A 17-year-old female with the second relapse of B-ALL received chimeric antigen T-cell (CART) salvage therapy, followed by co-transplantation of haploidentical stem cells and unrelated cord blood in September 2021. The patient had a previous disseminated pulmonary tuberculosis infection during the first relapse in July 2020. However, she recovered well after treatment with anti-tuberculosis drugs, including isoniazid (10 mg/kg/day), rifampicin (10 mg/kg/day), and levofloxacin (10 mg/kg/day) from July 2020 to April 2021, and continued to receive oral isoniazid prophylaxis until 3 days prior to HSCT. Chest computed tomography (CT) revealed no residual tuberculosis lesions and interferon-gamma (IFN-gamma) release assays was negative prior to transplantation. Furthermore, there was no evidence of fungal infection during chemotherapy or prior to HSCT.
The patient received a myeloablative conditioning regimen consisting of cyclophosphamide, busulfan, fludarabine, and thiotepa without total body irradiation. The post-transplant immunosuppressants included of post-transplant cyclophosphamide, cyclosporine, and mycophenolate mofetil. In addition, oral posaconazole (200 mg every 8h) was commenced 3 days after HSCT as an antifungal prophylaxis. Additionally, neutrophils and platelets were engrafted on 15 and 24 days after transplantation, respectively. Engraftment syndrome with fever, skin rashes, and elevated bilirubin levels was observed during cell engraftment from day 14 after transplantation. However, these symptoms resolved after intravenous administration of methylprednisolone (1 mg/kg/day for 4 days from day 15 to day 18, after which the dose was tapered and discontinued on 27 days after HSCT). No other severe complications were noted.
The patient began to cough slightly from 23 days after HSCT. Since this patient had a history of tuberculosis infection, rifapentine (600 mg per week) was administered in combination with isoniazid (10 mg/kg/day) for tuberculosis prophylaxis. However, the patient showed no signs of respiratory distress, including dyspnea, tachypnea, and hypoxemia. The cough lasted five days, and the patient developed a throbbing, dull pain in the back. A chest CT was performed, and a large nodular lesion (32.02 mm x 24.77 mm x 42.73 mm) with a faint surrounding vitreous subpleural of the right upper lobe was observed (Figure 1A and B). Therefore the patient was suspected of having tuberculosis or an IFI, and a bronchoscopy was performed. Caspofungin (loading dose at 70 mg/m2 for 1 day and then 50 mg/m2/day) was commenced on day 27 after HSCT, and posaconazole was switched to intravenous voriconazole (loading dose at 9mg/kg, every 12h, for 1 day and then 8mg/kg, every 12h) because the patient developed a fever 4 days later. The bronchoalveolar (BAL) fluid was positive for cytomegalovirus (CMV), human herpes virus 6 (HHV-6), and Actinomyces odontolyticus using next-generation sequencing. However, in contrast, using the PCR-based analysis, the BAL fluid was negative for fungi and tuberculosis. In addition, bacterial and fungal cultures of the BAL fluid were negative.
The antibiotics, imipenem (15mg/kg, every 6h) and high-dose penicillin (100,000 U/kg, every 6 h) were administered to treat Actinomyces infections for 2 months. Ganciclovir (5 mg/kg, every 12h) was also commenced for antiviral treatment. Despite the above treatment, the patient began to have hemoptysis, and a reassessment of the chest CT showed that the lung lesion was unresolved. Therefore, a wedge resection of the lung lesion was performed because the lesion was still localized. The next-generation sequencing analysis of the lung tissue revealed C. cinerea infection (NCBI accession PRJNA938261). This was later confirmed when septate hyphae were observed by both Wright-Giemsa and hexamine-silver staining of lung sections, indicative of C. cinerea infection (Figure 2). Therefore, antifungal treatment was switched to amphotericin B (starting from 0.1 mg/kg/day then gradually increased to 0.7 mg/kg/day) for 2 weeks, followed by oral voriconazole as follow-up therapy. Chest CT scans showed no new lung lesions 5 months after the wedge resection surgery (Figure 1C).
Chest computed tomography images of the patient before and after wedge resection of the lung lesions. coronal. CT scan images revealed a large nodular lesion (32.02 mm x 24.77 mm x 42.73 mm) with a faint surrounding vitreous subpleural located in the right upper lobe.