On July 18, 2019, a 51-year-old female presented to the hematology clinic complaining of an approximately one-month history of fatigue and reported a fever lasting for 24 hours. On admission, physical examination revealed a distended spleen. Other systemic examinations were unremarkable. At presentation, her body temperature was 37.4 °C, her blood pressure was 115/71 mmHg, and her pulse was 80 bpm. Her blood work showed an elevated white blood count of 33.17 × 109/L, hemoglobin 68 g/L, and platelets 44 × 109/L, and the percentage of primitive cells was 95% in peripheral blood.
The timeline of diagnosis and targeted therapy is shown in Table 1. Fever was relieved by anti-biotherapy introduction. The common type of acute B-lymphocytic leukemia (B-ALL) with the IKZF1 mutation was diagnosed by bone marrow pathology. Considering her history of familial diabetes and percutaneous coronary intervention (PCI), the chemotherapy program was initiated with a low dose of vindesine sulfate and dexamethasone and oral prophylactic treatment with fluconazole simultaneously. One month later, bone marrow pathology was repeated and showed 12% blast cells. A high-intensity IVCP program was performed. After 5 days, broad spectrum antibiotics and voriconazole were started due to febrile neutropenia.
Table 1
Time
|
Clinical features
|
Biology results
|
Therapy strategies
|
D1
|
Fever
|
High level of CRP
|
Levofloxacin 0.6 g/d and cefoperazone/sulbactam 9 g/d IV
|
D3
|
Bone marrow pathology
|
B-ALL
|
Chemotherapy introduction (vindesine sulphate 4 mg per week and dexamethasone 10 mg/d IV); prophylactic therapy (fluconazole 0.1 g/d p.o.)
|
D33
|
Repeated bone marrow pathology
|
Not completely relieved
|
Chemotherapy switched to IVCP (idarubicin 10 mg/d1-3, vindesine sulphate 4 mg per week, CTX 1.2 g/d 1,15, and dexamethasone 10 mg/d IV)
|
D39
|
Neutropenia
|
|
Antifungal combined therapy (voriconazole 0.4 g/d p.o.)
|
D41
|
Persistence of fever
|
High level of CRP
|
Levofloxacin 0.6 g/d and cefoperazone/sulbactam 9 g/d IV
|
D49
|
Febrile neutropenia and cough
|
Rising of CRP rate; abnormal chest CT scan
|
Switched antibiotherapy therapy (meropenem 3 g/d and linezolid 1.2 g/d IV)
|
D51
|
|
Filamentous fungi detected in sputum
|
Switched antifungal therapy (AmB 0.4 mg/kg/d IV)
|
D57
|
Fever resolution
|
|
|
D62
|
Abdominal pain and fever
|
Blood pressure 85/33 mmHg; high level of CRP
|
Adjusted to tigecycline 0.1 g/d, combined L-AmB 0.5 mg/kg/d and voriconazole 0.4 g/d IV
|
D63
|
|
Abnormal abdominal CT scan, acute peritonitis
|
Emergency surgery
|
D64
|
|
Hypha detected in jejunum histopathology
|
Adding L-AmB dose to 1.0 mg/kg/d IV
|
D66
|
Fever resolution
|
|
|
D83
|
Repeated bone marrow pathology
|
Completely relieved
|
Adding L-AmB dose to 1.2 mg/kg/d IV
|
D100
|
Regression of lesions on imagery
|
|
Switched antifungal therapy (posaconazole 0.8 g/d p.o.)
|
D130
|
Complete remission
|
Negative sputum
|
|
D day, CRP C-reactive protein, IV intravenous, B-ALL acute B-lymphocytic leukemia, p.o. per os, CT computed tomographic, CTX cyclophosphamide, AmB amphotericin B, L-AmB liposomal amphotericin B |
On day 49, significant pulmonary symptoms, such as productive cough, occurred, along with a persistent fever. Computed tomography (CT) showed a massive high-density shadow in the right superior lobe (Fig. 1) and rising levels of C-reactive protein (CRP). Blood culture was sterile, and serologies for (1,3)-beta-D-glucan, galactomannan (GM), syphilis, acquired immunodeficiency syndrome and hepatitis A–E were negative. Polymerase chain reaction for cytomegalovirus and EB virus were negative. Anti-biotherapy was switched to meropenem and linezolid, but there was no obvious relief in symptoms. Microbiological tests were implemented with low respiratory tract specimens. Classically, microscopic evaluation with Gram (Fig. 2a) and calcofluor white (Fig. 2b) staining revealed filamentous hyphae; one type was uniformly thinner, septate, and branching at acute angles, and the other had a variable width, was nonseptate, and had branching filamentous hyphae and a ribbon-like appearance. Cultures of specimens on Sabouraud dextrose agar (SDA) showed the features as Mucorales. Colonies appeared cotton and white-gray, both on the surface and reverse side (Fig. 2c). Lactophenol cotton blue staining revealed irregularly branching sporangiophores terminating prominently, and sporangioles borne off the vesicles (Fig. 2d). Cunninghamella bertholletiae was identified by mycological characteristics and ITS-based sequencing (accession no. MT470208). DNA sequences were analyzed using NCBI BLAST (https://blast.ncbi.nlm.nih.gov/Blast.cgi). Another pathogen isolated from specimens was Aspergillus flavus.
Based on the characteristics of the filamentous hyphae, we switched the antifungal therapy to intravenous amphotericin B (AmB) with an initial dose of 0.5 mg/kg/d. Persistent fever was resolved, but unexpectedly, acute abdominal pain with high fever and a “sudden drop” in blood pressure appeared on day 62. Anti-biotherapy was adjusted to tigecycline combined with liposomal amphotericin B (L-AmB). At midnight, the abdominal pain worsened, and acute diffuse peritonitis was considered. CT showed some free abdominal gas under the diaphragm, and peritoneal fluid was detected (Fig. 3). Emergency surgical management, including partial resection of the jejunum and ileum, was performed. There were 9 perforations in the jejunum 190 cm-210 cm from the curved ligament, with an aperture of approximately 1–2 cm, and a perforated ileum was detected approximately 25 cm from the ileocecal part.
Histopathology of specimens from the jejunum and ileum showed broad septate fungal hyphae (Fig. 4). Cultures of specimens from the jejunum also showed features such as Mucorales, and Cunninghamella bertholletiae was identified according to the same protocols mentioned above. Antifungal susceptibility tests according to Clinical and Laboratory Standards Institute (CLSI) M38-A2 [16] were implemented. The susceptibility profiles of C. bertholletiae showed fluconazole 256 µg/ml, itraconazole 0.5 µg/ml, posaconazole 0.5 µg/ml, voriconazole 8 µg/ml, AmB 2 µg/ml, flucytosine 64 µg/ml and echinocandins all 8 µg/ml. The susceptibility profiles of A. flavus showed itraconazole 1 µg/ml, posaconazole 0.5 µg/ml, voriconazole 0.25 µg/ml, and AmB 2 µg/ml.
L-AmB was added to 1.0 mg/kg/d for one week, followed by fever resolution. She was covered pre- and postsurgery with L-AmB for 8 weeks. Considering the relief of symptoms and regression of lesions on imagery, our strategy switched to oral posaconazole 0.8 g/d. The patient was discharged in good condition for continuous therapy with antifungal agents and for follow-up at the outpatient clinic.