Kun Soo Lee

Prevalence of primary immunodeficiency in Korea

This study represents the first epidemiological study based on the national registry of primary immunodeficiencies (PID) in Korea. Patient data were collected from 23 major hospitals. A total of 152 patients with PID (under 19 yr of age), who were observed from 2001 to 2005, have been entered in this registry. The period prevalence of PID in Korea in 2005 is 11.25 per million children. The following frequencies were found: antibody deficiencies, 53.3% (n = 81), phagocytic disorders, 28.9% (n = 44); combined immunodeficiencies, 13.2% (n = 20); and T cell deficiencies, 4.6% (n = 7). Congenital agammaglobulinemia (n = 21) and selective IgA deficiency (n = 21) were the most frequently reported antibody deficiency. Other reported deficiencies were common variable immunodeficiencies (n = 16), X-linked agammaglobulinemia (n = 15), IgG subclass deficiency (n = 4). Phagocytic disorder was mostly chronic granulomatous disease. A small number of patients with Wiskott-Aldrich syndrome, hyper-IgE syndrome, and severe combined immunodeficiency were also registered. Overall, the most common first manifestation was pneumonia. This study provides data that permit a more accurate estimation PID patients in Korea.

Clinical features and treatment outcomes of Langerhans cell histiocytosis: a nationwide survey from Korea histiocytosis working party.

A nationwide survey was conducted to clarify the clinical features and outcomes of Korean children with Langerhans cell histiocytosis (LCH). Korea Histiocytosis Working Party analyzed the data of 603 patients who were diagnosed with LCH between 1986 and 2010 from 28 institutions in Korea. Median age at diagnosis was 65 months (range, 0 to 276 mo). Bone was the most frequently affected organ (79.6%) followed by skin (19.2%). Initially, 419 patients (69.5%) had single-system involvement (SS), 85 (14.1%) with multisystem (MS) disease without risk organ involvement (MS-RO−), and 99 (16.4%) multisystem disease with risk organ involvement (MS-RO+). The 5-year overall survival (OS) rates in the SS, MS-RO−, and MS-RO+ groups were 99.8%, 98.4%, and 77.0%, respectively (P<0.001), and the 5-year reactivation rates were 17.9%, 33.5%, and 34.3%, respectively (P<0.001). The OS rate was lower in patients with RO involvement (P=0.025) and lack of response to initial treatment (P=0.001). MS involvement (P=0.036) was an independent risk factor for reactivation. Permanent consequences were documented in 99 patients (16.4%). Reactivation of disease, MS involvement, and age at diagnosis ⩽2 years were associated with higher incidence of permanent consequences. This study emphasized that further efforts are required to improve survival of MS-RO+ patients and reduce reactivation in younger patients with MS involvement.

Epidemiology and clinical long-term outcome of childhood aplastic anemia in Korea for 15 years: retrospective study of the Korean Society of Pediatric Hematology Oncology (KSPHO).

Purpose Aplastic anemia (AA) is a rare hematologic disease characterized by pancytopenia and hypocellular marrow. The Korean Society of Pediatric Hematology Oncology investigated retrospectively the incidence, survival, and transfusion independency according to treatment strategies in AA. Methods All the questionnaires were sent to members for medical records. We collected and analyzed 702 available data. Results The male and female ratio was 1.2, and the median age at diagnosis was 9.3 years. The annual incidence of Korean children with AA was 5.16 per million per year. Constitutional anemia was diagnosed in 44 children. In acquired AA, causes were identified in 39 children. Severe AA (SAA) at initial diagnosis was more common than nonsevere AA. The overall survival was 47.8% with supportive care, 68.1% with immunosuppressive therapy (IST), and 81.8% with hematopoietic stem cell transplantation. In IST, response rate was 65.7%, and relapse rate after response was 54.4% within a median of 23.0 months. The factors with overall survival were severity of disease in supportive care, severity and response in IST, donor type, graft failure, and posttransplant events in hematopoietic stem cell transplantation. Conclusions Long-term outcome in AA was dependent on treatment strategies. These Korean results may help research and prospective international clinical trials for childhood AA.

Efficacy of tandem high-dose chemotherapy and autologous stem cell rescue in patients over 1 year of age with stage 4 neuroblastoma: the Korean Society of Pediatric Hematology-Oncology experience over 6 years (2000-2005).

