A uniform conditioning regimen of busulfan, fludarabine, and antithymocyte globulin for allogeneic haematopoietic cell transplantation from haploidentical family, matched sibling, or unrelated donors-A single-centre, prospective, explorative study.

In a prospective, explorative study, the donor-source difference of haploidentical family (HF), matched sibling (MS), and unrelated donors (UD) was evaluated for the outcome of haematopoietic cell transplantations (HCT) in 101 patients with acute myeloid leukaemia (AML) in complete remission (CR). To eliminate compounding effects, a uniform conditioning regimen containing antithymocyte globulin (ATG) was used. After transplantation, there was a significantly higher cumulative incidence of acute graft-versus-host disease (GVHD) in HF-HCT patients (49%, 7%, and 16% for HF-, MS- and UD-HCT respectively; p < 0.001). A quarter of acute GVHD cases observed in HF-HCT patients occurred within three days of engraftment and were characterized by diffuse skin rash, fever, weight gain, and hypoalbuminaemia. This peri-engraftment acute GVHD was not observed in MS-HCT or UD-HCT patients. Additionally, a significantly higher proportion of HF-HCT patients achieved complete donor chimaerism in the peripheral mononuclear cells at one month (88%, 46%, and 69% for HF-, MS- and UD-HCT respectively; p = 0.001). There was no significant difference in engraftment, chronic GVHD, leukaemia recurrence, non-relapse mortality, and patient survival. In patients with AML in CR who received HCT using ATG-containing conditioning, stronger donor-patient alloreactivity was observed in HF-HCT, in terms of increased acute GVHD and higher likelihood of complete donor chimaerism.

Reduced-Intensity Conditioning with Busulfan, Fludarabine, and Antithymocyte Globulin for Hematopoietic Cell Transplantation from Unrelated or Haploidentical Family Donors in Patients with Acute Myeloid Leukemia in Remission.

To investigate the role of antithymocyte globulin (ATG)-containing reduced-intensity conditioning (RIC) in hematopoietic cell transplantation (HCT) from unrelated (UD) or haploidentical family donors (HFD), we conducted a phase 2 trial of 237 patients (age range, 16 to 69 years) with acute myeloid leukemia (AML) in remission. Patients undergoing UD-HCT (n = 93) or HFD-HCT (n = 59) received RIC comprising busulfan, fludarabine, and ATG, 9 mg/kg, whereas those undergoing HCT from matched sibling donors (MSD, n = 85) received myeloablative busulfan and cyclophosphamide conditioning or aforementioned RIC with ATG, 4.5 mg/kg. For graft-versus-host disease (GVHD) prophylaxis, cyclosporine and methotrexate were administered. The median follow-up period was 44.7 months after HCT for 161 survivors. For UD-HCT versus HFD-HCT, there were no significant differences in leukemia recurrence, nonrelapse mortality, relapse-free survival, grades 2 to 4 acute GVHD, and moderate-to-severe chronic GVHD. Furthermore, when the outcomes of UD-HCT and HFD-HCT were combined and compared with those of MSD-HCT, there were no significant differences in leukemia recurrence (3-year cumulative incidence, 30% versus 29%), nonrelapse mortality (3-year cumulative incidence, 7% versus 8%), relapse-free survival (3-year estimate, 63% versus 63%), and grades 2 to 4 acute GVHD (120-day cumulative incidence, 16% versus 13%). Moderate-to-severe chronic GVHD, however, occurred less frequently in UD/HFD-HCT (2-year cumulative incidence, 22% versus 40%; P = .006). The addition of ATG to conditioning regimen was a significant predictor for less chronic GVHD (subdistribution hazard ratio, .59). In AML in remission, UD/HFD-HCT after ATG-containing RIC achieved leukemia control equivalent to that of MSD-HCT. Despite HLA disparity in UD/HFD-HCT, chronic GVHD occurred less frequently after ATG-containing RIC, suggesting a strong GVHD-modulating effect of ATG.

Donor-Derived Natural Killer Cell Infusion after Human Leukocyte Antigen-Haploidentical Hematopoietic Cell Transplantation in Patients with Refractory Acute Leukemia.

