A 64-year-old woman with a history of refractory acute myeloid leukemia (AML), hypertension, and left ear deafness was admitted for allogeneic bone marrow transplant and subsequently died of intracerebral hemorrhage secondary to mucormycosis 13 days after receiving her stem cells.
This patient was originally diagnosed with AML 8 months prior to HSCT because of fatigue and pancytopenia on lab work. Peripheral smear at the time showed 43% blasts, and a subsequent bone marrow biopsy showed 60-70% myeloblasts consistent with a diagnosis of AML. Genetic studies done of the bone marrow showed deletions of 16q and 5q, and FLT3 was negative. She was started on induction treatment with 7 + 3 cytarabine/idarubicin which was complicated by neutropenic fever and AML retinopathy.
Neutropenic fever occurred on day 2 of induction treatment admission for which she was given piperacillin/tazobactam until she became afebrile on day 13 of admission. Fevers recurred on day 15 of admission for which cefepime and metronidazole were started. CT scan of her chest was done on day 16, showing a new right lower lobe opacity concerning for pneumonia along with 9 nodules in both the lungs, all less than 6 mm. Treatment dose voriconazole was added for fungal coverage. On day 19, she was broadened to meropenem and anidulafungin due to recurrent fevers. A repeat CT scan of her chest including her sinuses was done showing resolution of her previous consolidation with no evidence of significant sinus disease and no change in her lung nodules. She became afebrile on day 4 on meropenem and anidulafungin but was continued on these antibiotics until day 47 of admission awaiting her absolute neutrophil count (ANC) to reach 500. She was then switched to oral ciprofloxacin, amoxicillin/clavulanic acid, and voriconazole. She completed a total of 7 days of oral antibiotics and then was put on prophylactic voriconazole and acyclovir until HSCT.
After induction, she suffered from prolonged neutropenia and never reached an ANC above 1,130 in the time between the first induction and her death (about 7 months in total). Her treatment after 7 + 3 consisted of cladribine, mitoxantrone, decitabine, and venetoclax with venetoclax finally achieving remission. At the time of transplant, her disease status was in complete remission with incomplete hematologic recovery (CRi) due to sustained cytopenia. On the last office visit prior to being admitted for HSCT, she was noted to have no symptoms and felt overall well.
In terms of further imaging after initial diagnosis, she had a repeat CT scan 7 days prior to HSCT as part of her pretransplant workup to monitor the nodules previously seen. This scan showed stable nodules, all of which did not change in size or appearance. No consolidation or new findings were seen.
The patient was admitted and started on trimethoprim-sulfamethoxazole, fluconazole (switched to voriconazole one day prior to HSCT), and valacyclovir prophylaxis. She then started receiving a myeloablative conditioning (MAC) regimen with total body irradiation (TBI) (total dose 12 Gray (Gy) divided into 6 fractions). Two days following TBI completion, she received her donor leukocyte infusion (DLI), followed by cyclophosphamide and mesna 3 days after DLI. She then received her CD34+ stem cells 6 days following DLI infusion. She had her first recorded fever of 101.0 on day (-5) of her transplant, one day following DLI infusion. From this day until the date of death, she was noted to have daily fevers, as high as 104.0. Blood cultures were drawn daily, all of which showed no growth. Sputum cultures were not obtained due to lack of productive cough, and urine cultures showed no growth. She was initially started on cefepime for neutropenic fever which was eventually broadened to meropenem then to piperacillin-tazobactam and vancomycin. She was also switched from prophylactic voriconazole to treatment dose voriconazole 2 days prior to death. Switching to amphotericin B or brain imaging was not considered upon first fevers due to lack of consideration for mucormycosis.
Twelve days after receiving her stem cells, she started complaining of severe right shoulder pain; a chest X-ray was obtained which showed a right upper lobe consolidation. CT scan of the chest was done which showed ground glass consolidation with interlobular septal thickening and mucoid impaction. The day after the shoulder pain started, the patient became increasingly fatigue and more lethargic but was answering questions appropriately. Later that afternoon, she was noted by the nursing staff to be completely unresponsive. The patient was emergently intubated and taken for a noncontrast CT scan of the head which showed extensive cerebellar edema with peripheral hemorrhage in the cerebellar folia and petrosal surface of the cerebellum with upward herniation. There was also marked compression of the brainstem and effacement of the fourth ventricle with lucency of the brainstem compatible with ischemia (Figure 1) and associated upward herniation of the cerebellum (Figure 2). Additionally, there was a 7 mm focus of high density in the right frontal lobe and 4 mm focus of hyperdensity in the left frontoparietal junction. About 6 hours after this event, the patient was made comfort care and died shortly thereafter.
On autopsy of the brain, it was noted the patient had duret hemorrhage in the pons, cerebellar intraparenchymal hemorrhages and associated subarachnoid hemorrhage with cerebellar edema, right frontal lobe hemorrhagic infarct with angioinvasive fungi, and a small left thalamic hemorrhage. On fungal stain of the right frontal lobe, it was noted she had Mucor spp. as can be seen in Figure 3. No polymerase chain reaction (PCR) or fluorescent in situ hybridization (FISH) testing was done due to identifiable appearance on microscopic examination. No fungi were found in the brainstem as can be seen in the cross-sectional imaging of the pons in Figure 4. Acid-fast bacilli (AFB) stains were negative.
Her gross exam of her right lung showed a firm dark-red mass on the right upper lung lobe, measuring 9.5 x 8.0 x 6.8 cm, and the cut surfaces of this mass reveals a well circumscribed, homogenous, round, dark-red fleshy mass resembling a hemorrhagic infarction. On microscopic examination, extensive hemorrhagic areas, pulmonary edema, and small pulmonary infarct areas around some vessels occluded with thrombi were found. Aerobic and anaerobic cultures showed very light growth of vancomycin-resistant Enterococcus and very light growth of Serratia marcescens. Fungal cultures showed light growth of Mucor spp. AFB stains were negative. Fungal staining showed large, nonseptate hyphae with 90 degree angle branching and nonparallel walls consistent with Mucor spp. Again, no PCR or FISH testing was done due to identifiable appearance on microscopic examination. Examination of the sinuses showed no significant disease.
The sequence of events most likely leading to her death was concluded to be frontal lobe fungal invasion causing edema and hemorrhage leading to cerebellar tonsillar herniation, brainstem hemorrhage, and ultimately death.