The efficacy of tandem high-dose chemotherapy and autologous stem cell rescue (HDCT/ASCR) was investigated in patients with high-risk neuroblastoma. Patients over 1 yr of age who were newly diagnosed with stage 4 neuroblastoma from January 2000 to December 2005 were enrolled in The Korean Society of Pediatric Hematology-Oncology registry. All patients who were assigned to receive HDCT/ASCR at diagnosis were retrospectively analyzed to investigate the efficacy of single or tandem HDCT/ASCR. Seventy and 71 patients were assigned to receive single or tandem HDCT/ASCR at diagnosis. Fifty-seven and 59 patients in the single or tandem HDCT group underwent single or tandem HDCT/ASCR as scheduled. Twenty-four and 38 patients in the single or tandem HDCT group remained event free with a median follow-up of 56 (24-88) months. When the survival rate was analyzed according to intent-to-treat at diagnosis, the probability of the 5-yr event-free survival±95% confidence intervals was higher in the tandem HDCT group than in the single HDCT group (51.2±12.4% vs. 31.3±11.5%, P=0.030). The results of the present study demonstrate that the tandem HDCT/ASCR strategy is significantly better than the single HDCT/ASCR strategy for improved survival in the treatment of high-risk neuroblastoma patients.

Quantitative Comparison of CDKN2B Methylation in Pediatric and Adult Myelodysplastic Syndromes

Background/Aims: Transcriptional repression of tumor suppressor genes is determined by the quantity of promoter hypermethylation. We analyzed the methylation quantity of CDKN2B in pediatric myelodysplastic syndromes (MDS). Methods: Quantitative measurement of CDKN2B methylation was performed in 25 pediatric MDS patients and 12 controls using pyrosequencing, and the result was compared with those from 74 adult MDS cases and 31 adult controls. The association between CDKN2B methylation quantity and factors related to prognosis including bone marrow blast percentage and karyotype was analyzed. Results: Pediatric MDS patients showed a higher methylation level (MtL) of CDKN2B than pediatric controls (2.94 vs. 1.62; p = 0.031) but a lower level than adult MDS patients (8.76; p < 0.001). MtL was higher in pediatric MDS cases with >5% blasts than in pediatric controls (3.78 vs. 1.62; p = 0.052). Pediatric MDS cases with abnormal karyotype showed a higher MtL than pediatric controls (5.95 vs. 1.62; p = 0.045). Conclusions: We confirmed that methylation of CDKN2B is associated with the pathogenesis and prognosis in pediatric MDS. The difference in MtLs between pediatric and adult MDS might be related to the physiological hypermethylation of tumor suppressor genes in aging.

Efficacy, Safety, and Pharmacokinetics of Beroctocog Alfa in Patients Previously Treated for Hemophilia A

Purpose Beroctocog alfa is a second generation recombinant factor VIII manufactured by removing the B-domain from factor VIII. This prospective clinical trial was conducted to evaluate the efficacy, safety, and pharmacokinetics of beroctocog alfa in patients of ages ≥12 years previously treated for severe hemophilia A. Materials and Methods Seventy subjects received beroctocog alfa as an on-demand treatment for acute hemorrhage. Results The final hemostatic effect was excellent in 35 subjects (50%) and good in 26 subjects (37.1%). The drug showed an overall efficacy rate of 87.1%. The majority of acute hemorrhages was treated by administering the study drug once (86.2%) or twice (10.0%), and the mean dose administered per single infusion was 28.55±6.53 IU/kg. Ten subjects underwent 12 surgical procedures, and hemostatic efficacy was excellent in seven cases (58.3%) and good in five cases (41.7%), showing a 100% efficacy rate. A total of 52 of 88 subjects (59.0%) experienced 168 adverse events. There were 18 serious adverse events (10.7%) in 11 subjects, and two (mild dyspnea and facial edema) in one subject were related to the study drug. Only one subject formed a de novo factor VIII inhibitor, for an occurrence rate of 1.4% (one-sided 95% upper confidence limit: 3.85%). The final elimination half-life was 13.3 h and 12.6 h at baseline and 6 months after administration, respectively. Conclusion Our results suggest that beroctocog alfa is safe and efficacious as either an on-demand treatment for acute hemorrhage or a surgical prophylaxis in patients with hemophilia A.

Novel ELANE Gene Mutation in a Korean Girl with Severe Congenital Neutropenia

Severe congenital neutropenia is a heterozygous group of bone marrow failure syndromes that cause lifelong infections. Mutation of the ELANE gene encoding human neutrophil elastase is the most common genetic alteration. A Korean female pediatric patient was admitted because of recurrent cervical lymphadenitis without abscess formation. She had a past history of omphalitis and isolated neutropenia at birth. The peripheral blood showed a markedly decreased absolute neutrophil count, and the bone marrow findings revealed maturation arrest of myeloid precursors at the promyelocyte to myelocyte stage. Her direct DNA sequencing analysis demonstrated an ELANE gene mutation (c.607G > C; p.Gly203Arg), but her parents were negative for it. She showed only transient response after subcutaneous 15 µg/kg/day of granulocyte colony stimulating factor administration for six consecutive days. During the follow-up observation period, she suffered from subsequent seven febrile illnesses including urinary tract infection, septicemia, and cellulitis.

