Severe Candida glabrata pancolitis and fatal Aspergillus fumigatus pulmonary infection in the setting of bone marrow aplasia after CD19-directed CAR T-cell therapy – a case report

While the patient’s initial clinical course was fraught with complications, CT staging performed at day 36 demonstrated a partial response to CAR T-cell therapy according to Lugano and Lyric criteria (Fig. 2a-g). This was particularly evident for the pleural manifestations of the underlying DLBCL, which was accompanied by an interval decrease in pleural effusions and subjective dyspnea (Fig. 2a-b). Multiple nodal sites including paraaortic (Fig. 2c-d) and parailiac lymph nodes (Fig. 2e-f) exhibited significant regression of tumor size (Fig. 2g). Moreover, the patient displayed splenic hypodensities consistent with either tumor tissue necrosis or infection-associated inflammatory changes (inset, Fig. 2f). These CT-morphologic findings were accompanied by a decrease of LDH levels (Fig. 2h).

The patient presented with significant myelotoxicity and sustained transfusion dependency after CAR T-cell administration (Fig. 1c). The overall duration of profound neutropenia – defined as an ANC < 100/μl [10] – was 52 days. Because of the severity of ICANS, the clinicians chose to hold G-CSF during this time period due to concerns for risk of worsening toxicity [11].

While receiving broad anti-infectives (acyclovir, TMP/SMZ, posaconazole, meropenem), the patient developed breakthrough septic shock on day 24. He exhibited fever (39.5 °C), hypotension (70/30 mmHg), tachycardia (160/min), as well as lactic acidosis (lactate: 10.7 mmol/l). The patient was non-conversant, non-oriented, and was not able to localize symptoms. However, he had described epigastric tenderness and subtle changes in stool consistency and frequency on the previous day. As a result, abdominal CT imaging was obtained, which displayed severe pancolitis, as evidenced by pronounced mucosal thickening with edematous changes ranging from the ascending colon to the rectum (Fig. 3a-b). Labs were notable for an acute spike of serum inflammatory parameters (Il-6 > 500.000 pg/ml, CRP 5.7 mg/dl, Procalcitonin 11.2 ng/ml, Fig. 1d). Following ICU transfer, high-dose vasopressor support with norepinephrine was initiated together with volume resuscitation to maintain organ perfusion. Due to progressive loss of consciousness the patient was intubated and mechanically ventilated. To control the proinflammatory state, extracorporeal cytokine absorption (Cytosorb®) was performed, which resulted in a decrease of soluble inflammatory markers in the subsequent days. Arterial blood cultures were positive for vancomycin-resistant enterococci (VRE), and the antibiotic treatment was escalated to include linezolid along with meropenem (Fig. 1b). The ICU team transitioned antifungal prophylaxis from posaconazole to an echinocandine (micafungin 50 mg IV) due to ECG changes and concerns for drug interactions on day 24. Though he remained in critical condition, in the coming weeks his clinical condition stabilized and both the catecholamine rate and volume support could be reduced. To determine the origin of sustained myelosuppression, a bone marrow biopsy was obtained, which depicted a hypocellular marrow and severe aplasia affecting all hematopoietic lineages (Fig. 1e). On days 41 and 49, surveillance blood cultures were positive for Candida glabrata, a commensal fungal organism of human mucosal tissues [12] harboring an intrinsic azole resistance [13]. Susceptibility testing confirmed the azole-resistance of C. glabrata isolates. The antimycotic therapy was escalated from micafungin to liposomal amphotericin B. C. glabrata likely disseminated to the bloodstream secondary to the described gastrointestinal toxicity and was previously discovered on rectal swab (Fig. 1b) and fecal culture (day − 51).

Due to sustained neutropenia, BM aplasia and the availability of a suitable apheresis product, the CAR T-cell Taskforce proceeded with a stem cell boost of previously collected autologous CD34+ cells (3,1 × 10⁶ cells) on day 46. The combination of a sudden rise in serum inflammatory markers and a strongly positive serum galactomannan (GM) assay on day 49 prompted diagnostic bronchoscopy, which revealed a diffuse infiltrate of alveolar and peri-bronchial tissue by Aspergillus fumigatus, consistent with fulminant invasive fungal pneumonia. Over the next week, the patient became increasingly hemodynamically unstable with poor peripheral oxygenation. Repeat bronchoscopy with bronchial lavage was positive for A. fumigatus and C. glabrata. After 50 days of G-CSF refractory aplasia, the autologous stem cells slowly engrafted leading to neutrophil recovery. However, this likely exacerbated the local inflammatory reaction in the lung, contributing to rapid deterioration of his respiratory status. Despite extensive supportive measures, the patient died on day 58 after CAR T-cell transfusion. Cause of death was confirmed by autopsy as invasive fungal pneumonia with multi-organ septic spread. Post-mortem examination revealed Candida spores in intestinal, colonic and rectal tissue. Of note, histopathologic BM analysis revealed signs of burgeoning hematopoietic regeneration (Fig. 1e).