Clinical analysis of hospitalized patients with hemophilia A:single-hemophilia treatment center experience in Korea over 10 years

Background@#There is lack of data on admitted hemophilia patients in Korea. For this reason, this study was intended to analyze the hospitalization data of hemophilia patients in a regional Hemophilia Treatment Center (HTC) for the first time in Korea. @*Methods@#In this retrospective study, we surveyed hospitalized patients with Hemophilia A (HA) in a HTC for 14 years. Medical records of these hemophiliacs were reviewed and data regarding demographic characteristics, cause of admissions and their outcomes in each patient were obtained. In addition, the data of admitted days, type and amount of Coagulation factor concentrate (CFC) used, treatments other than CFC infusion during the admission days were also obtained from the medical record of each patient. @*Results@#A total 107 patients with hemophilia A were admitted during 14 years. Annual rate of admission of patients with HA was 8%. Mean age on admission was 29.63±19.51 years old and mean admission days were 11.28±5.46 days. Most admissions were occurred in severe and moderate hemophilia patients. The most common cause of admission was bleed control followed by surgery and other reasons. With modified WFH CFC supplementation guideline, all the bleeds were successfully controlled and all surgeries were also successfully conducted with less total CFC consumption compared to the consumed dose of other reports. @*Conclusion@#These results suggest that it is necessary to develop more specified regimens different from WFH.

Clinical analysis of hospitalized patients with hemophilia A:single-hemophilia treatment center experience in Korea over 10 years

Background@#There is lack of data on admitted hemophilia patients in Korea. For this reason, this study was intended to analyze the hospitalization data of hemophilia patients in a regional Hemophilia Treatment Center (HTC) for the first time in Korea. @*Methods@#In this retrospective study, we surveyed hospitalized patients with Hemophilia A (HA) in a HTC for 14 years. Medical records of these hemophiliacs were reviewed and data regarding demographic characteristics, cause of admissions and their outcomes in each patient were obtained. In addition, the data of admitted days, type and amount of Coagulation factor concentrate (CFC) used, treatments other than CFC infusion during the admission days were also obtained from the medical record of each patient. @*Results@#A total 107 patients with hemophilia A were admitted during 14 years. Annual rate of admission of patients with HA was 8%. Mean age on admission was 29.63±19.51 years old and mean admission days were 11.28±5.46 days. Most admissions were occurred in severe and moderate hemophilia patients. The most common cause of admission was bleed control followed by surgery and other reasons. With modified WFH CFC supplementation guideline, all the bleeds were successfully controlled and all surgeries were also successfully conducted with less total CFC consumption compared to the consumed dose of other reports. @*Conclusion@#These results suggest that it is necessary to develop more specified regimens different from WFH.

The prevalence and risk factors of inhibitor development of FVIII in previously treated patients with hemophilia A

BACKGROUND: Risk factors for the development of inhibitors in previously untreated patients (PUPs) have been reported; this is not the case in previously treated patients (PTPs) owing to fewer studies. Risk factors may differ for the development of PTP versus PUP inhibitors. We aimed to identify risk factors for PTP inhibitor development. METHODS: Participants were patients at a hemophilia treatment center in Korea with current or past history of factor VIII or factor IX alloantibodies. Observed inhibitors were classified as PUP or PTP inhibitors based on the cumulative number of exposure days. We compared the type and severity of hemophilia, mutation type, and family history of inhibitor between PUPs and PTPs. Events within 3 months before the first inhibitor detection, such as change of the factor concentrate used, short-term high exposure or continuous infusion of factor concentrate, history of surgery, infection, diagnosis of cancer, use of immunosuppressive or immunomodulator agents, and vaccination were compared between PUPs and PTPs. RESULTS: We observed 5 PUP inhibitors and 5 PTP inhibitors in 115 patients with hemophilia A. Events that might be related to the development of inhibitors within 3 months prior to the first inhibitor detection were observed in all 5 PTPs. On the contrary, no such events were observed in any PUPs. The observed events included a change in the factor concentrate used, subsequent chemotherapy, and short-term high exposure to factor concentrates for controlling hemorrhage and surgeries. CONCLUSION: Our results suggest a greater role of nongenetic factors in PTP inhibitor development.

