Specific COVID-19 risk behaviors and the preventive effect of personal protective equipment among healthcare workers in Japan.

As coronavirus disease 2019 (COVID-19) outbreaks in healthcare facilities are a serious public health concern, we performed a case-control study to investigate the risk of COVID-19 infection in healthcare workers. We collected data on participants' sociodemographic characteristics, contact behaviors, installation status of personal protective equipment, and polymerase chain reaction testing results. We also collected whole blood and assessed seropositivity using the electrochemiluminescence immunoassay and microneutralization assay. In total, 161 (8.5%) of 1,899 participants were seropositive between August 3 and November 13, 2020. Physical contact (adjusted odds ratio 2.4, 95% confidence interval 1.1-5.6) and aerosol-generating procedures (1.9, 1.1-3.2) were associated with seropositivity. Using goggles (0.2, 0.1-0.5) and N95 masks (0.3, 0.1-0.8) had a preventive effect. Seroprevalence was higher in the outbreak ward (18.6%) than in the COVID-19 dedicated ward (1.4%). Results showed certain specific risk behaviors of COVID-19; proper infection prevention practices reduced these risks.

Bacterial bloodstream infection in neutropenic adult patients after myeloablative cord blood transplantation: experience of a single institution in Japan.

Bacterial infection is one of the most important causes of morbidity and mortality after unrelated cord blood transplantation (CBT). In the present study, we studied 101 adult patients with respect to the incidence, outcome, and risk factors for bacterial bloodstream infection (BSI) within 30 days after CBT using a myeloablative conditioning regimen. Bacterial BSI occurred in 12 patients within 30 days after CBT. The cumulative incidence of bacterial BSI was 12%. The median time of onset was day +6 (range, day -1 to day +13) after CBT. In all patients, the neutrophil count was 0/microL at the onset of bacterial BSI. Eight (67%) and 4 (33%) of the isolates were Gram-positive and Gram-negative bacteria, respectively. Only 2 (17%) of the 12 patients who had bacterial BSI died within 100 days after CBT. No risk factors for the occurrence of bacterial BSI within 30 days after CBT were identified. The low mortality rate for bacterial BSI in the neutropenic period appeared to be associated with the low incidence (6%) of transplantation-related death at day +100 in our study patients. Early diagnosis of bacterial BSI and prompt treatment with effective antibiotics are necessary for neutropenic adult patients after myeloablative CBT.

Pancreatic hyperamylasemia and hyperlipasemia in association with cytomegalovirus infection following unrelated cord blood transplantation for acute myelogenous leukemia.

Cytomegalovirus (CMV)-associated pancreatitis is rare after allogeneic hematopoietic stem cell transplantation (SCT). We describe a patient who developed pancreatic hyperamylasemia and hyperlipasemia in association with CMV infection after cord blood transplantation (CBT). A 31-year-old man with acute myelogenous leukemia underwent CBT. A neutrophil count consistently greater than 500/microL was achieved on day +21. Positive results for CMV antigenemia on days +35 and +67 prompted 2 courses of preemptive therapy with ganciclovir or foscarnet. The CMV antigenemia value again became positive on day +134. On day +141, serum amylase and lipase activities markedly increased to 1221 IU/L and 894 IU/L, respectively. The patient had no abdominal symptoms. Ultrasonography and computed tomography results showed no abnormalities of the pancreas. A diagnosis of possible pancreatitis was made. After the initiation of foscarnet therapy, the CMV antigenemia results soon became negative, and serum amylase and lipase activities returned to normal. Therefore, CMV infection was considered to play a major role in the development of pancreatic hyperamylasemia and hyperlipasemia in our patient. The present report indicates that CMV infection should be included in the differential diagnosis for patients with pancreatic hyperamylasemia after SCT.

Varicella-zoster virus encephalitis in a patient undergoing unrelated cord blood transplantation for myelodysplastic syndrome-overt leukemia.

