Bone Marrow Transplantation (2003) 31, 69–72 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Case report Granulocyte transfusion as a treatment for enterococcal meningoencephalitis after allogeneic bone marrow transplantation from an unrelated donor Y Tsukada1, H Nagayama1, T Mori1, T Shimizu1, N Sato1, N Takayama1, A Ishida2, M Handa2, Y Ikeda1 and S Okamoto1 1Division of Hematology, Department of Medicine, Keio University School of Medicine, Tokyo, Japan; and 2Blood Center, Keio University School of Medicine, Tokyo, Japan Summary: serious problem during the pre-engraftment period follow- ing BMT.1–3 However, Enterococci rarely cause CNS Bacterial meningoencephalitis occurring in the pre-en- infection in granulocytopenic patients, and there are few graftment period after bone marrow transplantation anecdotal cases of meningoencephalitis due to Enterococcus (BMT) is a rare complication, and the feasibility of faecalis after BMT.4–6 Transfusion of normal granulocytes granulocyte transfusion (GTX) in such cases remains to be is a logical treatment for severe bacterial infections in elucidated. A 37-year-old man developed enterococcal neutropenic patients. However, granulocyte transfusion meningoencephalitis during a severely granulocytopenic (GTX)had a limited role in the treatment of such infections pre-engraftment period after BMT. Despite therapy with before the wide clinical use of granulocytes colony appropriate antibiotics, cultures of blood and cerebro- stimulating factor (G-CSF). A major reason for the lack spinal fluid (CSF) continued to grow Enterococcus of efficacy was that the dose of granulocytes collected and faecalis, and he developed rapid mental deterioration transfused was inadequate. The availability of G-CSF and seizure. Granulocytes were collected from his HLA- prompted several investigators to re-evaluate the efficacy mismatched, ABO-matched sibling with subcutaneous of GTX in the treatment of uncontrolled bacterial and injection of granulocyte colony-stimulating factor (G- fungal infection during granulocytopenia. Bielorai et al CSF) and oral dexamethazone. Transfusion of 4.4 Â 1010 reported a case of VRE septicemia in a neutropenic patient, granulocytes resulted in a 12-h post-transfusion granulo- which was successfully treated with GTX.3 The phase I/II cyte increment of 2.0 Â 109/l, and maintained peripheral trials of GTX mobilized by G-CSF for the treatment of blood granulocyte counts above 0.5 Â 109/l for 3 days. A infections complicated with hematological disorders also rapid increase of granulocytes in CSF was also observed, demonstrated its efficacy.7 These trials also demonstrated and cultures of blood and CSF became negative after the migratory activity of transfused granulocytes to the GTX. A transient worsening of seizure was observed as a tissue site; however, whether transfused granulocytes potential side effect of GTX. The patient subsequently migrate to the central nervous system (CNS)remains developed septic shock because of Pseudomonas aerugi- unknown. nosa and died. Further studies are warranted to evaluate In this report, we describe a case of enterococcal the clinical efficacy of GTXfor the treatment of meningoencephalitis before marrow engraftment, and uncontrolled infections in granulocytopenic stem cell discuss the feasibility and efficacy of GTX against CNS transplant recipients. infection. Bone MarrowTransplantation (2003) 31, 69–72. doi:10.1038/sj.bmt.1703780 Case report Keywords: enterococcus; meningoencephalitis; granulo- cyte transfusion; G-CSF; bone marrow transplantation A 37-year-old man was diagnosed with acute myeloblastic leukemia with tri-lineage dysplasia (tMDS-AML)in August 2000. Complete remission was achieved with Bacterial or fungal infections continue to be a major cause combination chemotherapy consisting of idarubicin (IDR) of morbidity and mortality during the post-transplant and cytosine arabinoside (CA). One additional course of period until engraftment. Recently, the incidence of the same chemotherapy was given and the patient was vancomycin-resistant Enterococcus (VRE)-related infec- followed as an outpatient without further chemotherapy. tion has been increasing, and its treatment has become a He was admitted to the Keio University Hospital in September 2001 to undergo allogeneic bone marrow Correspondence: Dr Nagayama, Division of Hematology, Department of Medicine, Keio University School of Medicine, 35, Shinanomachi, transplantation (BMT)from an HLA-matched unrelated Shinjyuku-ku, Tokyo 160-8582, Japan donor. Although the patient had remained in complete Received 15 April 2002; accepted 30 July 2002 remission, bone marrow examination 3 weeks before the GTX for meningoencephalitis after BMT Y Tsukada et al 70 transplant showed 21.6% blastic cells, indicating that he Table 1 Findings of cerebrospinal fluid before and after granulo- was in first relapse. A lumbar puncture on day À12 did not cyte transfusion show leukemic cells in the cerebrospinal fluid (CSF), and a Before GTX After GTX combination of