WBC image classification and generative models based on convolutional neural network.

BACKGROUND: Computer-aided methods for analyzing white blood cells (WBC) are popular due to the complexity of the manual alternatives. Recent works have shown highly accurate segmentation and detection of white blood cells from microscopic blood images. However, the classification of the observed cells is still a challenge, in part due to the distribution of the five types that affect the condition of the immune system. METHODS: (i) This work proposes W-Net, a CNN-based method for WBC classification. We evaluate W-Net on a real-world large-scale dataset that includes 6562 real images of the five WBC types. (ii) For further benefits, we generate synthetic WBC images using Generative Adversarial Network to be used for education and research purposes through sharing. RESULTS: (i) W-Net achieves an average accuracy of 97%. In comparison to state-of-the-art methods in the field of WBC classification, we show that W-Net outperforms other CNN- and RNN-based model architectures. Moreover, we show the benefits of using pre-trained W-Net in a transfer learning context when fine-tuned to specific task or accommodating another dataset. (ii) The synthetic WBC images are confirmed by experiments and a domain expert to have a high degree of similarity to the original images. The pre-trained W-Net and the generated WBC dataset are available for the community to facilitate reproducibility and follow up research work. CONCLUSION: This work proposed W-Net, a CNN-based architecture with a small number of layers, to accurately classify the five WBC types. We evaluated W-Net on a real-world large-scale dataset and addressed several challenges such as the transfer learning property and the class imbalance. W-Net achieved an average classification accuracy of 97%. We synthesized a dataset of new WBC image samples using DCGAN, which we released to the public for education and research purposes.

Natural-killer cell cytotoxicity as a diagnostic and prognostic marker for adult patients with secondary hemophagocytic lymphohistiocytosis: a prospective phase II observational study.

BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) can be life-threatening if not detected and treated appropriately. The diagnosis of HLH can be confusing due to other similar febrile diseases that present with cytopenia. Natural-killer cell (NK)-cytotoxicity is an important diagnostic parameter for primary HLH; however, its role in secondary HLH in adults has not been well-elucidated. METHODS: We prospectively enrolled 123 adult patients with febrile conditions accompanied by cytopenia or marrow hemophagocytosis. A diagnosis of HLH was based on HLH-2004 criteria and treated based on HLH-94 protocol. NK-cytotoxicity was calculated at the time of diagnosis by K562-cell direct lysis using flow-cytometry. RESULTS: HLH (n = 60) was determined to be caused by Epstein-Barr virus (EBV) (n = 11), infection other than EBV (n = 16), malignancies (n = 19), and unknown (n = 14). Febrile diseases other than HLH (n = 63) were diagnosed as autoimmune disease (n = 22), malignancies (n = 21), infection (n = 12), non-malignant hematological diseases (n = 6), and unknown (n = 2). A lower NK-cytotoxicity level was observed at diagnosis in patients with HLH, compared with other causes of febrile disease (12.1% versus 26.2%, p < 0.001). However, NK-cytotoxicity had a borderline effect on diagnosis of HLH, with an area under receiver operation characteristic curve of 0.689. It also showed no significant role for the prediction of survival outcome. Multivariate analysis revealed that malignant disease and high ferritin level were related with poor survival outcome. In non-malignant disease subgroups, old age, EBV-association, and low NK-cytotoxicity were related with poor survival. CONCLUSIONS: Febrile disease with cytopenia was associated with decreased NK-cytotoxicity, especially in adults with HLH; however, its diagnostic role for adult HLH is still arguable. The diagnostic criteria for adult HLH should be further discussed. TRIAL REGISTRATION: Clinical Research Information Service [Internet]; Osong (Chungcheongbuk-do), Korea, Centers for Disease Control and Prevention, Ministry of Health and Welfare (Republic of Korea); https://cris.nih.go.kr/cris/index.jsp; Feb, 16th 2016; KCT0001886 (KC15TISE0936).

Non-inferior long-term outcomes of adults with Philadelphia chromosome-like acute lymphoblastic leukemia.

Philadelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is associated with inferior outcomes in the chemotherapy setting. We hypothesized that allogeneic hematopoietic cell transplantation (allo-HCT)-based post-remission therapy would improve outcomes of this entity. We examined the frequency and long-term outcomes of adults with Ph-like ALL, particularly focusing on allo-HCT outcomes for Ph-like ALL versus non-Ph-like ALL. Ph-like ALL was determined by anchored multiplex PCR-based targeted next-generation sequencing. Of the 344 patients, 57 (16.6%) had Ph-like ALL, 197 (57.3%) had Ph-positive ALL, and 90 (26.1%) had B-other ALL. To further evaluate the prognosis of Ph-like ALL, outcome analyses were restricted to 147 patients, excluding Ph-positive ALL. The actual allo-HCT rates in complete remission were 87.7% for Ph-like ALL, 71.4% for B-other standard-risk ALL, and 70.4% for B-other poor-risk ALL. Patients with Ph-like ALL had a higher 5-year overall survival (60.6% vs 27.1%; P = 0.008) than B-other poor-risk ALL subgroup, while no difference was observed compared with B-other standard-risk ALL subgroup. Similar results were noted in a separate analysis for patients receiving allo-HCT in complete remission. In multivariate analyses, B-other poor-risk ALL was associated with poorer outcomes. Our data showed that allo-HCT-based post-remission therapy may have contributed to non-inferior outcomes of adult Ph-like ALL.

KRAS, NRAS, and BRAF mutations in plasma cell myeloma at a single Korean institute.

BACKGROUND: Plasma cell myeloma (PCM) is a genetically heterogeneous disease. The genetic spectrum of PCM has been expanded to mutations such as KRAS, NRAS, and BRAF genes in the RAS-RAF-MAPK pathway. In this study, we have evaluated the frequency of these mutations and their significance, including baseline characteristics and clinical outcomes. METHODS: We explored 50 patients who were newly diagnosed with PCM between 2009 and 2012 at a single Korean institute. Clinical and laboratory parameters were gathered through careful review of medical records. Mutation analysis was carried out using DNA from the bone marrow at the time of diagnosis. Pyrosequencing was performed to detect KRAS G12V, KRAS G13D, and NRAS G61R. BRAF V600E was analyzed by allele-specific real- time PCR. Comparison of clinical and laboratory parameters was carried out according to those mutations. RESULTS: We identified 14 patients (28%) with activating mutations in the RAS-RAF-MAPK pathway (RAS/RAF mutations): KRAS (N=3), NRAS (N=4), BRAF (N=7), and both KRAS and BRAF (N=1). RAS/RAF mutations were more frequently observed in patients with complex karyotypes and showed poorer progression free survival (PFS). Specifically, the BRAF V600E mutation had a significantly negative impact on median PFS. CONCLUSION: We first showed the frequency of RAS/RAF mutations in Korean patients with PCM. Screening of these mutations could be considered as a routine clinical test at the time of diagnosis and follow-up due to their influence on clinical outcome, as well as its potential as a therapeutic target.

Delayed NK Cell Reconstitution and Reduced NK Activity Increased the Risks of CMV Disease in Allogeneic-Hematopoietic Stem Cell Transplantation.

Cytomegalovirus (CMV) infection has a significant impact in patients after allogeneic hematopoietic stem cell transplantation (HSCT). We investigated natural killer (NK) cell reconstitution and cytotoxic/cytokine production in controlling CMV infection, especially severe CMV disease in HSCT patients. Fifty-eight patients with acute myeloid leukemia (AML) who received allo-HSCT were included. We monitored NK reconstitution and NK function at baseline, 30, 60, 90, 120, 150, and 180 days after HSCT, and compared the results in recipients stratified on post-HSCT CMV reactivation (n = 23), non-reactivation (n = 24) versus CMV disease (n = 11) groups. The CMV disease group had a significantly delayed recovery of CD56dim NK cells and expansion of FcRγ-CD3ζ+NK cells started post-HSCT 150 days. Sequential results of NK cytotoxicity, NK cell-mediated antibody-dependent cellular cytotoxicity (NK-ADCC), and NK-Interferon-gamma (NK-IFNγ) production for 180 days demonstrated delayed recovery and decreased levels in the CMV disease group compared with the other groups. The results within 1 month after CMV viremia also showed a significant decrease in NK function in the CMV disease group compared to the CMV reactivation group. It suggests that NK cells' maturation and cytotoxic/IFNγ production contributes to CMV protection, thereby revealing the NK phenotype and functional NK monitoring as a biomarker for CMV risk prediction, especially CMV disease.