Varicella-zoster virus (VZV) infection of the central nervous system (CNS) is rare after hematopoietic stem cell transplantation (SCT). Here, we describe the first patient who developed VZV encephalitis after cord blood transplantation (CBT). A 35-year-old man with myelodysplastic syndrome-overt leukemia underwent CBT. On day +23, a neutrophil count consistently greater than 0.5 x 10(9)/L was achieved. On day +42, 1 mg/kg per day of prednisolone therapy was initiated for grade III acute graft-versus-host disease (GVHD). Then, the dose of prednisolone was slowly reduced. For exacerbation of chronic GVHD, the dose of prednisolone was again increased to 1 mg/kg per day on day +231. On day +265, localized cutaneous zoster in the left thoracic region occurred, but soon resolved after acyclovir therapy. On day +309, he suddenly developed diplopia. Subsequently, right facial palsy and hearing impairment occurred. No skin rash was observed. Magnetic resonance imaging (MRI) scans revealed multifocal abnormal high-signal intensity in the CNS. A high level of VZV DNA was detected in a cerebrospinal fluid specimen. He was diagnosed with VZV encephalitis. Acyclovir was given intravenously for 40 days. Four months after the onset, the neurologic symptoms had incompletely resolved. MRI scans showed substantial resolution but with mild residual lesions. The present report indicates that VZV should be considered as a possible causative agent in patients who develop multifocal neurologic symptoms of the CNS after SCT.

Hemorrhagic cystitis in adults after unrelated cord blood transplantation: a single-institution experience in Japan.

Hemorrhagic cystitis (HC) is the main complication after hematopoietic stem cell transplantation (SCT). Adenovirus (AdV) is the leading cause of late-onset HC after SCT in Japan. The incidence and outcome of HC were studied in 77 adults who underwent unrelated cord blood transplantation (CBT). Thirty-two patients developed HC in a median of 19 days (range, 11-170 days) after CBT. The cumulative incidence of HC was 41.8% at 1 year. Ten patients developed gross hematuria. The cumulative incidence of moderate-to-severe HC was 13.2% at 1 year. Only 1 patient developed severe HC; AdV was detected in a urine sample from that patient. AdV was also detected in a urine sample from another patient with moderate HC after CBT. AdV in both patients was identified as AdV type 11. The cumulative incidence of AdV-induced HC was 2.8% at 1 year. The incidence of AdV-induced severe HC after CBT may be relatively low among Japanese adults. The role of other viruses, including BK virus, in the pathogenesis of HC after CBT needs to be examined.

Human herpesvirus 6 variant B infection in adult patients after unrelated cord blood transplantation.

Human herpesvirus 6 variant B (HHV-6B) infection was studied in 23 adult patients who underwent cord blood transplantation (CBT). HHV-6B DNA was detected by quantitative polymerase chain reaction analysis after CBT in the sera from 15 patients (65%) at day 14 or 15 (week 2), from 16 patients (70%) at day 21 or 22 (week 3), and from 3 patients (13%) at day 28 or 29 (week 4). HHV-6B DNAemia was found in none of the 20 patients examined at day 7 or 8 (week 1). The overall incidence of HHV-6B DNAemia reached 87% (20 of 23 patients). This incidence was much higher than after unrelated bone marrow transplantation (19%, P < .0001). In CBT patients, positive HHV-6B DNAemia at week 3 was significantly associated with early skin rash (88% versus 14%, P < .005) and grade II-IV acute graft-versus-host disease (aGVHD) (69% versus 14%, P < .05). In contrast, positive HHV-6B DNAemia at week 2 was associated with neither skin rash nor aGVHD. Prospective large-scale studies are needed to determine the role of HHV-6 infection in CBT patients.

Unrelated cord blood transplantation after myeloablative conditioning for adult patients with refractory anemia.

We report the results of unrelated cord blood transplantation (CBT) after myeloablative conditioning in 3 patients with myelodysplastic syndrome-refractory anemia (MDS-RA). All patients were treated with total body irradiation, cytosine arabinoside (Ara-C), and cyclophosphamide, followed by unrelated HLA-mismatched CBT. Granulocyte colony-stimulating factor was infused continuously, starting 12 hours before Ara-C therapy and continuing until the end of Ara-C therapy. All patients received standard cyclosporine and methotrexate therapy as graft-versus-host disease prophylaxis. All patients had myeloid reconstitution, and the times to reach an absolute neutrophil count >0.5 x 10(9)/L were 23, 20, and 26 days. All patients showed full donor chimerism at the time of the first bone marrow examination (on day +42, +43, and +62) after CBT. All patients are alive and free of disease at between 17 and 39 months after CBT. These results suggest that adult MDS-RA patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Unrelated cord blood transplantation with a reduced-intensity conditioning regimen following autologous transplantation for multiple myeloma.

