History Of Immunosuppressive Therapy Research Articles

A Second Look at Secondary Hypogammaglobulinemia.

Hypogammaglobulinemia is defined as a reduced immunoglobulin level, which can be either primary due to inborn errors of immunity or acquired in the setting of poor antibody production or increased antibody loss. Secondary hypogammaglobulinemia (SHG) should be considered in patients with a history of immunosuppressive therapy, transplant, protein loss syndromes, certain autoimmune conditions, and malignancies, as it can be associated with increased infectious risk. Appropriate history and lab-based screening in these populations can identify SHG allowing treatment and close monitoring as appropriate. Ideally, treatment focuses on control of underlying condition or removal of iatrogenic causes of SHG. However, in many cases, treatment of the underlying condition does not reverse SHG, or immunosuppressive therapy cannot be discontinued without significant risk to the patient. For these patients, strategies for risk mitigation against infectious complications include vaccination, antibiotic prophylaxis and immunoglobulin replacement therapy. This report aims to summarize the existing and emerging data in evaluation and management of SHG and highlight areas which require further investigation.

Efficacy and safety of Mahuang Fuzi and Shenzhuo Decoction for treatment of primary membranous nephropathy: a multicenter prospective trial

Background This study aims to undertake a comprehensive assessment of the effectiveness and safety profile of Mahuang Fuzi and Shenzhuo Decoction (MFSD) in the management of primary membranous nephropathy (PMN), within the context of a prospective clinical investigation. Methods A multicenter, open-label clinical trial was executed on patients diagnosed with PMN. These individuals were subjected to MFSD therapy for a duration of at least 24 months, with primary outcome of clinical remission rates. The Cox regression analysis was employed to discern the pertinent risk factors exerting influence on the efficacy of MFSD treatment, with scrupulous monitoring of any adverse events. Results The study comprised 198 participants in total. Following 24 months of treatment, the remission rate was 58.6% (116/198). Among the subgroup of 130 participants subjected to a 36-month follow-up, the remission rate reached 70% (91/130). Subgroup analysis revealed that neither a history of immunosuppressive therapy (HIST) nor an age threshold of ≥60 years exhibited a statistically significant impact on the remission rate at the 24-month mark (p > .05). Multivariate Cox regression analyses elucidated HIST, nephrotic syndrome, or mass proteinuria, and a high-risk classification as noteworthy risk factors in the context of MFSD treatment. Remarkably, no fatalities resulting from side effects were documented throughout the study’s duration. Conclusions This trial establishes the efficacy of MFSD as a treatment modality for membranous nephropathy. MFSD demonstrates a favorable side effect profile, and remission rates are consistent across patients, irrespective of HIST and age categories.

Application of metagenomic next-generation sequencing for the diagnosis of intracranial infection of Listeria monocytogenes.

BackgroundIntracranial infection of Listeria monocytogenes (LM) can lead to various manifestations, including meningitis, meningoencephalitis, brainstem encephalitis, and brain abscess, which often have a poor prognosis. Metagenomic next-generation sequencing (mNGS) is a promising new tool for the diagnosis of intracranial infection of LM. We describe the typical clinical manifestations of LM intracranial infection and highlight its rarity and severity to help physicians better understand the disease characteristics.MethodsSix cases of severe LM intracranial infection were diagnosed by mNGS. We conducted a retrospective analysis of the data on disease progression, diagnostic tools, treatments, and outcomes, and summarized the findings. We compared the differences in diagnostic accuracy and timeliness between mNGS and etiological cultures.ResultsAmong the 6 patients, 5 were males and 1 was female (age range 32–83). Three patients had a history of immunosuppressive therapy. Common symptoms included fever (100%) and a stiff neck (100%). Coma occurred early in severe patients (66%). Two healthy young patients had previously developed with meningitis, while coma occurred in 3 immunosuppressed patients and 1 elderly patient. Three immunosuppressed patients presented with brain abscess, brainstem encephalitis, and meningitis. 1 elderly patient presented with meningitis. Two patients developed septic shock complications early. Laboratory data showed normal or slightly increased leukocytes, neutrophils, and procalcitonin, and cerebrospinal fluid (CSF) tests were consistent with bacterial CSF infection. All 6 patients were examined for blood culture and CSF culture. The positive rate of blood culture and CSF culture was 50% and 16%. The average time from admission to positive culture findings was 91 h. All 6 patients were examined for CSF mNGS. Two were also examined for whole-blood mNGS. The positive rate for CSF mNGS and whole-blood mNGS results was 100%. The mean time from admission to positive mNGS report was 47 h. After diagnosis and treatment with sensitive antibiotics, 1 patient with brain abscess developed neurological sequelae, while the other 5 patients completely recovered.ConclusionsmNGS can improve accuracy in the diagnosis of LM intracranial infection and reduce the delay in diagnosis. Intracranial infection of Listeria monocytogenes responds well to the timely use of appropriate antibiotics.