Clonal Cell Proliferation in Paroxysmal Nocturnal Hemoglobinuria: Evaluation of PIGA Mutations and T-cell Receptor Clonality.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired pluripotent hematopoietic stem cell disorder associated with an increase in the number of glycosyl-phosphatidyl inositol (GPI)-deficient blood cells. We investigated PNH clonal proliferation in the three cell lineages-granulocytes, T lymphocytes, and red blood cells (RBCs)-by analyzing PIGA gene mutations and T-cell receptor (TCR) clonality. METHODS: Flow cytometry was used on peripheral blood samples from 24 PNH patients to measure the GPI-anchored protein (GPI-AP) deficient fraction in each blood cell lineage. PIGA gene mutations were analyzed in granulocytes and T lymphocytes by Sanger sequencing. A TCR clonality assay was performed in isolated GPI-AP deficient T lymphocytes. RESULTS: The GPI-AP deficient fraction among the three lineages was the highest in granulocytes, followed by RBCs and T lymphocytes. PIGA mutations were detected in both granulocytes and T lymphocytes of 19 patients (79.2%), with a higher mutation burden in granulocytes. The GPI-AP deficient fractions of granulocytes and T lymphocytes correlated moderately (rs=0.519, P=0.049) and strongly (rs=0.696, P=0.006) with PIGA mutation burden, respectively. PIGA mutations were more frequently observed in patients with clonal rearrangements in TCR genes (P=0.015). The PIGA mutation burden of T lymphocytes was higher in patients with clonal TCRB rearrangement. CONCLUSIONS: PIGA mutations were present in approximately 80% of PNH patients. PNH clone size varies according to blood cell lineage, and clonal cells may obtain proliferation potential or gain a survival advantage over normal cells.

Reclassification of Acute Myeloid Leukemia According to the 2016 WHO Classification.

We reviewed our leukemia database to reclassify 610 patients previously diagnosed as having acute myeloid leukemia (AML) according to the updated 2016 WHO classification. Nine patients were categorized as having myelodysplastic syndrome and myeloid neoplasms with germline predisposition. AML with recurrent genetic abnormalities accounted for 57.4% (345/601) of the patients under the 2016 WHO classification. AML with mutated NPM1 was the most common form (16.5%), with the majority associated with monocytic differentiation (63.6%). AML with double CEBPA mutations accounted for 8.3% of these cases, and the majority were previously diagnosed as AML with/without maturation (78.0%). These newly classified mutations were mutually exclusive without overlapping with other forms of AML with recurrent genetic abnormalities. AML with mutated NPM1 and AML with myelodysplasia-related changes comprised the oldest patients, whereas AML with RUNX1-RUNX1T1 included the youngest patients. The leukocyte count was highest in AML with mutated NPM1, and the percentage of peripheral blood blasts was the highest in AML with double CEBPA mutations. Our results indicate that implementation of the 2016 WHO classification of AML would not pose major difficulties in clinical practice. Hematopathologists should review and prepare genetic tests for the new classification, according to their clinical laboratory conditions.

CDKN2B downregulation and other genetic characteristics in T-acute lymphoblastic leukemia.

We identified principal genetic alterations in 97.1% (99/102) of patients with T-acute lymphoblastic leukemia (T-ALL) using integrative genetic analyses, including massive parallel sequencing and multiplex ligation-dependent probe amplification (MLPA). A total of 133 mutations were identified in the following genes in descending order: NOTCH1 (66.7%), FBXW7 (19.6%), PHF6 (15.7%), RUNX1 (12.7%), NRAS (10.8%), and DNMT3A (9.8%). Copy number alterations were most frequently detected in CDKN2B, CDKN2A, and genes on 9p21.3 in T-ALL (45.1%). Gene expression data demonstrated the downregulation of CDKN2B in most cases of T-ALL, whereas CDKN2A downregulation was mainly restricted to deletions. Additional quantitative methylation analysis demonstrated that CDKN2B downregulation stemmed from deletion and hypermethylation. Analysis of 64 patients with CDKN2B hypermethylation indicated an association with an older age of onset and early T cell precursor ALL, which involved very early arrest of T cell differentiation. Genes associated with methylation and myeloid neoplasms, including DNMT3A and NRAS, were more commonly mutated in T-ALL with CDKN2B hypermethylation. In particular, a CDKN2B biallelic deletion or high methylation level (≥45%), the age of onset, and the GATA3 and SH2B3 mutations were factors associated with a poor prognosis. This study clarifies that one of the most important genetic events in T-ALL, namely, CDKN2B downregulation, occurs mechanistically via deletion and hypermethylation. Different susceptible genetic backgrounds exist based on the CDKN2B downregulation mechanism.