Subgroup analysis of a phase 2/3 study of rurioctocog alfa pegol in patients with severe hemophilia A: efficacy and safety in previously treated Korean patients

BACKGROUND: The efficacy and safety of extended half-life, full-length, pegylated recombinant factor VIII rurioctocog alfa pegol [BAX 855, ADYNOVATE (USA)/ADYNOVI (Europe); Baxalta US Inc., a Takeda company, Lexington, MA, USA] was investigated in previously treated Korean patients with severe hemophilia A (HA). METHODS: A post hoc data analysis from the international, multicenter, phase 2/3 PROLONG-ATE study of rurioctocog alfa pegol in patients with severe HA (NCT01736475) determined annualized bleeding rates (ABRs) and rates of adverse events (AEs) in Korean patients treated in this study. RESULTS: All 10 enrolled Korean patients receiving rurioctocog alfa pegol (9 prophylaxis, 1 on-demand) completed the study [median (range) age, 28.0 (12–50) yr; weight, 64.8 (45–90) kg; 8 patients had ≥1 target joint at screening]. Median (range) ABR was 1.9 (0.0–14.5) for patients on prophylaxis and 62.2 for the patient receiving on-demand treatment. The hemostatic efficacy of rurioctocog alfa pegol was rated “excellent” or “good” and only single infusions were required per bleeding episode. ABRs improved in most patients compared with prestudy values. No dose adjustments were required for prophylaxis, and the dosing frequency was reduced in 8 patients, compared with their previous prophylaxis regimen. No serious AEs were reported; all 9 nonserious AEs (in 3 patients) were mild in severity and unrelated to the study treatment. CONCLUSION: This post hoc analysis of a small group of Korean patients with severe HA indicated that rurioctocog alfa pegol was effective, and no serious AEs were observed. For most patients, the dosing frequency was also reduced compared with their previous regimen.

A pediatric case of idiopathic Harlequin syndrome / 소아과

Harlequin syndrome, which is a rare disorder caused by dysfunction of the autonomic system, manifests as asymmetric facial flushing and sweating in response to heat, exercise, or emotional factors. The syndrome may be primary (idiopathic) with a benign course, or can occur secondary to structural abnormalities or iatrogenic factors. The precise mechanism underlying idiopathic harlequin syndrome remains unclear. Here, we describe a case of a 6-year-old boy who reported left hemifacial flushing and sweating after exercise. He had an unremarkable birth history and no significant medical history. Complete ophthalmological and neurological examinations were performed, and no other abnormalities were identified. Magnetic resonance imaging was performed to exclude lesions of the cerebrum and cervicothoracic spinal cord, and no abnormalities were noted. His final diagnosis was classic idiopathic harlequin syndrome. Herein, we report the first pediatric case of idiopathic harlequin syndrome in Korea.

Effects of coagulation factor concentrate prophylaxis in moderate and severe hemophilia A patients at a single hemophilia center in Korea / 소아과

PURPOSE: The aim of this study was to investigate prophylactic treatment effects in Korean patients with severe hemophilia A. METHODS: A prospective study of 32 severe hemophilia A patients was conducted with the approval of the Institutional Review Board at the Eulji University Hospital. Two patients received primary prophylaxis; whereas, the other 30 patients were divided into 2 groups-secondary prophylaxis (n=15) and on-demand (n=15)-on the basis of their consent for secondary prophylaxis. A 20-25 IU/kg dose of factor VIII concentrate was administered to the primary and secondary prophylaxis group patients every 3 days for 1 year. The prophylactic effect was evaluated by observing changes in the Pettersson scores, annual number of total and joint bleeds, and factor VIII consumption for 1 year. RESULTS: No moderate or severe bleeding was observed, and the Pettersson scores remained unchanged during the prophylaxis period in the patients who received primary prophylactic treatment. After the treatment was changed from on-demand to secondary prophylaxis, the annual number of total and joint bleeds in the secondary prophylaxis group decreased by 64.4%+/-13.0% and 70.0%+/-15.2%, respectively. The average increase in Pettersson scores within 1 year was 0.5+/-0.8 and 1.3+/-1.1 in the secondary prophylaxis and on-demand groups, respectively. Prophylactic effects were also observed in patients >17 years who had nearly the same initial Pettersson scores. CONCLUSION: Intermediate-dose prophylactic treatment may delay hemarthropathy progression and prevent its occurrence in Korean severe hemophilia A patients.

