Unmasking Cryptococcal Meningitis Immune Reconstitution Inflammatory Syndrome due to Granulocyte Colony-Stimulating Factor Use in a Patient with a Poorly Differentiated Germ Cell Neoplasm
A 56-year-old male visited his primary care physician to be evaluated for abdominal pain, and the subsequent workup revealed a large retroperitoneal mass measuring 21.8 × 17.5 × 11 cm. A diagnostic workup revealed a poorly differentiated germ cell neoplasm, most likely an embryonal carcinoma. Two months after his initial presentation he began chemotherapy (bleomycin, etoposide and cisplatin). By day 10 of cycle 3 (approximately 4 months after initial presentation), imaging showed a drastic decrease in tumor size.\nSix days after his most recent dose of chemotherapy, he presented to the emergency department noting intermittent fatigue, nausea, vomiting and diarrhea since his last chemotherapy treatment. He also noted headache and fever over the past day. In the emergency department (hospital day 0), he was found to be neutropenic with a total white blood cell (WBC) count of 0.6 × 109 cells/l and an absolute neutrophil count (ANC) of 0.4 × 109 cells/l. He appeared to be in no acute distress but febrile with a temperature of 38.7°C. No obvious signs of an infectious source were noted, including examination of his port-a-cath. The patient was started on cefepime and admitted to the inpatient oncology service for treatment of neutropenic fever.\nThe admitting physician noted tachycardia, but the patient's blood pressure was within normal limits. The only possible localizing sign of infection was a questionable cellulitis of the right lower leg. As the patient had previously been on prophylactic levofloxacin and had frequently been to infusion clinics, vancomycin was added for methicillin-resistant Staphylococcus aureus coverage. The patient was also started on G-CSF (480 μg/day) for neutropenia. Over the subsequent 2 days, his fever and tachycardia continued, and on hospital day 3 the patient became lethargic and confused. A chest radiograph (which showed no sign of pneumonia), blood and urine cultures and a CT scan of the head without contrast showed no acute changes. Throughout this period his ANC remained <1.0 × 109 cells/l.\nBy hospital day 4, the patient was unable to respond to commands and was transferred to our institution for further care; his WBC count had risen to 1.8 × 109 cells/l (ANC not measured) and he remained febrile. His vancomycin was continued while cefepime was changed to ceftazidime out of concern for cefepime-induced encephalopathy []; G-CSF was continued. Shortly after arrival, the patient had 2 tonic clonic seizures, and lorazepam and fosphenytoin were given. He became more lethargic, with periods of apnea, and was transferred to the intensive care unit for endotracheal intubation. An MRI of the brain and MRA of the brain and neck with and without contrast showed an acute punctate infarct in the right hippocampus and no major vascular findings. Continuous EEG monitoring was started. His WBC count shortly after intubation was 11.4 × 109 cells/l with an ANC of 7.0 × 109 cells/l. Fig. shows ANC, WBC count, G-CSF dosing and the patient's symptoms over time.\nA lumbar puncture was performed on hospital day 5 and revealed 64 WBC/μl, 30% neutrophils, 39% lymphocytes, glucose 37 mg/dl and protein 99 mg/dl. No organisms were seen on Gram staining. No cerebrospinal fluid opening pressure was measured. A thorough cerebrospinal fluid workup for infection was sent for evaluation, and empiric acyclovir was started. Cerebrospinal fluid India ink stain was completed in the early evening of hospital day 5 and showed rare encapsulated yeast, and the cerebrospinal fluid cryptococcal antigen (Latex Agglutination, IMMY, Inc., Norman, Okla., USA) was positive at a dilution of 1:32.\nThe infectious disease service was informed of the result, amphotericin B lipid complex was started at a dose of 5 mg/kg, and flucytosine 100 mg/kg/day was also ordered but was not but available until hospital day 7. On hospital day 6, the WBC count rose to 28.0 × 109 cells/l and G-CSF, acyclovir, ceftazidime and vancomycin were stopped.\nThroughout hospital days 6 and 7, the patient was minimally responsive despite no sedation since intubation; however, he did withdraw from painful stimuli. No additional seizures occurred. On hospital day 8, the patient moved his lower extremities on command, and his neurological function rapidly improved. Repeat lumbar puncture was performed on hospital day 9 with an opening pressure of 16 cm H20. By hospital day 10, the patient's neurologic status had improved, and he was extubated. His culture showed Cryptococcus neoformans resistant to flucytosine, and so flucytosine was replaced with fluconazole 800 mg daily.\nAfter 14 days total of amphotericin-based combination therapy, the patient continued on fluconazole 800 mg daily consolidation monotherapy. Repeat lumbar puncture at the time of stopping amphotericin showed a decreased cryptococcal antigen titer of 1:4 and an opening pressure of 22 cm H20. On hospital day 21, the patient was discharged to a transitional care unit. Since hospital discharge, the patient has continued to do well in terms of his CM, although he has required hospitalization for pericarditis. He is being maintained on fluconazole 200 mg daily for secondary prophylaxis, and further chemotherapy has been postponed pending improvement of his other health issues.