Two patients, 51- and 45-year-old men with stage III immunoglobulin G multiple myeloma, achieved partial and complete remissions, respectively, after conventional chemotherapy. They both received high-dose melphalan (200 mg/m2) with autologous stem cell transplantation (ASCT). Eighty-four and 78 days after ASCT, the patients underwent unrelated cord blood transplantation (CBT) following treatment with total-body irradiation (2 Gy), fludarabine (90 mg/m2), and melphalan (140 mg/m2). Neutrophil engraftment was attained on day +27 in patient 1 and day +15 in patient 2. Full donor chimerism of the marrow cells was confirmed. Regimen-related toxicity in both patients remained within grade I. Grades I and II acute graft-versus-host disease (GVHD) occurred in patients I and 2, respectively, but improved without steroid therapy. Both patients developed limited chronic GVHD of the skin but needed no treatment. The serum paraprotein level in patient 1 decreased further after ASCT and CBT but remained at minimally detectable levels. The serum and urine paraprotein levels in patient 2 remained below detectable limits. These results suggested that CBT with a reduced-intensity conditioning regimen after high-dose chemotherapy with ASCT is a new promising approach for the treatment of multiple myeloma.

Comparative single-institute analysis of cord blood transplantation from unrelated donors with bone marrow or peripheral blood stem-cell transplants from related donors in adult patients with hematologic malignancies after myeloablative conditioning regimen.

We studied the clinical outcomes of 171 adults with hematologic malignancies who received unrelated cord blood transplantation (CBT) as a primary unrelated stem-cell source (n=100), or bone marrow transplant (BMT) or peripheral blood stem-cell transplant (PBSCT) from related donors (n=71, 55 BMT and 16 PBSCT). All patients received myeloablative regimens including 12 Gy total body irradiation. We analyzed the hematologic recovery, and risks of graft-versus-host disease (GVHD), transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. Significant delays in engraftment occurred after cord blood transplantation; however, overall engraftment rates were almost the same for both grafts. The cumulative incidences of grades III to IV acute and extensive-type chronic GVHDs among CBT recipients were significantly lower than those among BMT/PBSCT recipients. Multivariate analysis demonstrated no apparent differences in TRM (9% in CBT and 13% in BMT/PBSCT recipients), relapse (17% in CBT and 26% in BMT/PBSCT recipients), and DFS (70% in CBT and 60% in BMT/PBSCT recipients) between both groups. These data suggest that unrelated cord blood could be as safe and effective a stem-cell source as related bone marrow or mobilized peripheral blood for adult patients when it is used as a primary unrelated stem-cell source.

Cord blood transplantation for acute myelogenous leukemia using a conditioning regimen consisting of granulocyte colony-stimulating factor-combined high-dose cytarabine, fludarabine, and total body irradiation.

The cytotoxic effect of cytarabine (Ara-C) on myeloid leukemic cells is enhanced by concomitant use of granulocyte colony-stimulating factor (G-CSF) in vitro. The feasibility of a conditioning regimen consisting of G-CSF-combined 24 g/m2 Ara-C, 90 mg/m2 fludarabine, and 12 Gy total body irradiation was studied for five patients with acute myelogenous leukemia in cord blood transplantation (CBT). Graft vs. host disease (GVHD) prophylaxis consisted of cyclosporine and methotrexate. After the conditioning regimen, 2.48 x 10(7)/kg (2.28-3.53) of cord blood nucleated cells was infused. Neutrophil counts consistently >0.5 x 10(9)/L was achieved 24 d (22-32) after CBT. Grade I stomatitis and gastrointestinal toxicities occurred in all patients. Grades I and II acute GVHD occurred in one and four patients, respectively, which resolved without steroid therapy. Sepsis and aspergillosis occurred in two and one patients, respectively. All patients were alive without leukemia relapse at a follow up of 15 months (12-43) after CBT. This conditioning regimen could avoid the toxicities of high-dose cyclophosphamide but might enhance the cytotoxic effect of Ara-C. Large-scale studies will be needed to determine the efficacy and safety of the conditioning regimen in CBT.

