Hideki Araoka

High incidence of haemophagocytic syndrome following umbilical cord blood transplantation for adults

Umbilical cord blood transplantation (CBT) is widely accepted, but one critical issue for adult patients is a low engraftment rate, of which one cause is haemophagocytic syndrome (HPS). We aimed to identify the contribution of HPS to engraftment failure after CBT, following preparative regimens containing fludarabine phosphate, in 119 patients (median age, 55 years; range; 17–69 years) with haematological diseases. Graft‐versus‐host disease prophylaxis comprised continuous infusion of a calcineurin inhibitor with or without mycophenolate mofetil. Of the 119 patients, 20 developed HPS within a median of 15 d (cumulative incidence; 16·8%) and 17 of them did so before engraftment. Donor‐dominant chimaerism was confirmed in 16 of 18 evaluable patients with HPS. Despite aggressive interventions including corticosteroid, ciclosporin, high‐dose immunoglobulin and/or etoposide, engraftment failed in 14 of 18 patients. Of these 14 patients, four received second rescue transplantation and all resulted in successful engraftment. Overall survival rates significantly differed between patients with and without HPS (15·0% vs. 35·4%; P < 0·01). Univariate and multivariate analysis identified having fewer infused CD34+ cells as a significant risk factor for the development of HPS (P = 0·01 and 0·006, respectively). We concluded that engraftment failure closely correlated with HPS in our cohort, which negatively impacted overall survival after CBT.

Clinical Characteristics of Bacteremia Caused by Helicobacter cinaedi and Time Required for Blood Cultures To Become Positive

ABSTRACT The aim of this study was to clarify the clinical characteristics of patients with Helicobacter cinaedi bacteremia and the time required for blood cultures to become positive. The medical records of all patients with H. cinaedi bacteremia at Toranomon Hospital and Toranomon Hospital Kajigaya between March 2009 and March 2013 were retrospectively reviewed. Sixty-three patients, 34 men and 29 women with a median age of 67 years (range, 37 to 88 years), were diagnosed with H. cinaedi bacteremia. A total of 51,272 sets of blood cultures were obtained during the study period, of which 5,769 sets of blood cultures were positive for some organism and 126 sets were H. cinaedi positive. The time required for blood cultures to become positive for H. cinaedi was ≤5 days in 69 sets (55%) and >5 days in 57 sets (45%). Most patients had an underlying disease, including chronic kidney disease (21 cases), solid tumor (19 cases), hematological malignancy (13 cases), diabetes mellitus (8 cases), chronic liver disease (6 cases), and postorthopedic surgery (3 cases). Only 1 patient had no apparent underlying disease. The clinical symptoms included cellulitis in 24 cases, colitis in 7 cases, and fever only in 27 cases, including 7 cases of febrile neutropenia. The 30-day mortality rate of H. cinaedi bacteremia was 6.3%. In conclusion, most cases of H. cinaedi bacteremia occurred in immunocompromised patients. We might have overlooked nearly half of the H. cinaedi bacteremia cases if the duration of monitored blood culture samples had been within 5 days. Therefore, when clinicians suspect H. cinaedi bacteremia, the observation period for blood cultures should be extended.

Impact of HLA disparity in the graft-versus-host direction on engraftment in adult patients receiving reduced-intensity cord blood transplantation

Delayed engraftment or graft failure is one of the major complications after cord blood transplantation (CBT). To investigate factors impacting engraftment, we conducted a retrospective analysis of adult patients who underwent reduced-intensity CBT at our institute, in which preparative regimens mainly consisted of fludarabine, melphalan, and total body irradiation with graft-versus-host (GVH) disease prophylaxis using single calcineurin inhibitors. Among 152 evaluable patients, the cumulative incidence of neutrophil engraftment was 89%. High total nucleated cell and CD34(+) cell dose were associated with the faster speed and higher probability of engraftment. In addition, the degree of human leukocyte antigen (HLA) mismatch in the GVH direction was inversely associated with engraftment kinetics, whereas no statistically significant association was observed with the degree of HLA mismatch in the host-versus-graft direction. Similarly, the number of HLA class I antigens mismatched in the GVH direction, but not in the host-versus-graft direction, showed a negative correlation with engraftment kinetics. HLA disparity did not have significant impact on the development of GVH disease or survival. This result indicates the significant role of HLA disparity in the GVH direction in the successful engraftment, raising the novel mechanism responsible for graft failure in CBT.