The optimum method of donor natural killer cell infusion (DNKI) after allogeneic hematopoietic cell transplantation (HCT) remains unclear. Fifty-one patients (age range, 19 years to 67 years) with refractory acute leukemia underwent HLA-haploidentical HCT and underwent DNKI on days 6, 9, 13, and 20 of HCT. Median DNKI doses were .5, .5, 1.0, and 2.0 × 108/kg cells, respectively. During DNKI, 33 of the 45 evaluated patients (73%) developed fever (>38.3°C) along with weight gain (median, 13%; range, 2% to 31%) and/or hyperbilirubinemia (median, 6.2 mg/dL; range, 1.0 mg/dL to 35.1 mg/dL); the toxicity was reversible in 90% of patients. After transplantation, we observed cumulative incidences of neutrophil engraftment (≥500/µL), grade 2 to 4 acute graft-versus-host disease (GVHD), chronic GVHD, and nonrelapse mortality of 84%, 28%, 30%, and 16%, respectively. The leukemia complete remission rate was 57% at 1 month after HCT and 3-year cumulative incidence of leukemia progression was 75%. When analyzed together with our historical cohort of 40 patients with refractory acute leukemia who underwent haploidentical HCT and DNKI on days 14 and 21 only, higher expression of NKp30 (>90%) on donor NK cells was an independent predictor of higher complete remission (hazard ratio, 5.59) and less leukemia progression (hazard ratio, .57). Additional DNKI on days 6 and 9 was not associated with less leukemia progression (75% versus 55%).

Single nucleotide polymorphism of Wilms' tumor 1 gene rs16754 in Korean patients with cytogenetically normal acute myeloid leukemia.

A recent study from Germany showed that WT1 single nucleotide polymorphism (SNP) rs16754 was an independent prognostic factor in cytogenetically normal acute myeloid leukemia (CN-AML). We analyzed clinical impact of the WT1 rs16754 genotype on disease characteristics and outcomes in Korean patients with CN-AML. A total of 73 patients with CN-AML were included in the study. All patients received standard induction chemotherapy and their bone marrow or peripheral blood samples were cryopreserved at the time of diagnosis. WT1 exons 7 and 9 were amplified using polymerase chain reaction and directly sequenced. The genotype frequency for WT1 rs16754 was 6.8% for AA, 39.7% for GA, and 53.4% for GG. G was a minor allele in German population, whereas it was a major allele in Korean (13.7% vs. 73.3%, P < 0.001). Complete remission was induced in 85.3% of patients with GA/AA and 84.6% of those with GG (P = 0.936). Survival rates were also similar between patients with GG and those with GA/AA. Asian and Western populations exhibited significant differences in allele and genotype frequencies of WT1 rs16754. In Korean patients with CN-AML, WT1 SNP rs16754 had no significant impact on clinical outcomes and further investigations are needed to define prognostic implication of WT1 SNP rs16754 in CN-AML.

Drug-resistant pandemic (H1N1) 2009, South Korea.

Eleven patients with drug-resistant pandemic (H1N1) 2009 were identified in South Korea during May 2009-January 2010. Virus isolates from all patients had the H275Y mutation in the neuraminidase gene. One isolate had the I117M mutation. Of the 11 patients, 6 were ≥ 59 months of age, and 5 had underlying immunosuppressive conditions.

Clinical characteristics and etiology of travelers' diarrhea among Korean travelers visiting South-East Asia.

The morbidity of travelers' diarrhea (TD) is still high. This study examined the incidence of common pathogens and characteristics of TD among Korean travelers who visited South-East Asian countries. We performed a prospective study involving 479 Korean travelers with diarrheal disease from February 2009 to April 2009 and stool samples were examined and questionnaire surveys were done after arrival. Enterotoxigenic Escherichia coli (ETEC) was found in 36.0% of TD cases, as were the following: Enteroaggregative Escherichia coli (EAEC) in 27.0%, Vibrio parahaemolyticus in 13.1%, and Norovirus in 11.5%. The detected rate of classic TD was higher in men (P = 0.007), in patients who had a shorter duration trip (P = 0.023) and in patients who drank more than 1 liter of water per day (P = 0.037). Positive stool culture rates were higher in men (P = 0.005), in hospitalized patients (P = 0.013). and in those who consumed impure water or raw foods (P = 0.033). A higher severity of disease corresponded to a significantly higher culture positivity rate (P = 0.029). We should consider the possibility of other pathogens in addition to ETEC in patients with TD who visit South-East Asia. Travelers need to educate about risk factors associated with TD.

Fatal cases of 2009 pandemic influenza A (H1N1) in Korea.