Natural course of childhood chronic immune thrombocytopenia using the revised terminology and definitions of the international working group: a single center experience.

Background The immune thrombocytopenia (ITP) criteria were newly standardized by the International Working Group. Thus, we analyzed the natural course of childhood chronic ITP to predict the prognosis based on the revised criteria. Methods The medical records of children with chronic ITP from May 2000 to February 2013 in our institute were reviewed. Results Forty-seven children with chronic ITP who were not undergoing corticosteroid therapy were included. Their initial platelet count was 23±25×109/L, and age at diagnosis was 6.3±4.1 years. The follow-up period was 5.4±3.7 years. Among them, 44.7% (21/47) showed spontaneous remission and maintained a platelet count ≥100×109/L. And 66.0% (31/47) maintained a platelet count ≥50×109/L until the last follow-up date. The time periods required for the platelet count to be maintained ≥50×109/L and ≥100 ×109/L were 3.1±2.7 and 3.6±2.7 years. Age at diagnosis in the ≥50×109/L group (5.7±4.4 years) was significantly lower than the age at diagnosis in the <50×109/L group (7.4±3.3 years) (P=0.040). And follow-up period was the factor influencing prognosis between the ≥100×109/L group and <50×109/L group (P=0.022). Conclusion Approximately 45% of children with chronic ITP recovered spontaneously about 3-4 years after the diagnosis and 2/3 of patients maintained a platelet count ≥50×109/L, relatively safe state. Age at diagnosis of ITP and follow-up period were the factors influencing prognosis in this study.

Progress of in vitro factor VIII coagulant activity from 0 to 8 hours after reconstitution

Background Continuous infusion of factor VIII (FVIII) is a more cost-effective method for treating hemophilia A than intermittent bolus injection. However, there is currently no specific data in Korea about the progress of in vitro FVIII coagulant activity (FVIII:C) after reconstitution from its lyophilized form. Methods Three commercial FVIII concentrate products (two recombinant FVIII and one plasma-derived) were used. In vitro FVIII:C was measured at 0, 2, 4, 6, and 8 hours following reconstitution in both the indoor light-exposed and light-shielded groups. Results For the three drugs, in vitro FVIII:C decreased over the 8 hours following reconstitution (P<0.001). The decline of FVIII:C was linear (P<0.001). In vitro FVIII:C for the indoor light-exposed groups was 95.3±1.9% and 90.6±2.5% after 4 and 8 hours following reconstitution, respectively, compared to baseline activity. In the light-shielded group, FVIII:C was 95.4±1.1% and 90.9±1.7% of the baseline activity after 4 and 8 hours, respectively. There was no statistical difference between FVIII:C in the indoor light-exposed and light-shielded groups (P=0.849). Conclusion In vitro FVIII:C decreased after reconstitution, but activity was maintained at over 90% of the baseline value during 8 hours. Exposure to indoor light did not accelerate the loss of FVIII:C over the experimental time. This result indicates that CI with FVIII is available in 8-hour intervals, with no indoor light-exposure precautions needed.