MO686: Effectiveness of SARS-CoV-2 Vaccination in Peritoneal Dialysis Patients

BACKGROUND AND AIMSChronic kidney disease (CKD) patients, especially those on renal replacement therapy, have a higher risk of infection and worse clinical outcomes after coronavirus disease 2019 (COVID-19) than the general population. Thus, this population must be promptly immunized against COVID-19. We aimed to assess the humoral response after two doses of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) vaccine in peritoneal dialysis (PD) patients. We also aimed to identify potential factors associated with vaccine response and the prevalence of COVID-19 in a PD unit.METHODWe conducted a single-center, retrospective study to evaluate the immunogenicity in terms of antibody response after COVID-19 vaccination. Three types of vaccine [BNT162b2 messenger RNA vaccine (Pfizer-BioNTech), messenger RNA-1273 (Moderna) and ChadOx1 nCoV-19/AZD1222 (AstraZeneca)] were administered in the PD unit. The detection of anti-spike IgG antibodies (with a cutoff of 0.8 U/mL) was done at least after 21 days of the two vaccine doses. We also evaluated the presence of COVID-19 infections, hospital admissions (including in intensive care unit) and deaths.RESULTSThis study enrolled 70 prevalent patients. We excluded patients with only one vaccine dose (n = 4), those who did not consent to the collection (n = 5) or were vaccinated before starting PD (n = 11). Among the 50 patients included, the mean age was 59 n}{} pm 15 years, 60% were male and the dialysis vintage was 22.1 (IQR 6–34.3) months. Six (12%) patients were receiving immunosuppressive therapy and 16 (32%) had diabetes. The mean interval between administration of the second vaccine dose and antibodies evaluation was 7.2 n}{} pm 0.7 months. Overall, after two doses, there was a significant increase in antibody level, with median of 1495 (IQR 37.8–546.8) U/mL. Only two (4%) patients did not increase their antibody level (remained seronegative). History of immunosuppressive therapy was associated with no response after two doses (91.7% versus 8.3%, P = 0.012). There were two COVID-19 infections after the complete vaccination, with mild symptoms (one with hospital admission). Furthermore, there were no intensive care unit admissions or deaths.CONCLUSIONWe found that immunization against COVID-19 was effective in generating an overall humoral response and in preventing severe disease in CKD patients on PD, which emphasizes the importance of the vaccination against COVID-19 in this population. These results also suggest the impact of the immunosuppressive therapy on vaccine response in PD patients.

Cost-Effectiveness Analyses of an Absorbable Antibacterial Envelope for Use in Patients at Increased Risk of Cardiac Implantable Electronic Device Infection in Germany, Italy, and England

ObjectivesTo model the cost-effectiveness of the TYRX Absorbable Antibacterial Envelope when used in patients at increased risk of cardiac implantable electronic device (CIED) infection in the context of 3 European healthcare systems: Germany, Italy, and England. MethodsA decision tree model with a lifetime horizon was populated using data from the Worldwide Randomized Antibiotic Envelope Infection Prevention Trial, a large multicenter randomized controlled trial. Use of the antibacterial envelope adjunctive to standard of care was compared to standard of care infection prevention alone. Patients in the model were divided into subgroups based on presence of factors known to increase infection risk. ResultsThe antibacterial envelope had the most favorable cost-effectiveness profile when patients had previously experienced CIED infection, had a history of immunosuppressive therapy, or had a Prevention of Arrhythmia Device Infection Trial (PADIT) score indicating high risk of infection (scores ≥6) at cost-effectiveness thresholds of €50 000 in Germany (assumed in the absence of an official threshold), €40 000 in Italy, and £30 000 in England. Probabilistic sensitivity analysis indicated that the antibacterial envelope was likely to be cost-effective in patients with other risk factors (including replacement of high power CIEDs, generator replacement with lead modification, and PADIT scores indicating intermediate risk of infection) when used with some device types and in some countries. ConclusionsThe absorbable antibacterial envelope was associated with cost-effectiveness ratios below European benchmarks in selected patients at increased risk of infection, suggesting the envelope provides value for European healthcare systems by reducing CIED infections.