Tal1/Scl gene transduction using a lentiviral vector stimulates highly efficient hematopoietic cell differentiation from common marmoset (Callithrix jacchus) embryonic stem cells.

The development of embryonic stem cell (ESC) therapies requires the establishment of efficient methods to differentiate ESCs into specific cell lineages. Here, we report the in vitro differentiation of common marmoset (CM) (Callithrix jacchus) ESCs into hematopoietic cells after exogenous gene transfer using vesicular stomatitis virus-glycoprotein-pseudotyped lentiviral vectors. We transduced hematopoietic genes, including tal1/scl, gata1, gata2, hoxB4, and lhx2, into CM ESCs. By immunochemical and morphological analyses, we demonstrated that overexpression of tal1/scl, but not the remaining genes, dramatically increased hematopoiesis of CM ESCs, resulting in multiple blood-cell lineages. Furthermore, flow cytometric analysis demonstrated that CD34, a hematopoietic stem/progenitor cell marker, was highly expressed in tal1/scl-overexpressing embryoid body cells. Similar results were obtained from three independent CM ESC lines. These results suggest that transduction of exogenous tal1/scl cDNA into ESCs is a promising method to induce the efficient differentiation of CM ESCs into hematopoietic stem/progenitor cells.

Unrelated cord blood transplantation for adult patients with advanced myelodysplastic syndrome.

We report the results of unrelated cord blood transplantation (CBT) for 13 adult patients with advanced myelodysplastic syndrome (MDS). The median age was 40 years, the median weight was 51 kg, and the median number of infused nucleated cells was 2.43 x 107/kg. Twelve patients had myeloid reconstitution, and the median time to more than 0.5 x 109/L (5 x 108/L) absolute neutrophil count was 22.5 days. A self-sustained platelet count more than 50 x 109/L was achieved in 11 patients at a median time of 49 days. Acute graft versus host disease (GVHD) occurred in 9 of 12 evaluable patients and chronic GVHD in 8 of 11 evaluable patients. Ten patients are alive and free of disease at between 171 and 1558 days after transplantation. The probability of disease-free survival at 2 years was 76.2%. These results suggest that adult advanced MDS patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Varicella-zoster virus infection in adult patients after unrelated cord blood transplantation: a single institute experience in Japan.

Varicella-zoster virus (VZV) infection was studied in 40 adult patients who underwent cord blood transplantation (CBT) from unrelated donors. Twenty-five patients developed VZV reactivation at a median of 5 months after CBT (range 1.7-26 months). The cumulative incidence of VZV reactivation after CBT was 80% at 30 months. Twenty-two patients developed localized herpes zoster. The remaining three patients developed atypical non-localized herpes zoster, which was associated with visceral dissemination in one patient. All the patients responded well to antiviral therapy. Unexpectedly, the absence of grade II-IV acute graft-versus-host disease (GVHD) was associated with a higher rate of VZV reactivation after CBT (100% versus 55%, P=0.01). These results suggest that recovery of VZV-specific immune responses after CBT is delayed even in patients without severe acute GVHD.

Ganciclovir-related neutropenia after preemptive therapy for cytomegalovirus infection: comparison between cord blood and bone marrow transplantation.

