Association between Platelet-Associated Immunoglobulin G Levels and Response to Corticosteroid Therapy in Patients with Newly Diagnosed Immune Thrombocytopenia.

OBJECTIVE: Platelet-associated immunoglobulin G (PA-IgG) refers to IgG attached to the surface of platelets, while the immature platelet fraction (IPF) reflects the state of platelet production in bone marrow. Since PA-IgG and IPF are increased in patients with immune thrombocytopenia (ITP), reflecting amounts of platelet antibodies and compensatory platelet production, respectively, we hypothesized that these laboratory findings may provide useful markers for predicting treatment response in patients with ITP. We therefore retrospectively investigated associations between levels of these markers at diagnosis and response to first-line therapy in patients with ITP. METHODS: Forty-three patients diagnosed with ITP at Oita Kouseiren Tsurumi Hospital between May 2010 and November 2018 were included. Patients were divided into 2 groups based on response to corticosteroid as first-line therapy. Laboratory findings were compared between responders and nonresponders. RESULTS: Median PA-IgG was 285 ng/107 cells (range, 45.5-18,200 ng/107 cells), and median IPF was 15.5% (range, 5.4-62.1%). Median levels were higher than the respective upper limits of normal range (PA-IgG, 0-46 ng/107 cells; IPF, 1.1-9.5%). First-line therapy was performed using standard-dose prednisolone (0.5-1.0 mg/kg/day) in 32 patients and high-dose dexamethasone (40 mg/day, 4 days) or methylprednisolone (125-1,000 mg/day, 3-4 days) in 11 patients. Twenty-four patients (55.8%) responded to first-line therapy. In univariate analysis, type of corticosteroid (p = 0.17) tended to differ between groups but did not differ significantly, and no difference in IPF level was apparent between responders (15.35%; range, 5.4-41.5%) and nonresponders (16.7%; range, 6.3-62.1%; p = 0.15). PA-IgG was significantly higher among nonresponders (430 ng/107 cells; range, 101-18,200 ng/107 cells) than among responders (254.5 ng/107 cells; range, 45.5-470 ng/107 cells; p = 0.004). Multivariate analysis revealed PA-IgG was independently associated with response to first-line therapy (odds ratio, 1.000; 95% confidence interval, 1.000-1.010; p = 0.029). CONCLUSION: Our data suggested that PA-IgG at diagnosis could offer a useful predictor of response to first-line corticosteroid therapy for ITP.

Kinetics and clinical significance of human herpesvirus 6 DNA shedding in saliva after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Little is known about the kinetics and clinical significance of saliva human herpesvirus-6 (HHV-6) DNA after hematopoietic stem cell transplantation (HSCT). METHODS: In this observational study, we quantified HHV-6 DNA in serially collected plasma and saliva from allogeneic HSCT recipients. Associations between the status of salivary HHV-6 DNA and the development of HHV-6 encephalitis, depression, and oral mucosal graft-versus-host disease (GVHD) were retrospectively analyzed. RESULTS: A total of 787 plasma and 434 saliva samples were collected from 56 patients. The cumulative incidence of HHV-6 DNA in plasma and saliva at 60 days after transplantation was 51.8% and 83.9%, respectively. The peak level of salivary HHV-6 DNA was significantly higher in patients who displayed plasma HHV-6 DNA than in those who did not (median, 51,584 copies/mL vs 587 copies/mL; P < .0001). Salivary HHV-6 DNA levels increased after positive plasma HHV-6 DNA was detected and remained high during observation period. Despite the frequent occurrence of positive salivary HHV-6 DNA, no patient developed depression. Positivity of salivary HHV-6 DNA was not significantly associated with the development of HHV-6 encephalitis (P = 1.00, Fisher's exact test) or oral mucosal GVHD (P = .71, Grey's test). No significant relationship between salivary HHV-6 DNA and these diseases was found even when comparing higher HHV-6 DNA loads in saliva. CONCLUSION: Salivary HHV-6 DNA levels increased after HHV-6 DNA was detected in the blood. However, no epidemiological evidence was shown to support a role of salivary HHV-6 in the development of HHV-6 encephalitis, depression, and oral mucosal GVHD.