Clinicopathological characteristics and outcome of plasmablastic lymphoma patients: A single-center retrospective analysis.

e20034 Background: Plasmablastic lymphoma (PBL) is a rare CD20-negative lymphoma with an aggressive clinical course and short median survival ranging from 9 to 32 months. It is often associated with HIV infection but it also affects immunocompetent patients. Due to the rare occurrence most data comes from small, retrospective series. Methods: This is a retrospective single-center analysis of PBL patients (pts) referred to MSCNRIO between 2003-2019. Diagnosis was established according to the WHO 2017 classification criteria. Kaplan–Meier method was used for calculating overall survival (OS) and progression-free-survival (PFS) and the log-rank test for comparisons. Univariate analysis of prognostic factors was carried out. Results: 24 pts with a diagnosis of PBL were included. The median age at diagnosis was 54 years (range 29-90). 15 pts (63%) were men. LDH was elevated in 10 pts (41%). Stage III or IV was reported in 21 (87.5%) pts, IPI score of 3-5 in 12 (50%) and ECOG performance status > 1 in 7 pts (29%). 20 pts (83.3%) had extranodal involvement, including oropharynx (n = 12), gastrointestinal tract (n = 1), bone marrow (n = 7), skeletal bone (n = 9), central nervous system (n = 3), skin and subcutaneous tissue (n = 2). Only 3 pts (13%) were infected by HIV, 2 had history of immunosuppressive therapy. Pathologically, all cases were negative for CD20 and positive for CD38 or CD138 expression. Ki67 > 90% was noted in 16 cases (66%). 11 pts received CHOP chemotherapy, 3 pts - thalidomide- and 4 pts - bortezomib-based regimens, 1 was treated with both agents. 4 pts received different protocols; 1 pt received no treatment. CR was observed in 8 pts (33%), PR in 6 (25%) and no response in 10 (42%). 2 pts received ASCT in the 1st remission. 17 pts (71%) experienced relapsed/progressive disease. 16 pts died: 11 from disease progression, 2 from other neoplasm. With a median follow-up of 20 months (range 2-122) median OS was 21 months and 2-year OS rate was 46% (95%C.I 27%, 65%). 2-year PFS rate was 37% (95% C.I. 17%, 57%), with median PFS 12 months (range 0.7-105). On univariate analysis there was a trend for correlation of high IPI with PFS; (95%C.I 0.99-1.03, P= 0.08). Achieving CR significantly correlated with better OS (HR 5; 95% C.I. 1.41-17; P= 0.01)) and PFS (HR 5.1, 95%C.I. 1.4, 18; P= 0.004). Conclusions: Our results confirm other reported data on PBL. Patients in our cohort shared typical clinical features but majority of them were immunocompetent. PBL prognosis remains poor despite incorporating novel agents into treatment and requires new therapeutic approaches.

Potential role of plasmapheresis in severe cytomegalovirus infection with ongoing immunemediated hemolysis and low complement level

Symptomatic cytomegalovirus (CMV) infections are rare in patients with no previous history of immunosuppressive therapy or condition. A 33-year-old woman with type-2 diabetes, endstage renal disease (ESRD) and unexplained lower extremity weakness was admitted with failure to thrive, ongoing hemolysis, low haptoglobin and C3 levels and suppressed IgM and IgG globulin fractions. Multiple cultures and serologic workup for autoimmune disorders remained negative. CMV viral titer by serum polymerase chain reaction (PCR) revealed massive elevation at 9.2 million copies/mL. Initial CMV IgG titer was positive, IgM titer remained consistently negative and CMV was recovered from cerebrospinal fluid, as well. She received treatment with I.V. ganciclovir, CMV immune globulin (CytoGam) and three sessions of plasmapheresis (PLEX). The extreme viremia without neutropenia, lack of IgM antibody reconversion and CMV-mediated hemolysis with a low complement level were all very unusual features. Timely initiation of PLEX may have contributed to recovery

