subsequent days, as displayed in Fig. 1. This clinical pattern, combined with observations suggesting the possibility of non-viable Aspergillus persisting in the affected sites, and the correlation with granulocyte recovery, fostered the initial suspicion of tissue damage attributable to an IRIS. In response, an increased dose of 150 mg/day of prednisolone was given and daily infusions of immunoglobulins was initiated, in line with current literature [2].

During the further course, the granulocyte count decreased again and the pneumothorax resolved. However, the detection of an abdominal abscess mandated further surgical intervention and the microbiological work-up of abscess content revealed Saccharomyces cerevisiae. Complicating matters further, liver dysfunction also emerged. The patient tragically suffered an extensive bronchial hemorrhage and multi-organ system failure, which most likely led to the deterioration resulting in the patient’s passing on September 30th, 3 months after initial admission. The relatives declined an autopsy.