Prognostic implications of TdT expression in acute myeloid leukemia with an intermediate-risk karyotype.

Terminal deoxynucleotidyl transferase (TdT) is expressed on precursor lymphoblastic neoplasms and some acute myeloid leukemia (AML) cells. The clinical impact of TdT expression on AML outcomes remains unclear. Here, we conducted a retrospective analysis to identify prognostic implications of TdT expression in AML with an intermediate-risk karyotype. Forty-eight cases of intermediate-risk AML were enrolled. TdT positivity was defined as expression on ≥ 10% of the gated cells. Of 48 cases, 12 (25%) were positive for TdT [median expression rate of TdT 0.9% (range 0-86.9%)]. No significant differences in patient characteristics or complete remission rate were observed between TdT-positive and TdT-negative cases. The probability of overall survival (OS) and event-free survival (EFS) at 1 year was not significantly different between TdT-positive and TdT-negative cases (OS: 58.3% vs. 65.2%, p = 0.32; EFS: 33.3% vs. 57.1%, p = 0.06). Relapse-free survival (RFS) probability at 1 year was significantly lower for TdT-positive than TdT-negative cases (10% vs. 71.3%, p = 0.002). Multivariate analyses revealed that TdT positivity was an independent significant adverse factor for RFS [hazard ratio: 3.309, 95% confidence interval: 1.334-8.209, p = 0.009]. Our results suggest that TdT expression is associated with increased risk of relapse in patients with intermediate-risk AML.

Correlations of cytokine levels in cerebrospinal fluid and peripheral blood with outcome of HHV-6B encephalitis after hematopoietic stem cell transplantation.

BACKGROUND: Human herpesvirus (HHV)-6B encephalitis has been recognized as a serious complication after allogeneic hematopoietic cell transplantation (allo-HCT). Little is known about the pathogenic mechanism for its progression. STUDY DESIGN: We retrospectively evaluated the 16 kinds of cytokines and chemokines in cerebrospinal fluid (CSF) and plasma in patients who developed HHV-6B encephalitis. Among a total of 20 patients, 12 were categorized as the poor prognosis group (died of encephalitis; n = 8 and retained sequelae; n = 4), and other eight patients were categorized as the good prognosis group (complete recovery; n = 8). RESULTS: Concentrations of CSF IL-6 and IL-8 at the onset of encephalitis were significantly higher in the poor prognosis group than in the good prognosis group (median CSF IL-6, 28.27 pg/mL vs 14.32 pg/mL, P = .004; median CSF IL-8, 128.70 pg/mL vs 59.43 pg/mL, P = .043). Regarding plasma, the concentration of each cytokine at the onset of encephalitis was not significantly different between the two groups, except IL-5. However, higher levels of IL-6, IL-7, and MCP-1 and lower levels of IL-12 were observed 1 week before the development of encephalitis in patients with poor prognosis (median IL-6; 464.17 pg/mL vs 47.82 pg/mL, P = .02; median IL-12; 1.63 pg/mL vs 6.57 pg/mL, P = .03). CONCLUSION: We found that one week before onset of HHV-6B encephalitis, poor prognosis patients had high plasma concentrations of IL-6, IL-7, and MCP-1 and low concentrations of IL-12. At the onset of encephalitis, high concentrations of IL-6 and IL-8 in CSF were more common in the poor prognosis group, consistent with other evidence that IL-6 can have a role in CNS disturbances. Our findings show that specific cytokine status is associated with severe brain damage in patients with HHV-6B encephalitis, demonstrate prognostic value of plasma IL-6 concentrations, and suggest evaluation of anti-cytokine therapeutics in patients with HHV-6B encephalitis.

Comparison of HHV-6 DNA detection in plasma and whole blood in allogeneic hematopoietic stem cell transplant recipients: frequent false-positive results for active HHV-6 infection using whole blood samples.

