Hematopoietic Cell Transplantation with Reduced Intensity Conditioning Using Fludarabine/Busulfan or Fludarabine/Melphalan for Primary Immunodeficiency Diseases.

PURPOSE: The purpose of our study was to compare the safety and efficacy of hematopoietic cell transplantation (HCT) using fludarabine (Flu)-based reduced intensity conditioning (RIC) with busulfan (BU) or melphalan (Mel) for primary immunodeficiency diseases (PID). METHODS: We retrospectively analyzed transplant outcome, including engraftment, chimerism, immune reconstitution, and complications in 15 patients with severe combined immunodeficiency (SCID) and 27 patients with non-SCID PID. The patients underwent Flu-based RIC-HCT with BU (FluBU: 7 SCID, 16 non-SCID) or Mel (FluMel: 8 SCID, 11 non-SCID). The targeted low-dose BU with therapeutic drug monitoring was set to 30 mg hour/L for SCID. RESULTS: The 2-year overall survival of all patients was 79.6% and that of patients with SCID in the FluBU and FluMel groups was 100% and 62.5%, respectively. In the FluBU group, all seven patients achieved engraftment, good immune reconstitution, and long-term survival. All five patients receiving umbilical cord blood transplantation achieved complete or high-level mixed chimerism and sufficient specific IgG production. In the FluMel group, six of eight patients achieved complete or high-level mixed chimerism. Viral reactivation or new viral infection occurred in one FluBU group patient and four FluMel group patients. In the non-SCID group, 10 of 11 patients (91%) who received FluMel achieved complete or high-level mixed chimerism but had variable outcomes. Patients with WAS (2/2 patients), NEMO deficiency (2/2 patients), and X-linked hyper IgM syndrome (2/3 patients) who received FluBU achieved complete or high-level mixed chimerism and long-term survival. CONCLUSIONS: RIC-HCT with FluBU is a safe and effective strategy for obtaining high-level donor chimerism, immune reconstitution including B cell function, and long-term survival in patients with SCID. In patients with non-SCID PID, the results varied according to the subtype of the disease. Further prospective studies are required to optimize the conditioning regimen for non-SCID PID.

Hemophagocytic lymphohistiocytosis complicating invasive pneumococcal disease: a pediatric case report.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is an infrequent but life-threatening disease due to excessive immune activation. Secondary HLH can be triggered by infections, autoimmune diseases, and malignant diseases. Streptococcus pneumoniae is a pathogenic bacterium responsible for invasive pneumococcal disease (IPD) such as meningitis and bacteremia. Although the pneumococcal conjugate vaccine (PCV) has led to reductions in IPD incidence, cases of IPD caused by serotypes not included in PCV are increasing. There are few reports of secondary HLH caused by IPD in previously healthy children. We herein report a rare case of a previously healthy boy with secondary HLH complicating IPD of serotype 23A, which is not included in the pneumococcal 13-valent conjugate vaccine (PCV-13). CASE PRESENTATION: An 11-month-old boy who had received three doses of PCV-13 was hospitalized with prolonged fever, bilateral otitis media, neutropenia and elevated C-reactive protein (CRP) levels. Blood culture on admission revealed S. pneumoniae, leading to a diagnosis of IPD. HLH was diagnosed based on a prolonged fever, neutropenia, anemia, hepatosplenomegaly, hemophagocytosis in the bone marrow, and elevated serum levels of triglycerides, ferritin, and soluble interleukin-2 receptor. He received broad-spectrum antibiotics and intravenous immunoglobulins for IPD and high-dose steroid pulse therapy and cyclosporine A for HLH; thereafter, his fever resolved, and laboratory findings improved. The serotype of the isolated S. pneumoniae was 23A, which is not included in PCV-13. CONCLUSIONS: It is important to consider secondary HLH as a complication of IPD cases with febrile cytopenia or hepatosplenomegaly, and appropriate treatment for HLH should be started without delay.

Haploidentical Bone Marrow Transplantation With Clofarabine and Busulfan Conditioning for a Child With Multiple Recurrent Acute Lymphoblastic Leukemia.

Outcome of children with acute lymphoblastic leukemia (ALL) has improved over the years, but not for those with multiple recurrences because of high therapy resistance and heavily pretreated history that potentially cause physical damages. We describe the case of an 11-year-old boy with a third relapse of ALL and a history of 2 allogeneic bone marrow transplantations. He was successfully treated with clofarabine combination chemotherapy and achieved a fourth remission at 16 months following haploidentical bone marrow transplantation with conditioning regimen of clofarabine and busulfan. Clofarabine/busulfan conditioning might be a preferable option for children with multiple recurrent ALL, and warrants further investigation.

Rothia mucilaginosa Meningitis in a Child with Myelodysplastic Syndromes.