Considerations for monitoring minimal residual disease using immunoglobulin clonality in patients with precursor B-cell lymphoblastic leukemia.

BACKGROUND: Minimal residual disease (MRD) monitoring is a powerful tool to predict the risk of relapse. Herein, we present an MRD monitoring strategy for B-cell lymphoblastic leukemia (B-ALL) using high-throughput sequencing (HTS) of immunoglobulin (Ig) clonality before implementation into routine practice. METHODS: We selected 74 bone marrow (BM) specimens from 47 patients who were diagnosed with B-ALL. Ig clonality was analyzed using both fragment analysis and HTS. The performance of Ig clonality was evaluated through comparison of the results from real-time quantitative polymerase chain reaction (qPCR) of leukemia-specific fusion transcripts and flow cytometry. RESULTS: IGH clonality was observed in all patients, and the sum of clonal burden varied (9.47%-96.77%). IGK clonality was identified in 70% of patients and availed in cases with low IGH clonal burden. The total IGH clonal burden was significantly correlated with the proportion of leukemic blasts, leukemia-specific fusion transcripts, and flow cytometry. We recognized the different responses of each clone and emerging clones originating from the trace of Ig rearrangement presented in the initial specimen. IGH clonal burden after chemotherapy represented patient outcomes well. IGH assay also provided information of repertoire diversity of IGH rearrangement. CONCLUSION: The Ig clonality assay via HTS will be a promising tool for MRD monitoring of B-ALL through an adequate strategy to identify and monitor individual clones and determine repertoire diversity.

Development of a Novel Flow Cytometry-Based System for White Blood Cell Differential Counts: 10-color LeukoDiff.

BACKGROUND: Flow cytometry (FCM) is commonly used to identify many cell populations. We developed a white blood cell (WBC) differential counting system for detecting abnormal cells using FCM incorporating 10 colors and 11 antibodies in a single tube, called "10-color LeukoDiff," and evaluated its performance. METHODS: Ninety-one EDTA-anti-coagulated peripheral blood samples from 76 patients were analyzed using 10-color LeukoDiff. We compared 10 color LeukoDiff results with the results of manual differential count (manual diff). WBCs were classified into 17 cell populations: neutrophils, total lymphocytes, T lymphocytes, B lymphocytes, CD5 and CD19 co-expressing lymphocytes, natural killer cells, total monocytes, 16+ monocytes, eosinophils, immature granulocytes, basophils, myeloblasts, B-blasts, T-blasts, myeloid antigen-positive B-blasts, CD19- plasma cells, and 19+ plasma cells. RESULTS: The correlations between the 10-color LeukoDiff and manual diff results were strong (r>0.9) for mature neutrophils, lymphocytes, eosinophils, immature granulocytes, and blasts and moderate for monocytes and basophils (r=0.86 and 0.74, respectively). There was no discrepancy in blast detection between 10-color LeukoDiff and manual diff results. Furthermore, 10-color LeukoDiff could differentiate the lineage of the blasts and separately count chronic lymphocytic leukemic cells and multiple myeloma cells. CONCLUSIONS: The 10-color LeukoDiff provided an accurate and comprehensive WBC differential count. The most important ability of 10-color LeukoDiff is to detect blasts accurately. This system is clinically useful, especially for patients with hematologic diseases, such as acute leukemia, chronic lymphocytic leukemia, and multiple myeloma. Application of this system will improve the development of FCM gating strategy designs.

Development of a Rapid Automated Fluorescent Lateral Flow Immunoassay to Detect Hepatitis B Surface Antigen (HBsAg), Antibody to HBsAg, and Antibody to Hepatitis C.