The Effectiveness of High Dose Dexamethasone for the Initial Treatment of Childhood Acute Idiopathic Thrombocytopenic Purpura

BACKGROUND: Corticosteroids and intravenous immunoglobulin (IV-Ig) have been used asfirst line treatments for acute idiopathic thrombocytopenic purpura (AITP) in children. High dose dexamethasone (HD) has been reported to be effective for chronic refractory ITP and for the initial treatment of AITP in adults. There has been no report about HD as the initial treatment for childhood AITP. We assessed the effectiveness of HD for the initial treatment of childhood AITP, as compared to IV-Ig. METHODS: 25 Patients with newly diagnosed AITP were enrolled. We conducted a prospective, randomized study to compare the two treatment options. 11 patients were treated with IV-Ig and 14 patients were treated with HD. The platelet counts were assessed at 3, 5, 7, 14 and 21 days after the beginning of the treatment. The adverse effects were noted, and the patients were followed for more than 6 months. RESULTS: Both the IV-Ig and HD groups showed a rapid rise of the platelet counts and the platelet counts were maintained at 3, 5, 7, 14 and 21 days. The difference of platelet counts between the two groups was significant at day 5 (P<0.05). During the follow-up period, 5 patients had a recurrence: 2 in IV-Ig group and 3 in HD group. All 5 patients were re-treated with HD and they had a good response. One of the recurred patients in the IV-Ig group had chronic ITP. Some side effects were observed, but they were not severe enough to necessitate the discontinuation of treatment. CONCLUSION: We conclude that HD is as effective and safe as high dose IV-Ig for the initial treatment of childhood AITP. The choice between these treatment options can be made according to the cost-effectiveness and the therapy-related risks.

Reticulocyte hemoglobin content for the diagnosis of iron deficiency in young children with acute infection / 소아과

PURPOSE: Early identification of iron deficiency in young children is essential to prevent damaging long-term consequences. It is often difficult for the pediatrician to know which indices should be used when diagnosing these conditions especially in hospitalized young children. This study investigated the clinical significances of reticulocyte hemoglobin content in young children with acute infection. METHODS: We studied 69 young children aged from 6 to 24 months admitted with acute infection in a single center. Venous blood was drawn to determine hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), hemoglobin content (CH), reticulocyte hemoglobin content (CHr), and red blood cell distribution width (RDW) using ADVIA 120 (Bayer Diagnostics, NY, USA). For evaluating iron status, iron, total iron binding capacity, ferritin and transferrin saturation (Tfsat) were determined. Iron deficiency was defined as Tfsat less than 20%, and iron deficiency anemia as Tfsat less than 20% and Hb level less than 11 g/dL. RESULTS: In all, 47 were iron deficient; 17 of these had iron deficiency anemia. CHr was the only significant predictor of iron deficiency (likelihood ratio test=71.25; odds ratio=0.67; P<0.05). Plasma ferritin level had no predictive value (P=0.519). Subjects with CHr less than 27.4 pg had lower Hb level, MCH, CH, Tfsat, and iron levels than those with CHr 27.4 pg or more (P<0.05 for all). CONCLUSION: CHr level was a sensitive screening tool and the strongest predictor of iron deficiency in hospitalized infants with acute infection; it was cost saving and avoiding additional sampling. However its reference range should be established.

Acute Epididymo-orchitis in Newborn Infant

Acute scrotum in newborn infants is unusual and it is even more unusual with infectious origin. The causes of acute scrotum in newborn infants include hydrocele, testicular torsion, torsion of an appendix testis, epididymo-orchitis, meconium peritonitis, testicular tumor, scrotal hematoma and reducible or incarcerated inguinal hernia. Because of lack of typical symptoms and signs, the correct diagnosis of surgical emergencies such as testicular torsion and incarcerated inguinal hernia are often delayed. Recently, color Doppler ultrasonography and testicular scans are being used for differential diagnosis of acute scrotum, although the latter is often technically unsatisfactory due to small size of the testicles in newborn infants. We report a seven day-old male infant with acute scrotum who was diagnosed as acute epididymo-orchitis by color Doppler ultrasonography, and saved from unnecessary surgical interventions. Although color Doppler ultrasonography can not give diagnostic clue for acute scrotum, it can reduce the need for explorative surgery.