Rothia mucilaginosa is a Gram-positive coccus and an opportunistic pathogen in immunocompromised hosts. The microorganism has been implicated in serious infections, including bacteremia meningitis or endocarditis. However, there is a dearth of investigations on meningitis, especially in children. As this infection is rare and only a few cases have been recorded, evidence-based guidelines for adequate infection treatment are lacking. We herein report the case of a 12-year-old boy with myelodysplastic syndromes (MDS) presenting with a change in mental status who was diagnosed as having febrile neutropenia and bacterial meningitis caused by R. mucilaginosa at 23 days after unrelated cord blood transplant. In our case, the minimum inhibitory concentrations (MICs) of meropenem and vancomycin (VCM) were both ≤1 µg/mL, whereas the MIC of daptomycin (DAP) was 4 µg/mL. The patient was treated with intravenous antimicrobial therapy due to meropenem for 43 days because he had febrile neutropenia. During follow-up, the patient had no neurological complications. We retrospectively reviewed the antimicrobial susceptibility of all R. mucilaginosa isolates (n = 5) from blood or cerebrospinal fluid cultures at our hospital. The MIC of VCM was <0.5 µg/mL for all strains, whereas the MIC of DAP was ≥2 µg/mL for all strains. The MIC of MEPM was >1 µg/mL for one strain. We recommend choosing VCM as the primary treatment for invasive R. mucilaginosa infections until antimicrobial susceptibility results are known, especially in immunocompromised children.

Malignant Ovarian Steroid Cell Tumor, Not Otherwise Specified, Causes Virilization in a 4-Year-Old Girl: A Case Report and Literature Review.

We report a case of a 4-year-old girl with an ovarian steroid cell tumor, not otherwise specified (SCT-NOS). She was admitted to the hospital with progressing virilization and Cushing's syndrome, which included abnormality of the perineum, hirsutism, hypertrichosis, flushing of face, hoarseness, and weight gain. Blood testing showed a significantly increased testosterone level and slightly increased cortisol level. Computed tomography scan revealed an 8.0 × 5.0 × 5.0 cm tumor of the right ovary. The patient underwent right salpingo-oophorectomy, and pathological examination showed malignant potential. Three courses of bleomycin, etoposide, and cisplatin were administered as postoperative chemotherapy. After tumor resection, her testosterone decreased to undetectable levels. However, during the course of the treatment, the patient suffered from adrenal insufficiency resulting in the need for hydrocortisone replacement therapy. Although SCT-NOS in childhood are typically benign, pathological findings should be carefully observed for potential malignancy. In cases of cortisol-producing SCT-NOS, serum levels should be monitored, and hydrocortisone replacement therapy should be considered before resection.

Mesenchymal Stem Cell Therapy Overcomes Steroid Resistance in Severe Gastrointestinal Acute Graft-Versus-Host Disease.

The authors describe the high effectiveness of human mesenchymal stem cell (hMSC) therapy to treat steroid-refractory gastrointestinal acute graft-versus-host Disease (aGVHD) in a 15-year-old boy with acute lymphoblastic leukemia (ALL). He received allogeneic hematopoietic stem cell transplantation due to high-risk hypodiploid ALL. Around the time of engraftment, he developed severe diarrhea following high-grade fever and erythema. Although methylprednisolone pulse therapy was added to tacrolimus and mycophenolate mofetil, diarrhea progressed up to 5000~6000 ml/day and brought about hypocalcemia, hypoalbuminemia, and edema. Daily fresh frozen plasma (FFP), albumin, and calcium replacements were required to maintain blood circulation. After aGVHD was confirmed by colonoscopic biopsy, MSC therapy was administered. The patient received 8 biweekly intravenous infusions of 2×106 hMSCs/kg for 4 weeks, after which additional 4 weekly infusions were performed. A few weeks after initiation, diarrhea gradually resolved, and at the eighth dose of hMSC, lab data improved without replacements. MSC therapy successfully treated steroid-refractory gastrointestinal GVHD without complications. Despite life-threatening diarrhea, the regeneration potential of children and adolescents undergoing SMC therapy successfully supports restoration of gastrointestinal damage. Even with its high treatment costs, SMC therapy should be proactively considered in cases where young patients suffer from severe gastrointestinal GVHD.

Hematopoietic cell transplantation for myeloid/NK cell precursor acute leukemia in second remission.

Myeloid/natural killer cell precursor acute leukemia (MNKPL) is a rare leukemia subtype characterized by a high incidence of extramedullary infiltration. No appropriate treatment strategy has so far been developed. Acute myelogenous leukemia-type chemotherapy combined with L-Asparaginase is an effective treatment for MNKPL. Hematopoietic cell transplantation is a second option in refractory cases.