Second case of postpartum acquired hemophilia A in a Korean female

TO THE EDITOR: Acquired hemophilia A (AHA) is a very rare condition with an incidence of about 1.5 per million of the general population per year [1]. It develops in middle age due to autoantibody production directly against the factor VIII (FVIII) and occurs in both sexes equally. The underlying conditions associated with AHA are other autoimmune diseases, malignancy, drugs and pregnancy. However, about half of AHA has no specific cause, thus they are called idiopathic. Postpartum AHA is a special category with distinct clinical manifestation contributing to 7-21% of patients with AHA [2, 3, 4]. In Korea, the first case of postpartum AHA in a 40 years old female has been reported by Lee et al. [5]. To the best of our knowledge, the present case report is the second one in Korea. n nA previously healthy 18 years old female had several minor bruises on hands and feet at 5 months after delivery. There was no specific complication immediately after delivery. She previously didnt take any drugs which could result in AHA and her family history was nonspecific. The hemorrhagic symptoms were aggravated during the process of time and she visited a private medical doctor at 8 months after delivery. At the medical clinic, she was only supplemented with iron to treat her iron deficiency anemia. Because of a persistent migrating painful swelling on her knees and ankle joints, multiple bruises and menorrhagia, she was transferred to our institute at 9 months after delivery. n nHer initial laboratory test results were as follows: PT 10.2 sec (normal range, 10-14 sec), INR 0.95 (normal range, 0.85-1.50), aPTT 84.3 sec (normal range, 20-40 sec), FVIII activity 1.4% (moderately decreased), and anti-FVIII antibody 28 Bedestha units (BU). Thus, she was confirmed as postpartum AHA. To manage her persisting hemorrhagic symptoms, activated prothrombin complex concentrate, FEIBA (Baxter, Westlake Village, CA, USA) was infused to her based on the dose for joint hemorrhage (50-100 units/kg every 12 hours until pain/disabilities are improved, maximum 200 units/kg/day) and her bleeding symptoms resolved. We closely followed up her at the outpatient clinic with on-demand FEIBA injection. After 2 months, the last follow up PT/aPTT were 11.2/95.1 sec, FVIII activity 1.5% and anti-FVIII antibody 40 BU. We consider giving corticosteroid to her additionally. n nAccording to European Acquired Haemophilia (EACH2) registry, 42 cases of postpartum AHA developed from 2003 to 2008 in 13 European countries [4]. In other words, the medical personnel in hematology or obstetrics can experience one postpartum AHA patient every year or biyearly in one country. Because time to diagnosis of postpartum AHA was 21-120 days after delivery, pregnant women should be observed closely approximately 1-3 months after delivery [4]. n nUsually, AHA is often misunderstood as another bleeding disorder like disseminated intravascular coagulation because a hemorrhage into the skin (purpura) or soft tissue is the most common presenting sign of AHA, while a hemarthrosis, the hole mark of a congenital hemophilia, occurs rarely [1, 2]. According to EACH2, hemarthrosis was also a rare hemorrhagic symptom of postpartum AHA contributing about 5%. Subcutaneous (45%) or mucosal bleeding (43%) was most common. On the other hand, in case of our report, the patient was mistaken as to have rheumatic disease because the migrating painful swelling of her joints due to hemarthrosis was the main symptom. n nThe treatment of acute bleeding in case of postpartum AHA is not different from the general form. Two bypassing agents, FEIBA and the recombinant activated factor VII, NovoSeven (Novo Nordisk, Princeton, NJ, USA) are the main therapeutic agents to control acute hemorrhagic symptoms. The overall complete response rate of hemorrhages using FEIBA was 86% with the infusion of 75 units/kg every 8 to 12 hours [6]. And the efficacy rate using NovoSeven was 95% as first line therapy for AHA [7]. NovoSeven has some advantages that its blood born viral transmission is shut out and the risk of thromboembolism is lower than that of FEIBA [8, 9]. n nThe combination of bypassing agents for stopping the hemorrhage and immunosuppressive therapy is usually used together to eradicate the autoantibodies of FVIII in the general form of AHA. Prednisolone (prednisone), cyclophosphamide, azathioprine, 6-mercaptopurine, rituximab (anti-CD 20 monoclonal antibody), mycophenolate or cyclosporin have been used for treatment [1, 3, 10, 11, 12]. n nHowever, the immunosuppression may be individually reserved considering the advantages and disadvantages in case of postpartum AHA because of its more favorable prognosis compared to the general form. In retrospective reviews of postpartum AHAs, 86-100% of patients showed complete remission and survival rate was 97-100% [4, 12]. Further, there was no statistical difference of the time to complete remission between the postpartum AHA patients had immunosuppressive therapy and the rest of cohort [4]. On the other hand, the course of a general AHA is quite different. The relapse rate was about 20% after the cessation of immunosuppression and the survival rate was about 60% [1]. n nIn some international survey, the recurrence rate of postpartum AHA was 0% [13, 14]. However, there is a controversy over the recurrence rate of anti-FVIII antibody in case of subsequent pregnancy. Large-scaled study about the recurrence rate is not available yet. Thus the patients who experienced postpartum AHA should be observed carefully after subsequent pregnancies. n nIn the previous Korean case of postpartum AHA reported by Lee et al. [5], the patient was treated with a bypassing agent plus corticosteroid. In the present case, we are using on-demand FEIBA infusion for control of acute bleeding and postponed the immunosuppression considering a spontaneous remission. In our present case, the hemorrhagic symptoms of the patient were now solved using FEIBA. We expect that case presentations will help to increase the awareness on this rare condition among the medical personnel in the hematologic and obstetric field.