Normal intrathecal leukocyte cell number and composition do not decrease the incidence of post–lumbar puncture headache

The pathogenesis of post–lumbar puncture headache (PLPH) has remained unclear. A beneficial role of CSF cells in the repair of a post-traumatic dural CSF leak has been suggested. The primary purpose of this study was to investigate the effects of 8weeks of induction therapy with high-dose PF-00547659 on the cellular elements of CNS immune surveillance in patients with active Crohn's Disease and a history of immunosuppressive therapy (Clinicaltrials.govNCT01387594). PF-00547659 is a human monoclonal antibody that binds to mucosal addressin–cell adhesion molecule 1 (MAdCAM-1) on endothelial cells and blocks its interaction with beta7-integrin expressing lymphocytes. The study was executed in three parts or cohorts under two protocols. The incidence of a PLPH was 35% after the initial lumbar puncture, and 26% following the second lumbar puncture. After initiation of PF-00547659 anti-MAdCAM-1 therapy, there was a small and non-significant increase in the numbers of overall CSF leukocytes, and in lymphocyte subsets (CD3+, CD4+, and CD8+ T cells). The lymphocyte composition was unaltered by PF-00547659 anti-MAdCAM-1 therapy. Our observations suggest that normal numbers and composition of intrathecal leukocytes do not decrease the incidence of PLPH.

Surgical treatment for pulmonary aspergilloma - early and long-term results.

IntroductionPulmonary aspergilloma is a difficult therapeutic problem due to the low effectiveness of conservative treatment and high surgical morbidity.AimTo analyze the early and late results of surgical treatment for pulmonary aspergilloma.Material and methodsFrom 2005 to 2015, 49 patients were treated surgically for pulmonary aspergilloma. Symptoms occurred in 85.7% of cases, including recurrent hemoptysis in 53%. A history of immunosuppressive therapy or chemotherapy was noted in 24.5% of patients. Complex aspergilloma was diagnosed in 79.6% of cases. Immunological test results were positive in 10.2%, and bronchoalveolar lavage samples were positive for Aspergillus species in 18.5% of cases. In 59.2% of patients, the surgical risk was assessed as ASA 3. Thirty seven patients underwent lobectomy, 3 – pneumonectomy, 7 – wedge resection, 1 – decortication, and 1 – cavernostomy.ResultsIn-hospital mortality was 4.1%. Postoperative complications occurred in 63.3% of patients. The most common complications were: prolonged air leak (26.3%), arrhythmias (20.4%), residual pneumothorax (16.3%), respiratory failure (14.3%), atelectasis (12.3%), and bleeding (12.3%). Of the three patients that underwent pneumonectomy, one died, two required repeat thoracotomy because of bleeding, and all three required prolonged mechanical ventilation. Two patients died during the follow-up period. Aspergilloma did not recur in any of the patients who underwent pulmonary resection.ConclusionsDue to the high risk of complications, surgical treatment of pulmonary aspergilloma should be restricted to symptomatic patients in whom lobectomy can be performed. The long-term results of surgical treatment are good, preoperative symptoms abate in most patients, and the rate of aspergillosis recurrence is very low.

Bloodstream Infection after Stem Cell Transplantation in Children with Idiopathic Aplastic Anemia

Bloodstream infection (BSI) is the most common infectious complication of hematopoietic stem cell transplantation (HSCT) and can cause substantial morbidity and mortality. Identification of risk factors for BSI might be helpful in efforts to reduce transplantation-related death. This study analyzed the incidence of BSI and risk factors for BSI after HSCT in pediatric patients with aplastic anemia (AA). BSI occurred in 39 of the 351 patients with AA (11.1%). Onset of BSI occurred at a median of 8 days after HSCT (range, 0 to 92 days). The 5-year overall survival rate was lower in patients with BSI than in patients without BSI (63.32% ± 7.90% versus 93.35% ± 1.44%; P < .0001). Univariate analysis identified the following variables as associated with BSI: history of immunosuppressive therapy with antithymocyte globulin (ATG), transplantation from an unrelated donor, frequent blood transfusion before transplantation, major or major plus minor ABO type mismatch, graft-versus-host disease prophylaxis with tacrolimus and without cyclosporine, and long interval from diagnosis to transplantation. Among these factors, long interval from diagnosis to transplantation was the sole statistically significant risk factor for BSI on multivariate analysis. In patients who underwent HSCT from a related donor, age ≥14 years at transplantation was risk factor for BSI. In contrast, history of immunosuppressive therapy with ATG, frequent blood transfusion before HSCT, graft failure, and major or major plus minor ABO type mismatch were risk factors for BSI in patients who underwent HSCT from an unrelated donor. Because the overall 5-year survival rate without BSI was >90%, even in patients who were received a transplant from an unrelated donor, control of BSI is very important for successful HSCT in pediatric patients with AA.