Risk Factors of Renal Scar After Acute Pyelonephritis in Children

PURPOSE: In this study we re-evaluated the known risk factors of pyelonephritic scarring in children. METHODS: A prospective study was performed on 36 acute pyelonephritis(APN) patients who were diagnosed as first acute pyelonephritis on 99mTc-DMSA scan between September 1998 and March 2000 in Masan Samsung Hospital. According to the prescence of remnant lesions on the 99mTc-DMSA scan performed 6 months after the first 99mTc-DMSA scan, the patients were divided into scar(Group A, N=15) and non-scar groups(Group B, N=21). We compared known risk factors of renal scarring between the two groups. RESULTS: There were no differences in age, sex, cultured organisms and CRP level between the two groups. Most of the initial 99mTc-DMSA scan results were not different but bilateral multiple lesions were much more common in group A(40.0% of Group A patients) compared with group B (9.5% of Group B patients). Moderate to high grade vesicoureteral reflux was also much more commonly observed in group A(46.6% of Group A patients) compared with group B(4.8% of Group B patients). CONCLUSION: Bilateral multiple lesion on initial 99mTc-DMSA scan and moderate to high grade vesicoureteral reflux at diagnosis of acute pyelonephritis may be risk factors associated with renal scarring after acute pyelonephritis in children.

The Effect of High Dose Dexamethasone in Childhood Acute Idiopathic Immune Thrombocytopenia / 대한소아혈액종양학회지

PURPOSE: For preventing CNS hemorrhage, steroids and high dose immune globulin have been used as the first-line treatments of acute ITP. Most of the patients respond to these treatments with rapid rise of platelet count to safe level compared to patients who received no treatment. Although the exact incidence has not been known, there are patients who are not responding these first-line treatments. Insufficient humoral immune suppression is thought to be the main mechanism of this failure and it has been known that humoral immunity is suppressed only at high dose steroids. Therefore, high dose steroids, especially dexamethasone which has been reported recently as an effective treatment in chronic refractory ITP, can overcome this treatment failure. METHPDS: Among the 62 acute ITP patients who were admitted in pediatric department of Masan Samsung Hospital between March, 1998 and March, 2000, only 8 patients were resistant to high dose immune globulin and conventional dose of prednisone. High dose dexamethasone 25 mg/M(2)/day in three divided doses was given to the 8 treatment failure patients for consecutive 4 days and platelet count was followed at 3, 5 and 7days after beginning of the treatment and then weekly. Only when the initial medication cycle was effective the dexamethasone was given to the patients repeatedly with the same dose and schedule until the resolution of the disease. RESULTS: Platelet counts were increased to safe level (> 50x10(9)/L) within 5 days of the treatment in all the patients with the initial treatment of high dose dexamethasone and this effect was observed in subsequent cycles. The mean days of maintaining platelet count above 20x10(9)/L was 22.0+/-3.1 days. Weight gaining and facial flushing were observed in 57% and 30% of patients but hypertension and glucosuria were not observed. CONCLUSION: These results suggest that high dose dexamethasone may be effective in the treatment of childhood acute ITP who did not respond to conventional dose of prednisone previously.