In this prospective observational study, we compared the human herpesvirus-6 (HHV-6) DNA load in serially collected paired plasma and whole blood (WB) samples from allogeneic hematopoietic stem cell transplantation (HSCT) recipients. A total of 721 paired samples were collected from 68 recipients. The positive rate for HHV-6 DNA was 9.7 and 35.0% in plasma and WB samples, respectively (P < 0.001). The correlation of HHV-6 DNA load between plasma and WB was poor (R2 = 0.250). After reaching peak levels, HHV-6 DNA showed a delayed decrease in WB in comparison with plasma (median, 28 versus 7 days, P < 0.001). We additionally tested HHV-6 mRNA status in 95 samples from eight patients. To identify positive HHV-6 mRNA, plasma HHV-6 DNA showed 55.0% sensitivity and 100% specificity, whereas WB HHV-6 DNA showed 90.0% sensitivity and 68.0% specificity. The false-positive rate for identifying positive HHV-6 mRNA was 0% for plasma HHV-6 DNA and 32.0% for WB HHV-6 DNA. Although WB was more sensitive than plasma for detecting HHV-6 reactivation, the rates of false positivity for active HHV-6 infection were higher for WB than for plasma.

Analysis of five cases of human herpesvirus-6 myelitis among 121 cord blood transplantations.

Reports of myelitis associated with human herpesvirus-6 (HHV-6) following allogeneic transplantation are rare. Of 121 cases of cord blood transplantation (CBT) performed at Nagano Red Cross Hospital, five cases (4.1%) of HHV-6 myelitis developed at around the time of engraftment. The major symptom identified in all five patients was superficial pain or pruritus linked to segmental levels of the spinal cord. Other identified symptoms were fever or low-grade fever in all five patients, autonomic nerve disorder in four patients, bladder and rectal disturbance in two patients, and extrapyramidal disorder in two patients. These symptoms were experienced primarily 16-39 days after CBT. HHV-6 PCR tests were all positive for cerebrospinal fluid and for plasma. Of the four cases tested by magnetic resonance imaging (MRI), three showed spinal cord abnormality. Antiviral therapy using foscarnet or ganciclovir was effective in every case. Although one case treated from 12 days after onset experienced long-term pain resembling postherpetic neuralgia, symptoms in the four cases were completely relieved after antiviral therapy. In summary, the major symptoms of HHV-6 myelitis were superficial pain linked to segmental levels of the spinal cord. Prognosis may be improved by early initiation of antiviral therapy.

Successful Cord Blood Stem Cell Transplantation for an Adult Case of Chronic Active Epstein-Barr Virus Infection.

A 41-year-old man was referred to our hospital for treatment of anaplastic lymphoma kinase (ALK)-negative anaplastic large cell lymphoma. Chronic active Epstein-Barr virus (CAEBV) was diagnosed based on the findings of elevated EBV antibody titers and positive EBV-DNA in the peripheral blood, and cord blood stem cell transplantation (CBT) was performed. The EBV-DNA levels in the blood fell below the limit of detection. His lymphoma relapsed on Day 165 with the appearance of eruptions, which disappeared after the withdrawal of tacrolimus. One year after transplantation, there were no signs of recurrence. This encouraging result suggests that CBT should be considered for adult cases of CAEBV with aggressive clinical manifestations.

Human herpesvirus 6 (HHV-6) reactivation and HHV-6 encephalitis after allogeneic hematopoietic cell transplantation: a multicenter, prospective study.

BACKGROUND: The epidemiology of human herpesvirus 6 (HHV-6) encephalitis after allogeneic hematopoietic cell transplantation (HCT) and its relationship with HHV-6 reactivation have not been sufficiently characterized. METHODS: This prospective, multicenter study of 230 allogeneic HCT recipients investigated the epidemiology of HHV-6 reactivation and HHV-6 encephalitis. Plasma HHV-6 DNA load was prospectively evaluated twice weekly until 70 days after HCT. RESULTS: Cumulative incidence of positive HHV-6 DNA and high-level HHV-6 reactivation (plasma HHV-6 DNA ≥10(4) copies/mL) at day 70 after HCT was 72.2% and 37.0%, respectively. Multivariate analysis identified myeloablative conditioning (hazard ratio [HR], 1.9; P = .004), umbilical cord blood transplantation (UCBT) (HR, 2.0; P = .003), and male sex (HR, 1.6; P = .04) as risk factors for displaying high-level HHV-6 reactivation. HHV-6 encephalitis occurred in 7 patients, and cumulative incidence at day 70 was 3.0%. None of the144 patients without high-level HHV-6 reactivation and 7 of 86 patients (8.1%) with high-level HHV-6 reactivation developed HHV-6 encephalitis (P = .0009). Prevalence of HHV-6 encephalitis was significantly higher among patients receiving UCBT than in patients with other sources (cumulative incidence at day 70, 7.9% vs 1.2%, P = .008). In each of 7 patients with HHV-6 encephalitis, central nervous system (CNS) symptoms developed concomitant with peak plasma HHV-6 DNA (range, 21 656-433 639 copies/mL). CONCLUSIONS: High levels of plasma HHV-6 DNA are associated with higher risk of HHV-6 encephalitis. UCBT is a significant risk factor for HHV-6 encephalitis. HHV-6 encephalitis should be considered if CNS dysfunction develops concomitant to high-level plasma HHV-6 DNA after allogeneic HCT.