Consenso español actualizado sobre el uso del natalizumab (Tysabri®)-2013

IntroductionNatalizumab treatment has been shown to be very efficacious in clinical trials and very effective in clinical practice in patients with relapsing-remitting multiple sclerosis, by reducing relapses, slowing disease progression, and improving magnetic resonance imaging patterns. However, the drug has also been associated with a risk of progressive multifocal leukoencephalopathy (PML). The first consensus statement on natalizumab use, published in 2011, has been updated to include new data on diagnostic procedures, monitoring for patients undergoing treatment, PML management, and other topics of interest including the management of patients discontinuing natalizumab. Material and methodsThis updated version followed the method used in the first consensus. A group of Spanish experts in multiple sclerosis (the authors of the present document) reviewed all currently available literature on natalizumab and identified the relevant topics would need updating based on their clinical experience. The initial draft passed through review cycles until the final version was completed. Results and conclusionsStudies in clinical practice have demonstrated that changing to natalizumab is more effective than switching between immunomodulators. They favour early treatment with natalizumab rather than using natalizumab in a later stage as a rescue therapy. Although the drug is very effective, its potential adverse effects need to be considered, with particular attention to the patient's likelihood of developing PML. The neurologist should carefully explain the risks and benefits of the treatment, comparing them to the risks of multiple sclerosis in terms the patient can understand. Before treatment is started, laboratory tests and magnetic resonance images should be available to permit proper follow-up. The risk of PML should be stratified as high, medium, or low according to presence or absence of anti-JC virus antibodies, history of immunosuppressive therapy, and treatment duration. Although the presence of anti-JC virus antibodies is a significant finding, it should not be considered an absolute contraindication for natalizumab. This update provides general recommendations, but neurologists must use their clinical expertise to provide personalised follow-up for each patient.

Hepatosplenic T-Cell Lymphoma: Clinicopathological Features and Treatment Outcomes: Report From The North American Peripheral T-Cell Lymphoma Consortium