BACKGROUND: Accurate, rapid, and cost-effective screening tests for hepatitis B virus (HBV) and hepatitis C virus (HCV) infection may be useful in laboratories that cannot afford automated chemiluminescent immunoassays (CLIAs). We evaluated the diagnostic performance of a novel rapid automated fluorescent lateral flow immunoassay (LFIA). METHODS: A fluorescent LFIA using a small bench-top fluorescence reader, Automated Fluorescent Immunoassay System (AFIAS; Boditech Med Inc., Chuncheon, Korea), was developed for qualitative detection of hepatitis B surface antigen (HBsAg), antibody to HBsAg (anti-HBs), and antibody to HCV (anti-HCV) within 20 minutes. We compared the diagnostic performance of AFIAS with that of automated CLIAs-Elecsys (Roche Diagnostics GmbH, Penzberg, Germany) and ARCHITECT (Abbott Laboratories, Abbott Park, IL, USA)-using 20 seroconversion panels and 3,500 clinical serum samples. RESULTS: Evaluation with the seroconversion panels demonstrated that AFIAS had adequate sensitivity for HBsAg and anti-HCV detection. From the clinical samples, AFIAS sensitivity and specificity were 99.8% and 99.3% for the HBsAg test, 100.0% and 100.0% for the anti-HBs test, and 98.8% and 99.1% for the anti-HCV test, respectively. Its agreement rates with the Elecsys HBsAg, anti-HBs, and anti-HCV detection assays were 99.4%, 100.0%, and 99.0%, respectively. AFIAS detected all samples with HBsAg genotypes A-F and H and anti-HCV genotypes 1, 1a, 1b, 2a, 2b, 4, and 6. Cross-reactivity with other infections was not observed. CONCLUSIONS: The AFIAS HBsAg, anti-HBs, and anti-HCV tests demonstrated diagnostic performance equivalent to current automated CLIAs. AFIAS could be used for a large-scale HBV or HCV screening in low-resource laboratories or low-to middle-income areas.

Comparison of Four Automated Carcinoembryonic Antigen Immunoassays: ADVIA Centaur XP, ARCHITECT I2000sr, Elecsys E170, and Unicel Dxi800.

BACKGROUND: Carcinoembryonic antigen (CEA) is one of the tumor markers available for evaluating disease progression status after initial therapy and monitoring subsequent treatment modalities in colorectal, gastrointestinal, lung, and breast carcinoma. We evaluated the correlations and differences between widely used, automated CEA immunoassays at four different medical laboratories. METHODS: In total, 393 serum samples with CEA ranging from 3.0 to 1,000 ng/mL were analyzed on ADVIA Centaur XP (Siemens Diagnostics, Tarrytown, NY, USA), ARCHITECT i2000sr (Abbott Diagnostics, Abbott Park, IL, USA), Elecsys E170 (Roche Diagnostics, Indianapolis, IN, USA), and Unicel DxI800 (Beckman Coulter, Fullerton, CA, USA), and the results were compared. Deming regression, Passing-Bablok regression, and Bland-Altman analyses were performed to evaluate the data correlation and % differences among these assays. RESULTS: Deming regression analysis of data from Elecsys E170 and UniCel DxI800 showed good correlation (y=3.1615+0.8970x). According to Bland-Altman plot, no statistically significant bias (-1.78 ng/mL [95% confidence interval: -4.02 to 0.46]) was observed between Elecsys E170 and UniCel DxI800. However, the relative differences of CEA concentrations between assays exceeded the acceptable limit of 30%. Regarding the agreement of positivity with cut-off value 5.0 ng/mL, ARCHITECT i2000sr and Elecsys E170 showed the highest agreement (95.2%), whereas ADVIA Centaur XP and ARCHITECT i2000sr showed the lowest agreement (70.7%). CONCLUSIONS: Agreements between automated CEA immunoassays are variable, and individual CEA concentrations may differ significantly between assays. Standardization of serum CEA concentrations and further harmonization are needed.

Cytomegalovirus (CMV) immune monitoring with ELISPOT and QuantiFERON-CMV assay in seropositive kidney transplant recipients.

Although cytomegalovirus (CMV) specific cell-mediated immunity (CMI) has been suggested as a predictive marker for CMV infection, proper CMI monitoring strategy in CMV-seropositive recipients and optimal method are not defined. The aim of this study was to evaluate two interferon gamma release assays during early post-transplant period as a predictor of the development of CMV infection in CMV-seropositive patients. A total of 124 CMV-seropositive recipients who received kidney transplantation from CMV-seropositive donor were prospectively examined. At pre-transplant and post-transplant 1 and 3 months, CMV-CMIs were tested using QuantiFERON-CMV assay (QF-CMV) and CMV specific T cell ELISPOT against CMV pp65 and IE-1 antigens (pp65-ELISPOT, IE-1-ELISPOT). CMV DNAemia occurred in 16 (12.9%) patients within 3 months after transplant. Post-transplant pp65 or IE-1 ELISPOT response, but not QF-CMV, was significantly associated with CMV DNAemia. The pp65 ELISPOT (cut-off; 30 spots/200,000 cells) and IE-1 ELISPOT (10 spots/200,000 cells) at post-transplant 1 month predicted the risk of post-transplant CMV DNAemia (P = 0.019). Negative predictive values (NPV) for protection from CMV DNAemia in case of positive ELISPOT results were 94.5% (95% CI: 86.9-97.8%) and 97.6% (95% CI: 86.3-99.6%) in pp65-ELISPOT and IE-1-ELISPOT assays, respectively. These results suggest that the variability may exist between CMV ELISPOT assays and QF-CMV, and CMV ELISPOT at post-transplant 1 month can identify the risk of CMV DNAemia in seropositive kidney transplant recipients.