The aim of this study was to describe the features of deaths associated with the 2009 pandemic influenza A (H1N1) by 26 November 2009 in Korea. We collected standardized case reports on 115 confirmed deaths through a nationwide enhanced influenza surveillance system. The median age was 61 yr (interquartile range [IQR], 0.2-97 yr) and 58 (50.4%) were females. The case fatality rate was estimated as 16 per 100,000 cases. The age-related mortality rate had a J-shaped curve. Eighty-three patients (72.2%) had at least 1 underlying medical disease. Bacterial co-infections were detected in the blood or sputum specimens from 34 patients. Of the 63 patients who were hospitalized in the intensive care unit (ICU), the median time from symptom onset to hospital admission was 2 days (IQR, 0-22 days), and the median time from hospitalization to ICU admission was 1 day (IQR, 0-17 days). Neuraminidase inhibitors were administered to 100 patients (87.0%), 36% of whom began treatment within 2 days. In conclusion, fatal cases from the 2009 influenza A (H1N1) infection in Korea are mainly aged individuals with underlying disease, and associated with pneumonia, bacterial co-infections, and multi-organ failure.

A locally acquired falciparum malaria via nosocomial transmission in Korea.

A 57-year old man who was admitted to an emergency room of a tertiary hospital with hemoptysis developed malarial fever 19 days later and then died from severe falciparum malaria 2 days later. He had not traveled outside of Korea for over 30 years. Through intensive interviews and epidemiological surveys, we found that a foreign patient with a recent history of travel to Africa was transferred to the same hospital with severe falciparum malaria. We confirmed through molecular genotyping of the MSP-1 gene that Plasmodium falciparum genotypes of the 2 patients were identical. It is suggested that a breach of standard infection control precautions resulted in this P. falciparum transmission between 2 patients in a hospital environment. This is the first report of a nosocomial transmission of falciparum malaria in Korea.

Allogeneic hematopoietic cell transplantation in adult patients with myelodysplastic/myeloproliferative neoplasms.

BACKGROUND: In adults, the 2 main types of myelodysplastic/myeloproliferative neoplasms (MDS/MPN) are chronic myelomonocytic leukemia (CMML) and atypical chronic myeloid leukemia (aCML). Both are associated with a poor prognosis. Allogeneic hematopoietic cell transplantation (HCT) is the only known curative treatment modality for these diseases, but data on outcomes following such treatment are limited. We analyzed the outcomes of patients with MDS/MPN after allogeneic HCT. METHODS: This retrospective study included 10 patients with MDS/MPN who received allogeneic HCT at Asan Medical Center from 2002 to 2010. Of these 10 patients, 7 had CMML, 2 had aCML, and 1 had unclassifiable MDS/MPN. Five patients received a myeloablative conditioning (MAC) regimen (busulfan-cyclophosphamide), and 5 received reduced-intensity conditioning (RIC) regimen. RESULTS: Neutrophil engraftment was achieved in all patients. After a median follow-up of 47.5 months among surviving patients, 4 had relapsed and 5 had died. There was only 1 treatment-related death. The 5-year rates of overall, relapse-free, and event-free survival were 42.2%, 51.9%, and 46.7%, respectively. Relapse was the leading cause of treatment failure, and all relapses were observed in patients who had received RIC and who did not develop chronic graft-versus-host disease. CONCLUSION: Allogeneic HCT can induce durable remission in patients with MDS/MPN, but RIC cannot replace MAC in patients eligible for myeloablative treatments.

Study of the genetic discrimination between imported and autochthonous cases of malaria in South Korea.

There has been a great increase of Plasmodium vivax incidences in the Republic of Korea and the genetic diversity of the parasite became more complex with the rapid dissemination of newly introduced genotypes. Surveillance of imported malaria is very important, but there is no good way to determine imported vs. internal cases. In this study, we characterized imported vivax cases, analyzed the genetic sequence of three imported vivax malaria cases for the merozoite surface protein-1 (MSP-1) and circumsporozoite protein (CSP) genes, and clearly discriminated an imported vivax case that was misdiagnosed as indigenous by genetic analysis. PCR reaction for the merozoite surface protein-1 (MSP-1) and circumsporozoite protein (CSP) genes from three imported vivax cases were amplified and sequenced. The genetic variations were compared with a previously constructed database of South Korean isolates. The imported vivax cases showed various patterns on incubation period before onset. Most cases were from other parts of Asia. The MSP-1 gene sequence analysis of three imported cases showed that the imported cases had completely different sequences from any subtypes from Korean isolates. Case-1 and Case-2 exact match with an Indian isolate, and Case-3 had great similarity with isolates from countries neighboring Indonesia. CSP gene analysis based on the repeat patterns showed similar results that the sequences from the imported cases well matched with the patient's traveled countries and completely discriminated with indigenous cases. AMA-1 gene analysis also supported these results. We were able to clearly distinguish three imported vivax cases from indigenous by using a genetic database of Korean isolates and were able to suspect its origin by genotyping. This study demonstrated the usefulness of genetic survey on imported malaria cases.

Clinical characteristics of Korean pediatric patients critically ill with influenza A (H1N1) virus.