BackgroundHepatosplenic T-cell lymphoma (HSTCL) is an exceedingly rare subtype of mature T-cell lymphomas with dismal outcome despite combination chemotherapies. It is characterized by frequent involvement of splenic red pulp, liver sinusoids and bone marrow; nodal and other extranodal sites are rarely affected. Patients frequently present with cytopenias and B–symptoms. Malignant cells are medium-sized mature T-cells with cytotoxic phenotype. Most frequent chromosomal abnormalities are isochromosome 7q and trisomy 8. Gamma-delta phenotype is found in the majority of cases, but alpha-beta variant has been reported. All studies to date report very poor responses to standard lymphoma protocols and only few survivors after stem cell transplantation. We report the largest series of this rare malignancy to date including clinicopathologic features and treatment outcomes collected by several North American Institutions. MethodsThis is a retrospective multi-center cohort study conducted by the participating institutions. Data was collected from charts of previously diagnosed and treated HSTCL patients. Chart review protocol was approved by Institutional Review Boards of participating centers and a waiver of consent was obtained. University of Washington served as coordinating center for data collection and analysis. We obtained the following data from patients' medical charts: demographic characteristics, histologic findings, immunophenotypic and molecular analysis, cytogenetics, treatment regimens and disease responses, clinical outcomes and survival. Summary statistics was used to describe the clinical, demographic and pathological characteristics. Response was defined using the International Workshop NHL criteria. For survival analyses, overall survival (OS) was time between the diagnosis and the patient's last follow up or death. The Kaplan-Meier method was used to estimate survival distributions. ResultsForty-two patients were identified, 24 male and 18 female, with the median age of 35 (range, 17-79) years. Twenty-six (62%) patients were Caucasian, 8 (19%) were Asian, 6 (14%) were African American, and 2 (5%) were other. Splenomegaly was reported in 39/42 patients (93%), hepatomegaly in 23/40 (58%), and bone marrow involvement in 32/39 (82%) patients. Lymph nodes were involved in only 12/40 (30%) patients. Anemia was present (median HCT=30.5%) in 30/37 (81%), leucopenia (median WBC=4.3K/ul) in 9/41 (22%), thrombocytopenia (median platelet count = 80K/ul) in 33/41 (80%) of reported patients. Abnormal liver function tests were found in 31/38 (82%) of the reported cases. Gamma-delta and alpha-beta phenotype was found in 84% and 16% of reported cases (n=37), respectively. Isochromosome 7q was found in 6/23 (26%) of patients while 6/23 (26%) had other aberrations. History of immunosuppressive therapy was present in 13/42 (31%) reported patients, including 4 patients receiving prior therapy with TNF-alpha inhibitors. Nine out of 42 patients (21%) had history of inflammatory bowel disease. All patients received multi-agent chemotherapy. Overall response rate (ORR) to initial therapy was 63%, with 44% achieving complete remission (CR). Twenty-three out of 42 (55%) reported patients underwent autologous (n=2) or allogeneic (n=19) stem cell transplantation, and 2 underwent both. Twenty-nine (69%) patients have died. Of note, all but one of the surviving patients have undergone allogeneic stem cell transplantation. With the median follow-up of 56 (range 15-105) mo for living patients, the median OS was 15.8 mo (Fig. 1). Detailed histo-pathologic data and treatment regimens will be reported at the meeting. [Display omitted] ConclusionsThis is the largest study to date of hepatosplenic T-cell lymphomas. This is a rare malignancy associated with poor outcomes after contemporary treatments. Response to initial therapies is suboptimal, relapses are frequent and median overall survival is short. Stem cell transplantation in first remission should be considered for all patients achieving response to initial therapy. Novel therapies are needed to improve outcomes. Disclosures:No relevant conflicts of interest to declare.

Risk Factors for Donor-Type Aplasia After Bone Marrow Transplant in Children with Acquired Bone Marrow Failure Syndrome