High incidence of cytomegalovirus, human herpesvirus-6, and Epstein-Barr virus reactivation in patients receiving cytotoxic chemotherapy for adult T cell leukemia.

The etiology of cytomegalovirus (CMV), human herpesvirus-6 (HHV-6), and Epstein-Barr virus (EBV) reactivation and the potential for complications following cytotoxic chemotherapy in the absence of allogeneic transplantation are not clearly understood. Patients with adult T cell leukemia (ATL) are susceptible to opportunistic infections. In this study, the incidence, kinetics and clinical significance of reactivation of CMV, HHV-6, and EBV in ATL patients were investigated. Viral DNA in a total of 468 plasma samples from 34 patients was quantified using real-time PCR. The probability of CMV, HHV-6, and EBV reactivation by 100 days after the start of chemotherapy was 50.6%, 52.3%, and 21.6%, respectively. Although most CMV reactivations were self-limited, plasma CMV DNA tended to persist or increase if the CMV DNA levels in plasma reached ≥ 10(4) copies/ml. CMV reactivation was negatively associated with survival, but the P-value for this association was near the borderline of statistical significance (P=0.052). One patient developed fatal interstitial pneumonia concomitant with peak CMV DNA accumulation (1.6 × 10(6) copies/ml plasma). Most HHV-6 and EBV reactivations were self-limited, and no disease resulting from HHV-6 or EBV was confirmed. HHV-6 and EBV reactivation were not associated with reduced survival (P=0.35 and 0.11, respectively). These findings demonstrated that subclinical reactivation of CMV, HHV-6, and EBV were common in ATL patients receiving chemotherapy. There were differences in the viral reactivation patterns among the three viruses. A CMV load ≥ 10(4) copies/ml plasma was indicative of subsequent exacerbation of CMV reactivation and developing serious clinical course.

Human herpesvirus 6 DNA in plasma after allogeneic stem cell transplantation: incidence and clinical significance.

BACKGROUND: Human herpesvirus 6 (HHV-6) is increasingly recognized as an opportunistic and potentially life-threatening pathogen in recipients of allogeneic stem cell transplants (SCTs). METHODS: To clarify the incidence and clinical relevance of active HHV-6 infection, serial titers of plasma HHV-6 DNA were determined for 50 allogeneic SCT recipients, using real-time polymerase chain reaction. RESULTS: HHV-6 DNA was detected in plasma from 24 patients (48%). HHV-6 DNA was most frequently apparent approximately 14-27 days after transplantation. An increased risk of a positive result for HHV-6 DNA was associated with transplantation from an allelic-mismatch donor (P = .02) and administration of steroids (P = .04). Steroid use was associated with high HHV-6 DNA loads (P = .02). High HHV-6 DNA loads were correlated with delayed platelet engraftment (P = .04). Among patients who had positive results for HHV-6 DNA, the HHV-6 DNA load was higher in plasma from those who developed limbic encephalitis (n = 4) (P < .0001). CONCLUSIONS: Active HHV-6 infection is not rare in SCT recipients. SCT from allelic-mismatch donors is associated with increased risk of active HHV-6 infection. Steroid therapy is associated with not only increased incidence of infection but also accelerated viral replication. Development of limbic encephalitis is associated with high HHV-6 DNA load.