Natural killer cell activity for IFN-gamma production as a supportive diagnostic marker for gastric cancer.

BACKGROUND/AIM: Decreased Natural killer cell activity (NKA) for interferon-gamma production (NKA-IFNγ) has been reported in cancer patients. The aim of this study was to determine the diagnostic performance of NKA-IFNγ for gastric cancer (GC). RESULTS: NKA-IFNγ levels were decreased in 261 GC patients with all stages of tumor compared to those in 48 healthy donors (P < 0.001), and lower levels of NKA-IFNγ were associated with higher GC stages. NKA-IFNγ levels were also associated with clinicopathological parameters including tumor size, depth of invasion, and lymph node metastasis. NKA-INFγ assay had better diagnostic value (AUC = 0.822) compared to serum CEA (0.624) or CA19-9 assay (0.566) (P < 0.001). Using different cut-off levels, serum CEA and CA19-9 showed sensitivities of 6.1-14.2% and 4.2-28.0%, respectively, which were much lower than that of NKA-IFNγ (55.6-66.7%). METHODS: This study included 261 patients with newly diagnosed GC and 48 healthy donors. NKA for IFNγ was determined by enzyme immunoassay after incubation of whole blood, and diagnostic performance was evaluated. CONCLUSIONS: NK cell activities for IFNγ production could be used as a supportive non-invasive tumor marker for GC diagnosis.

Electrostatic Modification for Promotion of Flavin-Mediated Oxidation of a Probe for Flavin Detection.

Electrostatic effects on the redox photochemistry of synthetic probes (1, 2, and 1-Zn) are examined by adjusting the thermodynamic driving force of their oxidation reactions. The redox photochemistry was simply controlled by introducing a zinc binding site (2,2'-dipicolylamine (DPA)) on the coumarin moiety of probe 2. Zinc complexation produced a positively charged environment on the coumarin (1-Zn), which lowered the electron density of a nearby 9 H-xanthene ring, attenuating the auto-oxidation of 1-Zn by 45 % compared with that of probe 1 at 298 K. The positive net charge of 1-Zn also provided an attractive Coulombic force toward the phosphate of flavin mononucleotide and flavin adenine dinucleotide, which lowered the reduction potential of the electron acceptor (isoalloxazine) and improved intermolecular electron transfer from the 9 H-xanthene ring to isoalloxazine. The flavin-mediated oxidation rate of 1-Zn was increased to 1.5 times that of probe 2. Probe 1-Zn showed highly selective sensing behaviour toward flavins, producing an intense brightness (ϵΦF =2.80×103 m-1  cm-1 ) in the long-wavelength regions (λmax =588 nm) upon flavin-mediated oxidation. Furthermore, probes 1-Zn and 2 were successfully applied to eosinophil imaging and the differential diagnosis of eosinophilia; this demonstrates their use as diagnostic tools.

Systemic Epstein-Barr Virus-positive T-Cell Lymphoproliferative Disease of Childhood With Good Response to Steroid Therapy.

Systemic Epstein-Barr virus (EBV)-positive T-cell lymphoproliferative disease of childhood is a rare disease and has a very fulminant clinical course with high mortality. A 21-month-old female patient was referred to our hospital with a 1 week history of fever and was subsequently diagnosed with systemic Epstein-Barr virus-positive T-cell lymphoproliferative disease of childhood. After starting treatment with dexamethasone, she showed early defervescence and improvement of laboratory parameters, and has remained disease-free after stopping steroid treatment, although longer follow-up is necessary. Our report underscores the possibility that this disease entity may be heterogenous in terms of prognosis.