Abstract 3474Graft rejection is a major cause of aplasia after bone marrow transplant (BMT) in patients with bone marrow failure syndrome (BMFS). However, we have experienced several patients with acquired BMFS who developed persistent aplasia with full donor chimerism after BMT (donor-type aplasia).To clarify risk factors for donor-type aplasia, we reviewed the clinical data of 58 children (male, n = 36; female, n = 22) with acquired BMFS who received allogeneic BMT at Nagoya University Hospital and Japanese Red Cross Nagoya First Hospital between January 1997 and December 2010. The median age at diagnosis was 10 (range, 1 – 20) years. The median interval between diagnosis and BMT was 30 (range, 0.70 – 105) months. Twenty-five of the 58 patients received > 20 units of red blood cell (RBC) transfusions. We retrospectively reviewed BM smears and samples of trephine biopsies according to the 2008 WHO classification. Of the 58 patients, 26 and 32 were diagnosed with aplastic anemia (AA) and refractory cytopenia of childhood (RCC), respectively. Twenty, five and 33 patients received BMT from HLA-matched and mismatched related donors and unrelated donors, respectively. Conditioning regimens consisting of cyclophosphamide (CY), antithymocyte globulin (ATG) with or without TBI and of fludarabine, CY, ATG and TBI (fludarabine regimen) were administered to 38 and 18 patients, respectively. Marrow grafts (median dose, 4.2 ×108 nucleated cells/kg) were not T cell–depleted. Prophylaxis against graft versus host disease (GVHD) consisted of cyclosporine/methotrexate (MTX) for 26 patients and tacrolimus/MTX for 32 others. Donor-type aplasia was defined as hypocellular BM with persistent cytopenia (hemoglobin < 8 g/dl; neutrophils < 1 ×109/L or platelets < 50 ×109/L) for > 6 months after achieving engraftment with full donor chimerism. We evaluated the following variables to determine risk factors for donor type aplasia; age at BMT, sex, BM morphology at BMT, year of BMT, period between diagnosis and BMT, units of RBC transfusion, history of immunosuppressive therapy (IST) before BMT, HLA disparity, BM cell dose, conditioning regimen, GVHD and viral infection.Eleven (19%) of the 58 children developed donor-type aplasia. All received BMT after 2003 and had the BM morphology of RCC. Three and five of them received BMT from HLA-mismatched and unrelated donors, respectively. Fludarabine regimens were administered to eight patients. Seven patients received ganciclovir to treat CMV reactivation and two received rituximab to treat Epstein-Barr virus reactivation before aplasia developed. The onset of donor-type aplasia ranged from 46 – 710 days after BMT. Donor-type aplasia continued for over three years in five patients. Eight patients required transfusions with either RBC or platelets or granulocyte stimulating factor (G-CSF). Donor-type aplasia improved in five patients within 203 – 1789 days. All patients with donor-type aplasia remained alive for 20 – 103 months after developing donor-type aplasia. Univariate analysis revealed BM morphology, year of BMT and the fludarabine regimen as risk factors for donor-type aplasia and multivariate analysis confirmed these findings. The cumulative incidence (CI) of donor-type aplasia was significantly higher in children who received the fludarabine regimen (45%) or had RCC (35%) than in those who received a non-fludarabine regimen (5%) or had AA (0%) (p = 0.001, respectively). The CI of donor-type aplasia was significantly higher in children with RCC who received the fludarabine regimen (62%) than in those who did not (15%). In contrast, none of the children with AA developed donor-type aplasia irrespective of the fludarabine regimen.The fludarabine regimen was identified as a risk factor for donor-type aplasia in children with RCC. Children with RCC should not be conditioned with the regimens used for children with AA. Disclosures:No relevant conflicts of interest to declare.

播種性トリコスポロン症を発症した関節リウマチの 1 例

A 75-year-old man who developed disseminated trichosporonosis had a long history of immunosuppressive therapy with weekly methotrexate and low-dose prednisolone for rheumatoid arthritis (RA). He had been administered 30 mg of prednisolone per day for organizing pneumonia, probably due to the RA, for about 3 months before admission for a lumbar compression fracture. He then developed bilateral aspiration pneumonia with pleural effusion, treated successfully with broad-spectrum antibiotics meropenem and ciprofloxacin, and fluid management. He then developed acute, progressive respiratory failure with changes in both lung lobes in chest computed tomography (CT). Meropenem, ciprofloxacin, micafungin, and pulsed steroid administration were ineffective. He died of respiratory failure, after which Trichosporon asahii was first detected in blood and urine culture. Disseminated trichosporonosis was determined based on positive blood culture, elevated serum glucuronoxylomannan antigen and beta-D glucan, and the man's lack of clinical progress. He had numerous risk factors for trichosporonosis, including neutrophilic dysfunction due to prolonged steroid therapy, administration of broad-spectrum antibiotics and micafungin, and central venous catheterization. Disseminated trichosporonosis is a chiefly hematological infection and case reports without hematological disorders are rare, so we report this instructive case.

First Report of Septic Arthritis Caused by Klebsiella oxytoca

Klebsiella oxytoca is known to be a pathogen in immunodeficient adults and children. Here we report the first case of a K. oxytoca infection associated with spontaneous arthritis of the knee in a child with no history of immunosuppressive therapy or previous bacterial infections. Despite an initial antibiotic treatment failure, a second treatment led to a cure of the infection with no joint sequelae.