Analysis on the Causes of Death After Neutropenic Fever Episodes in Pediatric Cancer Patients / 대한소아혈액종양학회지

BACKGROUND: Despite the development of empiric antibiotics in treatment of neutropenic fever(NF) in pediatric cancer patients, bacterial infection is still the most important cause of death in these patients. In this study the authors analyzed clinical characteristics and tried to find out the possible risk factors of the pediatric cancer patients who succumbed to the documented bacterial infection after episodes of neutropenic fever. METHODS: 17 pediatric cancer patients expired after episodes of neutropenic fever(NF) in the pediatric department of Asan Medical Center from Mar. 1990 to Feb. 1996 were grouped by the results of bacterial culture. 7 cases (Group A) had documented bacterial culture results and 10 cases (Group B) had negative culture results. The clinical characteristics of these two groups were analyzed retrospectively. RESULTS: There were no differences in the types of cancer between the two groups. All the documented bacteria were gram negative organisms and all cultured from the blood. There were no differences between the two groups in the treatment duration, known risk factors of infection before and at the onset of fever, antibiotics administered, and interval from the onset of NF to the administration of antibiotics. The response rate of initial empiric antibiotics was lower in group A(14%) compared to Group B(40%), even though all the cultured organisms except 2 cases in Group A were sensitive to initial empirical antibiotics. Septic shock was the cause of death in 86% of Group A patients, but only in 10% of Group B patients. The other causes of death were progression of cancer, bleeding, hepatic failure, adult respiratory distress syndrome and multiple organ failure, which showed no difference between the 2 groups. The interval from the onset of fever to death was significantly shorter in Group A(6.2+/-2.3 days) compared to Group B(24.9+/-18.6 days). CONCLUSIONS: Bacterial infection is still the most frequent cause of death after NF. Most patients succumbed to the documented bacterial infection showed rapid progression of bacteremia to septic shock despite administration of sensitive antibiotics. The known risk factors of infection before the onset of NF and other treatment factors shows no differences between the two groups in this study. These results suggest that the bacteremia is obvious risk factor of poor outcome after NF episode, and antibiotics alone may be insufficient to prevent the rapid progression of septic shock in these patients.

A Clinical Study on Hemophagocytic Lymphohistiocytosis / 대한소아혈액종양학회지

BACKGROUND: Hemophagocytic lymphohistiocytosis(HLH) is a rare and fatal disorder in children. Recently its clinical characteristics and etiology of uncontrolled activation of cellular immune system in genetically predirected patients have keen elucidated. The authors analyzed the clinical characteristics and response to immunosuppressive agents of HLH patients in single institute. METHODS: The authors retrospectively analyzed various clinical data including CSF and bone marrow examination at diagnosis and follow up period in the 6 patients who were diagnosed as HLH at Asan Medical Center during last 2 years. Antithymocyte globulin(ATG : 10 mg/kg/day) and methylprednisolone(methyl-PD: 5 mg/kg/day) for 5 consecutive days as induction treatment and cyclosporin A(CsA) as maintenance treatment after induction with weekly intrathecal methotrexate for 5-6 weeks were given to the recently diagnosed 3 patients. RESULTS: All the patients except one were infants. Persistent fever, hepatosplenomegaly and pancytopenia were observed in all the patients. Family history of suspicious HLH was observed in 4 patients(67%). The characteristic elevated serum triglyceride(TG) level and/or decreased fibrinogen level were noted in all. Mild to moderate CSF pleocytosls with increased lymphocytes and monocytes was also observed in all during the disease course. Variable degree of nonqr-Langerhans cell histiocytic infiltration and hemophagocytosis were observed in all the cases. Of the 3 patients treated with ATG and methyl-PD, one achieved complete remission and the others achieved partial remission within 2 weeks of treatment, but all expired after 5 months, remission with CsA. Regardless of treatment regimen, all the 6 patients expired due to CNS sequelae of HLH. CONCLUSIONS: HLH mainly developed in infants. Persistant fever, hepatosplenomegaly and pancytopenia were observed in most cases with the characteristic change of serum TG and/or fibrinogen level. HLH should be included in the differential diagnosis in patients with these features especially when the family history of suspicious HLH is present, and histologic comfirmation of HLH could be easily accomplished with bone marrow study in most cases. Remission induction of HLH could be achieved with immunosuppressive treatment but it was difficult to maintain long term remission.