BACKGROUND: Novel influenza A (H1N1) virus infection has persisted mainly through person-to-person transmission in schools. However, data on critically ill patients infected with H1N1 are currently limited. This study was conducted to investigate the epidemiological characteristics, clinical features, treatment modalities, and clinical outcomes of pediatric patients critically ill with H1N1 infection. METHODS: Subjects included 30 critically ill pediatric patients reported to the Korea Centers for Disease Control and Prevention (KCDC) between June and November 2009. Data were obtained by medical record review and interviews with primary treating physician. RESULTS: Of the 30 patients, 14 died and 16 were discharged from the hospital with complete recovery. The median patient age was 7 years (range, 2 months to 18 years). Nineteen patients belonged to the high-risk group. Cough was the most common initial symptom, followed by fever. In most patients, serum levels of C-reactive protein and lactate dehydrogenase were elevated. Oseltamivir, an antiviral agent, was administered to 29 patients. The most common causes of death were encephalopathy and myocarditis, with a higher mortality rate in the high-risk group. Platelet counts were significantly lower than normal and serum aspartate aminotransferase levels significantly higher in the non-survivors. CONCLUSIONS: The results of this study suggest that Korean high-risk pediatric patients have an elevated mortality rate following infection with novel influenza A (H1N1) virus. Further studies involving high-risk pediatric patients classified using consistent criteria are needed to confirm our results.

[Acute health effects of the Hebei oil spill on the residents of Taean, Korea].

OBJECTIVES: On December 7, 2007, the Hebei Spirit oil tanker spilled out 12,547 kl of crude oil on the Yellow Sea 10 km away from the cost of Taean Province, Korea. As the coastline has been contaminated, local residents have been exposed to crude oil. Because the residents were showing many symptoms, we investigated the acute health effects of this oil spill on them. METHODS: We conducted a cross-sectional study consisting of the heavy and moderately oil soaked area in Taean and the lightly oil soaked area in Seocheon. Ten seashore villages were selected from each area, and 10 male and female adults were selected from each village. We interviewed the subjects using a structured questionnaire on the characteristics of residents, the cleanup activities, the perception of oil hazard, depression and anxiety, and the physical symptoms. The odds ratios and 95% confidence intervals were analyzed using logistic regression analysis. The logistic regression model was adjusted for age, gender, education, smoking, the perception of oil hazard and anxiousness. RESULTS: The more highly contaminated the area, the more likely it was for residents to be engaged in cleanup activities and have a greater chance of exposure to oil. The indexes of anxiety and depression were higher in the heavy and moderately oil soaked areas. The increased risks of headache, nausea, dizziness, fatigue, tingling of limb, hot flushing, sore throat, cough, runny nose, shortness of breath, itchy skin, rash, and sore eyes were significant. CONCLUSIONS: The results suggest that exposure to crude oil is associated with various acute physical symptoms. Long-term investigation is required to monitor the residents' health.

[Seroprevalence and risk factors of brucellosis among slaughterhouse workers in Korea].

OBJECTIVES: The incidence of zoonoses in Korea has increased recently. However, the study of high risk groups for zoonoses has not been conducted to date in Korea. Thus, we did this study to obtain data on brucellosis among slaughterhouse workers in Korea. METHODS: We evaluated the structure of slaughterhouses and the process of slaughtering by reviewing the relevant literature and doing field studies. We visited 73 slaughterhouses and 62 residual products handle houses across the country. In addition, we conducted a questionnaire survey of the work activities, and obtained blood samples in order to determine the seroprevalence and risk factors of brucellosis. The titers of brucellosis antibodies were measured using the standard tube agglutination test (SAT). We diagnosed subjects as seropositive for Brucellosis if the titers were more than 1:160. The data collected was evaluated using SPSS ver. 17.0. RESULTS: We included 1,503 subjects and obtained 1,482 blood samples among them: 849 workers involved in slaughtering, 351 handlers of residual products, 190 inspectors and their assistants, and 92 grading testers and their assistants. The seroprevalence of brucellosis among the slaughterhouse workers was 0.8% (95% CI=0.4-1.5). Broken down, the seroprevalence of brucellosis among the workers involved in slaughtering was 0.7% (95% CI=0.3-1.6), the handlers of residual products was 1.7% (95% CI=0.7-3.9) respectively. Risk factors for contracting brucellosis among slaughterhouse workers were being splashed with cattle blood around the mouth, cattle secretions around the body and not putting on protective apron while at work. CONCLUSIONS: An educational program is needed for high risk groups on zoonoses about the prevention of infection. Thus, effective working guidelines for workers who participate in the slaughter of animals must be developed in order to protect them from zoonoses.