Immunosuppressive therapy in dermatology and PML

Progressive multifocal leukoencephalopathy (PML) is a rare, demyelinating disease of the central nervous system that usually leads to death or severe disability. Affected patients present with signs and symptoms including impaired cognition, visual disturbances, hemiparesis, altered mental state and behavioural changes. PML is caused by activation of the John Cunningham (JC) virus. JC virus resides in latent form in up to 80 percent of adults. Reactivation of JC virus occurs in immunocompromised patients. The factors leading to activation of the latent infection are not fully understood. The diagnosis of PML is established based on a detailed medical history, physical examination, suggestive MRI findings and the presence of the JC virus detected in the cerebrospinal fluid by PCR. PML has been reported in the published literature in HIV-positive patients, as well as in patients receiving immunosuppressive agents because of organ transplantation, cancer or autoimmune diseases. PML has been reported in patients receiving classical immunosuppressive drugs or biologics or both [1]. There are no known interventions that can prevent or treat PML successfully. Recently, two confirmed cases of PML have been reported in US patients receiving efalizumab (Raptiva®) for chronic plaque psoriasis [2]. One male patient (age 70) and one female patient (age 73) had received efalizumab for 4 and 3.8 years, respectively. These are the first confirmed cases of PML in psoriasis patients receiving immunosuppressive therapy. Today, the global exposure of patients on efalizumab is 47,000 patient-years. Until more information is available and further guidance is received from the health authorities, a group of independent expert dermatologists advise to strictly follow the Summary of Product Characteristics of efalizumab [3]. Dermatologists should carefully weigh risks and benefits in patients during long-term therapy with efalizumab and particularly in those of advanced age or with a history of immunosuppressive therapy. In patients receiving any immunosuppressive therapy, dermatologists should be vigilant for signs and symptoms suggestive of PML. Suspicious cases should be referred to a neurologist.

Outcome of Allogeneic Stem Cell Transplantation for Patients with Severe Aplastic Anemia after Conditioning with Procarbazine, ATG and Cyclophosphamide: A Single Center Experience.

Background: Cyclophosphamide (CY, 200 mg/kg) plus ATG seems to be accepted as a standard conditioning regimen in HLA-matched sibling stem cell transplantation (SCT) for severe aplastic anemia (SAA). We report herein the outcome of allogeneic SCT for the patients with SAA conditioned with procarbazine (PCB), ATG and CY.Methods: Between January 1995 and March 2004, consecutive one hundred and sixty two patients with SAA received matched sibling SCT after conditioning with PCB, ATG and CY. The median age of patients was 28.5 (16~50) and median interval between diagnosis and SCT was 10.5 months (1~216). Fifty-five patients (34%) had a history of immunosuppressive therapy before SCT. The conditioning regimen consisted of PCB (6.25 mg/kg/day, 6 days), CY (50 mg/kg/day, 4 days) and ATG (1.25 mg/kg/day, 3 days). No graft manipulation was performed in 92 patients (52%), and donor marrow expansion and megadose transplantation (bone marrow plus CD34+ isolated PB as a stem cell source) were done in 35 patients (21.6%). All patients received of cyclosporine and methotrexate as GVHD prophylaxis.Results: The median dose of CD34+ and CD3+ cells infused were 4.8 x 106/kg (0.8~49.6) and 5.1 x 107/kg (0 ~ 38), respectively. Median time to neutrophil recovery more than 500/μL and platelet recovery more than 20,000/μL were 13 days (0~49) and 19 days (0~150), respectively. All patients achieved successful primary engraftment, but delayed engraftment failure developed in 18 patients (11%). Ten among 18 patients who developed graft failure received second SCT, resulting survival of 9 patients. The incidence of acute (more than grade II) and chronic GVHD were 9.3% (n=15) and 13.0 % (n=21), respectively. DFS and overall survival (OS) at 6 years was also 90%. Factors influencing on DFS on univariate analysis were patient and donor's age, development of acute and chronic GVHD, and times of pregnancy (over 2 times). Development of acute and chronic GVHD, and occurrence of rejection were factors that influence DFS on multivariate analysis. Causes of death (n=15) were pneumonia (n=4), rejection (n=4), GVHD±infection (n=2), chronic GVHD (n=1), MOF (n=1), CVA (n=1), autoimmune hemolytic anemia (n=1), and unknown (n=1).Conclusions: These data suggest that the conditioning regimen used in this study is feasible for patients with SAA who received matched sibling SCT. GVHD and rejection were the most important factors that influence DFS.

Postinflammatory Hydrocephalus and Intracranial Mass Lesion From Candida in an Immunocompetent Child

Central nervous system Candida infection may occur in systemic Candida infection when host defenses are impaired. We report here a 20-month-old boy with normal immune status and no history of immunosuppressive therapy who developed left facial weakness, decreased left hand strength and coordination, and worsening gait. This paper describes the diagnostic procedures and management strategies employed in this unique case.