Successful sustained engraftment after reduced-intensity umbilical cord blood transplantation for adult patients with severe aplastic anemia.

We retrospectively analyzed 12 consecutive adult severe aplastic anemia patients who received unrelated umbilical cord blood transplantation after a reduced-intensity conditioning regimen (RI-UCBT). The conditioning regimen consisted of 125 mg/m² fludarabine, 80 mg/m² melphalan, and 4 Gy of total body irradiation. The median infused total nucleated cell number and CD34(+) cell number were 2.50 × 10⁷/kg and 0.76 × 10⁵/kg, respectively. Eleven of the 12 patients achieved primary neutrophil and platelet engraftment. All patients who achieved engraftment had complete hematologic recovery with complete donor chimerism, except for one patient who developed late graft failure 3 years after RI-UCBT. Two of the 12 patients died of idiopathic pneumonia syndrome, and the remaining 10 patients are alive, having survived for a median of 36 months. Our encouraging results indicate that RI-UCBT may become a viable therapeutic option for adult severe aplastic anemia patients who lack suitable human leukocyte antigen-matched donors and fail immunosuppressive therapy.

Mycophenolate and tacrolimus for graft-versus-host disease prophylaxis for elderly after cord blood transplantation: a matched pair comparison with tacrolimus alone.

Background. The optimal graft-versus-host disease (GVHD) prophylaxis after umbilical cord blood transplantation has not been established. Our previous observation using single calcineurin inhibitors revealed a high incidence and severity of early immune-mediated complications, especially for older patients or those with poor performance status. Methods. We conducted a single institute pilot study assessing the safety and effectiveness of mycophenolate mofetil (MMF) and tacrolimus (FK) combination as a GVHD prophylaxis for 29 patients (FK+MMF), and the results were compared with matched-pairs extracted from our historical database who received FK alone as GVHD prophylaxis (control). Results. FK+MMF group showed superior engraftment rate compared with control group (cumulative incidence until day 60 posttransplant; 90%±0% vs. 69%±1%, P=0.02). A cumulative incidence of severe type preengraftment immune reactions was significantly decreased in FK+MMF group (16%±1%) compared with that of control group (52%±2%, P=0.03), and, remarkably, there was no nonrelapse mortality (NRM) observed up to day 30 posttransplant in FK+MMF group, whereas 21%±1% of NRM was observed in the control group. However, the incidences of acute and chronic GVHD, estimated overall and progression-free survivals were comparable between two groups. Conclusions. MMF and FK in combination was well tolerated and decreased early NRM possibly by better control of preengraftment immune reactions. Subsequent NRM or disease progression needs to be overcome to further improve survival.

Monobactam and aminoglycoside combination therapy against metallo-β-lactamase-producing multidrug-resistant Pseudomonas aeruginosa screened using a ‘break-point checkerboard plate’

Abstract Metallo-β-lactamase-producing multidrug-resistant Pseudomonas aeruginosa (MDR P. aeruginosa) is a cause of life-threatening infections. With parenteral colistin not available in Japan, we treated MDR P. aeruginosa sepsis with monobactam and aminoglycoside combination therapy, with screening using a ‘break-point checkerboard plate’.

A surveillance of high-level gentamicin-resistant enterococcal bacteremia

Enterococci have recently been recognized as a causative organism of intractable infections, including severe sepsis and infective endocarditis, in immunocompromised patients. This study investigated the epidemiological, microbiological, and prognostic characteristics of high-level gentamicin-resistant (HLGR) enterococcal bacteremia, including severe cases of infective endocarditis, in Japan. A total of 155 enterococcal bacteremia episodes were identified between July 2007 and December 2009. HLGR strains accounted for 28% of all enterococcal strains: HLGR Enterococcus faecalis/Enterococcus faecium strains accounted for 32%/24%. The 30-day mortality rate was 31%. There was no significant difference in the 30-day mortality rates between HLGR and non-HLGR enterococcal bacteremia. There were two cases of HLGR enterococcal endocarditis, which were successfully treated with ampicillin plus ceftriaxone. We consider it important to examine the presence or absence of HLGR strains in all cases of intractable enterococcal infection, especially infective endocarditis.