A study of bone mineral density of lumbar spine by dual energy x-ray absorptiometry (DEXA) in children / 영남의대학술지

The bone mineral density(BMD) of the lumbar spine (L2L4) was measured by using dual energy x-ray absorptiometry(Norland M6 DEXA) in 80 children aged between 2months and 15years (group I:2monthlyears, group 2: 1year5years, group3:6years10years, group4*: 11years15years). The correlation coefficient of BMD with age, body weight, height and Tanner stage were 0.696, 0.693, 0.717 and 0.636 respectively. There were sigificant difference. in BMD(g/cm2) between-group 1(BMD : 0.335 0.175) and group 2(BMD : 0.627 0.200), and group 3(BMD : 0.714 0.189) and group.4(BMD : 0. 8730.163) (P<0.05). There was no significant difference of BMD between boys and girls(P<0.05). BMD also increased significantly with development of Tanner stages(Tanner stage 1 : 0.547 0.234, Tanner stage 2 : 0.783 0.136, Tanner stage 3 : 0.998 0.080) (P<0.05). These data indicate that the BMD was correlated with age, body weight, height and Tanner stage significantly and BMD increased significantly during growth spurt occured in 1 to 4years of age and puberty.

Effects of Thyroxine on Hyperkalemia and Renal Cortical Na(+), K(+) - ATPase Activity Induced by Cyclosporin A

Cyclosporin A (CsA)-induced hyperkalemia is caused by alterations in transepithelial K(+) secretion resulting from the inhibition of renal tubular Na(+), K(+) -ATPase activity. Thyroxine enhances renal cortical Na(+), K(+) -ATPase activity. This study investigated the effect of thyroxine on CsA-induced hyperkalemia. Sprague-Dawley rats were treated with either CsA, thyroxine, CsA and thyroxine, or olive-oil vehicle. CsA resulted in an increase in BUN and serum K(+), along with a decrease in creatinine clearance, fractional excretion of potassium, and renal cortical Na(+), K(+) -ATPase activity, as compared with oil vehicle administration. Histochemical study showed reduced Na(+), K(+) -ATPase activity in the proximal tubular epithelial cells of the CsA-treated compared with the oil-treated rats. Histologically, isometric intracytoplasmic vacuolation, disruption of the arrangement and swelling of the mitochondria, and a large number of lysosomes in the tubular epithelium were characteristic of the CsA-treated rats. Co-administration of thyroxine prevented CsA-induced hyperkalemia and reduced creatinine clearance, Na(+), K(+) -ATPase activity, and severity of the histologic changes in the renal tubular cells when compared with the CsA-treated rats. Thyroxine increased the fractional excretion of potassium via the preservation of Na(+), K(+) -ATPase activity in the renal tubular cells. Thus, the beneficial effects of thyroxine may be suited to treatment modalities for CsA-induced hyperkalemia.

A Multicenter Clinical Study on Second Malignancies after Treatment of Childhood Cancer / 대한소아혈액종양학회지

BACKGROUND: This study was undertaken to investigate the frequency, causes, and outcome of second malignancies(SM) following treatment of childhood cancer in Korea. METHODS: The Korean Society of Pediatric Hematology-Oncology(KSPHO) reviewed the records of patients who developed SM during the period of 1981-1997 through nationwide search. RESULTS: Twenty four cases were collected, among which 7 AML, 5 osteosarcoma and 5 ALL were observed. Fifteen of them were boys, and 9 girls (1.7:1). Familial cancer was registered in 5 cases among direct relatives. No interrelationship between first and SM was observed except in 2 retinoblastoma patients who developed osteosarcoma. The SM developed in a period of 8 to 144 months (mean:55 months) after the initiation of treatment for the first malignancy. Sixteen cases had radiotherapy for the first malignancy, and in 6 of them the SM developed in the irradiated area. Fifteen patients were treated with alkylating agents, 12 received anthracyclines and 7 received etoposide. They survived 1 to 110 months (mean:15 months) after development of the SM. Sixteen patients are dead, 3 currently free of disease, and 5 alive with disease. CONCLUSION: AML, osteosarcoma and ALL were most prevalent SM in Korean children. The mean latent period was 55 months, and showed poor mean survival period of 15 months. Radiotherapy seems to be a significant risk factor for the development of SM, but more cases are needed to assess the actual risk of certain chemotherapeutic agent. For this purpose, KSPHO continues to collect the cases of SM and to follow up the registered patients.