methotrexate (MTX), CA, and hydrocorti- (Day +13) (Day +17) sone sodium succinate was given intrathecally for the Total cell count (mm3)27 966 prophylaxis of CNS leukemia. Culture of CSF was not Monocytes (mm3)25 139 performed. A pretransplantation evaluation that included Neutrophils (mm3)2 827 whole body computed tomography (CT), radioisotope Total protein (mg/dl)333 72 imaging, and ophthalmologic, oto-rhino-pharyngeal, den- LDH (IC/l)88 83 tal, and perianal examination failed to detect any infectious Chloride (mEq/l)114 114 Glucose (mg/dl)94 110 foci. Oral ciprofloxacin hydrochloride (CPFX)at a dose of Plasma glucose (mg/dl)145 284 600 mg/day and fluconazole (FCZ)at a dose of 200 mg/day Granulocyte counts (PB)100 2000 were started on day À14 as gut decontamination. The conditioning regimen consisted of total body irradiation (2 Gy twice daily for three consecutive days)followed by CA (3 g/m2 twice daily i.v. for four consecutive days). The WBC count was 2.6 Â 109/L on the day of starting the ml)to CPFX in vitro. Cardiac echography failed to detect conditioning (day À8), and became less than 0.5 Â 109/L on any vegetations in the heart. day À2. Transplantation of 1.8 Â 108/kg of bone marrow Despite therapy with appropriate antibiotics, the infec- mononuclear cells from an HLA-matched unrelated donor tion remained uncontrolled, and GTX was performed using was then performed, and intravenous G-CSF at a dose of an HLA-mismatched ABO-compatible elder brother as 5 mg/kg/day was started from day +1. Cyclosporine (CyA) donor. After providing his informed, written consent, the and short-term MTX were administered for GVHD donor received dexamethasone 8 mg orally and G-CSF prophylaxis. Acyclovir (ACV)was administered intrave- 10 mg/kg subcutaneously approximately 12 h before the nously from day À3 to day +14 of BMT as prophylaxis scheduled granulocyte collection. Granulocytes were col- against herpes viruses. Surveillance cultures before trans- lected as per standard leukapheresis, processing 8 l of plantation revealed the presence of methicillin-sensitive blood. No serious adverse events, apart from bone pain, Staphylococcus aureus (MSSA)and a-hemolytic strepto- insomnia, and flushing, were observed in the donor. coccus in the throat, and Staphylococcus epidermidis in the Granulocytes 44 Â 109 were collected and irradiated at nasal cavity. Repeat urine and stool cultures failed to grow 25 Gy, then transfused to the patient on day +13 any bacteria, including Enterococcus faecalis. On day À2, (Figure 1). Peripheral blood granulocyte counts rose to the patient began to complain of lower abdominal 2.0 Â 109/l at 12 h after GTX and remained above 0.5 Â 109/ cramping pain and watery diarrhea. The diarrhea became l for 3 days. Cultures of peripheral blood and CSF more frequent on day +2, and was accompanied by an became negative and serum CRP levels gradually de- elevated serum CRP value (2.07 mg/dl)and low-grade fever creased. Table 1 shows the CSF findings before and after (37.31C). Oral CPFX was discontinued, and intravenous GTX. The absolute granulocyte count in the CSF increased ceftazidime (CAZ)(4 g/day)and arbekacin sulfate (ABK) dramatically after GTX, suggesting migratory activity (150 mg/day once daily)were started. The fever and CRP of transfused granulocytes into the CSF. However, a resolved gradually, but the diarrhea continued. On day +9, transient worsening of the seizures was observed. On day his body temperature rose to 39.61C. Because the throat +16, CFPM was discontinued and intravenous and and stool cultures taken on day +5 grew Enterococcus intrathecal administration of gentamicin sulfate (GM) faecalis, the intravenous antibiotics were changed to was started. Blood cultures grew Pseudomonas aeruginosa meropenem trihydrate (MEPM)(1.5 g/day)and vancomy- on day +20, and the patient went into septic shock. cin hydrochloride (VCM)(1.5 g/day).On day +11, he Repeated GTX was not planned because he developed began to complain of severe headache, then developed a multiorgan failure. He died on day +20 without any grand mal seizure. Results of a CT scan of the brain were evidence of marrow recovery. Permission for an autopsy unremarkable. The patient was placed on phenytoin and was declined by his family. valproate sodium, and intravenous ampicillin sodium (ABPC)(12 g/day),and cefepime dihydrochloride (CFPM) (4 g/day)were started in addition to VCM and ACV. Discussion Mechanical ventilation was required on day +13 to control persistent convulsions. Blood cultures on days +9 and Two important aspects of this case merit attention: the +10 grew Enterococcus faecalis. Lumbar puncture yielded presence of enterococcal meningitis, a rare infectious cloudy CSF with protein 333 mg/dl, glucose 94 mg/dl complication immediately after BMT, and the use of (serum glucose 134 mg/dl), and a cell count of 27/mm3 GTX as part of its treatment.1,2 (with monocytes 25/27, and granulocytes 2/27). The culture Enterococci are unusual etiologic agents of bacterial of CSF also grew Enterococcus faecalis (Table 1).