Serum (1,3)-beta-D-glucan is an inefficient marker of breakthrough candidemia

The aim of this study was to evaluate the usefulness of serum (1,3)-beta-D-glucan (BDG) for earlier detection of breakthrough candidemia. We reviewed the medical records of patients with candidemia from January 2008 to March 2013. Serum BDG was measured by Wako turbidimetric assay. During the study period, a total of 147 cases of candidemia were identified, and 31 patients met the criteria for breakthrough candidemia. Serum BDG levels were measured in 25 patients with breakthrough candidemia and 67 patients with nonbreakthrough candidemia. Almost all of the patients with breakthrough candidemia had hematological malignancies. More candidemia were caused by non-C. albicans Candida in the breakthrough group than in the nonbreakthrough group (92.0% vs. 61.8%, p = .005). The median BDG value was significantly lower in breakthrough episodes than in non-breakthrough episodes (18.5 pg/ml vs. 90.4 pg/ml, p = .01). Moreover, BDG values under the cutoff was significantly higher in patients with breakthrough candidemia than in those with nonbreakthrough candidemia (44% vs. 19%, p = .03). In summary, BDG alone was insufficient to detect breakthrough candidemia, and candidemia could occur in patients being treated with antifungal agents, even when the BDG value was under the cutoff value.

Aeromonas caviae is the most frequent pathogen amongst cases of Aeromonas bacteremia in Japan

Abstract Background: Aeromonas species can cause various infections including bacteremia, gastroenteritis, cholangitis, and wound infections. To date, most studies on Aeromonas species have been reported from countries other than Japan. The aim of this study, therefore, was to evaluate Aeromonas bacteremia in Japan. Methods: We reviewed the medical records of patients with Aeromonas bacteremia from January 1994 to December 2010 in Toranomon Hospital, Tokyo, and Toranomon Hospital Kajigaya, Kanagawa, Japan. Results: Thirty-six cases of Aeromonas bacteremia were identified. Of these 36 strains, 18 were Aeromonas caviae, 13 were Aeromonas hydrophila, and 5 were Aeromonas veronii biovar sobria. The underlying diseases were solid tumor (21 cases), chronic hepatic disease (13 cases), diabetes mellitus (9 cases), hematological malignancies (4 cases), autosomal dominant polycystic kidney disease (2 cases), and aplastic anemia (2 cases). Patients with a solid tumor more frequently presented with A. caviae bacteremia than non-A. caviae bacteremia (14/18 vs 7/18; p = 0.041). Additionally, 16 of the 36 episodes were polymicrobial, and of these, 12 had stenosis or stasis of the bile duct or pancreatic duct (75%). The overall 30-day mortality was 19%. Conclusions: To the best of our knowledge, this is the first report to identify A. caviae as the most frequent causative pathogen of Aeromonas bacteremia in Japan. Additionally, compared with previous studies, most patients in our study had solid tumors. These findings suggest that the characteristics of Aeromonas bacteremia vary among study populations.

Cunninghamella bertholletiae pneumonia showing a reversed halo sign on chest computed tomography scan following cord blood transplantation

This is the first reported case of a patient who developed fungal pneumonia caused by Cunninghamella bertholletiae (= C. elegans) following cord blood transplantation and who showed a reversed halo sign on a chest computed tomography scan (CT). In addition, the pathological findings related to the reversed halo sign are described in detail for the first time. The patient died due to respiratory failure and at autopsy, a consolidation corresponding to the reversed halo sign noted on CT was found histologically to be composed of a central infarct with some retained air spaces surrounded by a peripheral ring-like hemorrhagic band. Pulmonary vasculatures were occluded by thrombi containing numerous Zygomycetes hyphae within the central infarct and less frequently along the surrounding hemorrhagic band. A reversed halo sign may be an early marker to initiate preemptive therapy against Zygomycetes including C. bertholletiae.