We studied ganciclovir (GCV)-related neutropenia after preemptive therapy for cytomegalovirus infection: 9 of 17 (53%) cord blood transplantation (CBT) patients and 18 of 20 (90%) bone marrow transplantation (BMT) patients developed GCV-related neutropenia with an absolute neutrophil count (ANC) of less than 1,000/microl. Among the patients who did not receive granulocyte colony-stimulating factor, 2 (13%) and 1 (7%) CBT patients, and 10 (56%) and 8 (44%) BMT patients, developed neutropenia with an ANC of less than 500 and 250/microl, respectively. The incidences of neutropenia in patients with an ANC of less than 1,000, 500, and 250/microl were significantly lower after CBT in comparison with BMT. Two BMT patients, but no CBT patients, developed neutropenic fever, and both patients recovered after antibiotic therapy. In CBT patients, a creatinine clearance rate of less than 50 ml/min and an absence of steroid therapy were associated with a greater incidence of GCV-related neutropenia. No risk factors for GCV-related neutropenia were found in BMT patients. These results suggest that GCV may be less toxic to myeloid progenitor cells from cord blood than those from bone marrow.

Unrelated cord blood transplantation after myeloablative conditioning in patients over the age of 45 years.

We report the results of unrelated cord blood transplantation (CBT) after myeloablative conditioning in 21 patients over the age of 45 years. Among the patients the median age was 48 years (range, 45-53 years), the median weight was 58.6 kg (range, 43.6-76.2 kg) and the median number of cryopreserved nucleated cells was 2.45 x 10(7)/kg (range, 1.63-3.71 x 10(7)/kg). Nineteen patients had myeloid reconstitution and the median time to more than 0.5 x 10(9)/l absolute neutrophil count was 22 d. A self-sustained platelet count more than 50 x 10(9)/l was achieved in 17 patients at a median time of 49 d. Acute graft-versus-host disease (GVHD) above grade II occurred in 7 of 19 evaluable patients and chronic GVHD occurred in 14 of 16 evaluable patients. Among 14 chronic GVHD patients, in seven patients the disease was extensive. Fifteen patients were alive and free of disease at between 217 and 1798 d after transplantation. With a median follow-up of 847 d, the probability of disease-free survival at 2 years was 71.4%. These results suggest that patients over 45 years of age without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.

Single-institute comparative analysis of unrelated bone marrow transplantation and cord blood transplantation for adult patients with hematologic malignancies.

Unrelated cord blood transplantation (CBT) has now become more common, but as yet there have been only a few reports on its outcome compared with bone marrow transplantation (BMT), especially for adults. We studied the clinical outcomes of 113 adult patients with hematologic malignancies who received unrelated BM transplants (n = 45) or unrelated CB transplants (n = 68). We analyzed the hematopoietic recovery, rates of graft-versus-host disease (GVHD), risks of transplantation-related mortality (TRM) and relapse, and disease-free survival (DFS) using Cox proportional hazards models. The time from donor search to transplantation was significantly shorter among CB transplant recipients (median, 2 months) than BM transplant recipients (median, 11 months; P < .01). Multivariate analysis demonstrated slow neutrophil (P < .01) and platelet (P < .01) recoveries in CBT patients compared with BMT patients. Despite rapid tapering of immunosuppressants after transplantation and infrequent use of steroids to treat severe acute GVHD, there were no GVHD-related deaths among CB transplant recipients compared with 10 deaths of 24 among BM transplant recipients. Unrelated CBT showed better TRM and DFS results compared with BMT (P = .02 and P < .01, respectively), despite the higher human leukocyte antigen mismatching rate and lower number of infused cells. These data strongly suggest that CBT could be safely and effectively used for adult patients with hematologic malignancies.

Unrelated cord blood transplantation for adult patients with de novo acute myeloid leukemia.

We report the results of unrelated cord blood transplantation (CBT) for 18 adult patients with de novo acute myeloid leukemia (AML). The median age was 43 years, the median weight was 55.2 kg, and the median number of cryopreserved nucleated cells was 2.51 x 107/kg. Seventeen patients had myeloid reconstitution and the median time to more than 0.5 x 109/L absolute neutrophil count was 23 days. A self-sustained platelet count more than 50 x 109/L was achieved in 16 patients at a median time of 49 days. Acute graft-versus-host disease (GVHD) above grade II occurred in 11 of 17 evaluable patients and chronic GVHD occurred in 14 of 17 evaluable patients. Fourteen patients are alive and free of disease at between 185 and 1332 days after transplantation. The probability of disease-free survival at 2 years was 76.6%. These results suggest that adult AML patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT.