Ampaiwan Chuansumrit

A variant in the CD209 promoter is associated with severity of dengue disease

Dengue fever and dengue hemorrhagic fever are mosquito-borne viral diseases. Dendritic cell–specific ICAM-3 grabbing nonintegrin (DC-SIGN1, encoded by CD209), an attachment receptor of dengue virus, is essential for productive infection of dendritic cells. Here, we report strong association between a promoter variant of CD209, DCSIGN1-336, and risk of dengue fever compared with dengue hemorrhagic fever or population controls. The G allele of the variant DCSIGN1-336 was associated with strong protection against dengue fever in three independent cohorts from Thailand, with a carrier frequency of 4.7% in individuals with dengue fever compared with 22.4% in individuals with dengue hemorrhagic fever (odds ratio for risk of dengue hemorrhagic fever versus dengue fever: 5.84, P = 1.4 × 10−7) and 19.5% in controls (odds ratio for protection: 4.90, P = 2 × 10−6). This variant affects an Sp1-like binding site and transcriptional activity in vitro. These results indicate that CD209 has a crucial role in dengue pathogenesis, which discriminates between severe dengue fever and dengue hemorrhagic fever. This may have consequences for therapeutic and preventive strategies.

A scoring system for the classification of β-thalassemia/Hb E disease severity

β‐Thalassemia intermediate patients show a remarkable clinical heterogeneity. We examined the phenotypic diversity of 950 β‐thalassemia/Hb E patients in an attempt to construct a system for classifying disease severity. A novel scoring system based on six independent parameters, hemoglobin level, age at disease presentation, age at receiving first blood transfusion, requirement for transfusion, spleen size, and growth and development, was able to separate patients into three distinctive severity categories: mild, moderate, and severe courses. This system, therefore, can increase the accuracy of studies of genotype–phenotype interactions and facilitate decisions for appropriate patient management. Am. J. Hematol. 2008.

Recombinant activated factor VII in children with acute bleeding resulting from liver failure and disseminated intravascular coagulation.

&NA; Recombinant activated factor VII (rFVIIa) was given to three children with acute bleeding resulting from liver failure and disseminated intravascular coagulation. Cases I and II (girls aged 3 years and 6 years, respectively) were diagnosed with Dengue hemorrhagic fever and prolonged shock. Case III, a boy aged 9 months, underwent left lobe hepatectomy for a hepatoblastoma, during which 60% of his liver was removed. This case was complicated by myoglobinuria, liver and renal impairment and early disseminated intravascular coagulation. All three patients exhibited active bleeding. Cases I and II received rFVIIa combined with other blood component replacement, while Case III received rFVIIa as the only hemostatic agent. A bolus of 40‐180 &mgr;g/kg b.w. was administered followed by 16.5‐33 &mgr;g/kg b.w. per h continuous infusion. As a result, bleeding was controlled, the prothrombin time was shortened and FVII clotting activity was significantly increased. In conclusion, rFVIIa has shown some efficacy in controlling acute bleeding in children with liver failure and disseminated intravascular coagulation. Blood Coagul Fibrinolysis 11 (suppl 1):S101‐S105

Use of an Immunotherapeutic Vaccine to Treat a Life-Threatening Human Arteritic Infection Caused by Pythium insidiosum

A 14-year-old Thai boy presented because of a history of headache, mandibular swelling, and facial nerve palsy. A microorganism identified as Pythium insidiosum was cultured from the mandibular abscesses. Despite treatment with amphotericin B, iodides, ketoconazole, and surgery, the infection progressed. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) of the neck revealed an aneurysm in the external carotid artery. The aneurysm was removed. MRA performed later showed stenosis of the internal carotid artery. Immunotherapy was recommended as a last resort. One hundred microliters of the P. insidiosum vaccine was subcutaneously injected into the patients left shoulder, and 14 days later a similar dose was administered. Four weeks following the first vaccination, the patients headache had disappeared, the facial swellings had dramatically diminished, the cervical lymph node had shrunk, and the proximal left internal carotid artery stenosis had significantly improved. One year after the vaccinations, the boy was considered clinically cured.

Management of haemophilia in the developing world

Summary. The problems with management of haemophilia in developing countries are poor awareness, inadequate diagnostic facilities and scarce factor concentrates for therapy. The priorities in establishing services for haemophilia include training care providers, setting up care centres, initiating a registry, educating affected people and their families about the condition, providing low‐cost factor concentrates, improving social awareness and developing a comprehensive care team. A coagulation laboratory capable of reliably performing clotting times with correction studies using normal pooled, FVIII and FIX deficient patient plasma and factor assay is most essential for diagnosis. More advanced centralized laboratories are also needed. Molecular biology techniques for mutation detection and gene tracking should be established in each country for accurate carrier detection and antenatal diagnosis. Different models of haemophilia care exist. In India, there is no support from the government. Services, including import of factor concentrates, are organized by the haemophilia Federation of India, with support from other institutions. Haemophilia is managed with minimal replacement therapy (about 2000 i.u./PWH/year). In Malaysia, where the system is fully supported by the government, facilities are available at all public hospitals and moderate levels of factor concentrates are available ‘on‐demand” (about 11,000 i.u./PWH/year) at the hospitals. Haemophilia care in South Africa is provided through major public hospitals. Intermediate purity factor concentrates are locally produced (about 12,000 i.u./PWH/year) at low cost. The combined experience in the developing world in providing haemophilia services should be used to define standards for care and set achievable goals.

The use of dengue nonstructural protein 1 antigen for the early diagnosis during the febrile stage in patients with dengue infection.

Background: To evaluate the use of dengue nonstructural protein 1 (NS1) antigen for the early diagnosis during the febrile stage in patients with dengue infection. Methods: A total of 445 sera obtained from 165 patients [dengue fever (DF): 42, dengue hemorrhagic fever (DHF) grade I: 50, II: 63, III and IV: 10] and 8 other febrile illnesses 5–15 years of age, were assayed for the NS1 antigen, dengue-specific Ig M and Ig G antibodies. Results: The positive rates of NS1 antigen among patients with either DF or DHF was 100% (7 of 7) on day 2, 92.3% (12 of 13) on day 3, 76.9% (40 of 52) on day 4, 56.5% (61 of 108) on day 5 of fever; and declined to 43.1% (59 of 137) on day 6 with defervescence and 29.8% (25 of 84) on day 7 (1 day after defervescence). The positive rates of patients with DF were higher than those with DHF but no statistically significant difference was found. However, patients with primary DHF infection had significantly higher positive rates than those with secondary DHF infection. The positive rates of Ig M antibodies were in reverse proportion to those of NS1 antigen. The additional Ig M antibody determination increased the positive rates to 90.4% (47 of 52) on day 4, 83.3% (90 of 108) on day 5 of fever; 95.6% (131 of 137) on day 6 with defervescence, and 88.1% (74 of 84) on day 7. Conclusions: Dengue NS1 antigen testing is suggested as a helpful tool for the early diagnosis of dengue infection after the onset of fever. The additional Ig M antibody determination increased the diagnostic rates.

Bone mineral density, biochemical and hormonal profiles in suboptimally treated children and adolescents with β‐thalassaemia disease

objective Thalassaemia/haemoglobinopathy is a hereditary disease causing increased erythropoiesis and expansion of the bone marrow cavity. As a consequence, there is a reduction in trabecular bone tissue resulting in osteopenia/osteoporosis. The present study was performed to assess bone mineral density (BMD) in children and adolescents with β‐thalassaemia disease and to determine biochemical and hormonal changes that may affect BMD.

Control of bleeding in children with Dengue hemorrhagic fever using recombinant activated factor VII: a randomized, double-blind, placebo-controlled study.

ObjectivesWe evaluated the efficacy and safety of recombinant activated factor VII (rFVIIa) in children aged < 18 years old with grade II or grade III Dengue hemorrhagic fever (DHF) who required blood component therapy for controlling bleeding episodes. Study designPatients were randomized to the rFVIIa group or placebo group in a ratio of 2: 1. rFVIIa or placebo (100 μg/kg body weight) was given by intravenous bolus injection. When bleeding was not effectively controlled, a second dose of rFVIIa or placebo (100 μg/kg) was given 30 min after the first dose. ResultsNine and 16 patients received placebo and rFVIIa, respectively. The demographics, bleeding manifestations and grade of DHF were similar for the rFVIIa and placebo groups. Apart from petechiae and ecchymosis, one to four additional bleeding sites were found in each patient, including hematemesis (n = 15), epistaxis (n = 14), gum bleeding (n = 12), melena (n = 7), hypermenorrhea (n = 4), hematochezia (n = 2) and hematuria (n = 2). The mean total dose of rFVIIa (138.4 ± 50.9 μg/kg) and placebo (145.4 ± 53.7 μg/kg) were comparable. The efficacy of bleeding control at 2 h after the first dose was completely ceased (rFVIIa 75.0% versus placebo 44.4%), decreased (rFVIIa 18.7% versus placebo 11.2%), and unchanged or worsened (rFVIIa 6.3% versus placebo 44.4%). Some patients with active bleeding received platelet concentrates 3–12 h after the first dose of rFVIIa or placebo. The subsequent efficacy of bleeding control at 6, 12 and 24 h was comparable between the two groups. The cumulative use of red blood cells (rFVIIa 31.3% versus placebo 33.3%) and plasma (rFVIIa 25% versus placebo 22%) during the 24-h period was not significantly different between the two groups. In contrast, platelet concentrate requirement in the rFVIIa group (6.3%) was lower than the placebo (33.3%). No clinical evidence of thromboembolic complications or mortality as a result of bleeding was observed. ConclusionrFVIIa appears to be a useful adjunctive treatment to blood component transfusion for controlling active bleeding in children with DHF especially when platelet concentrate is not readily available.

Elevated Soluble Thrombomodulin in the Febrile Stage Related to Patients at Risk for Dengue Shock Syndrome

Background: Children with dengue hemorrhagic fever (DHF) are at risk to develop dengue shock syndrome (DSS) for which neither marker has been demonstrated. Objective: The study was designed to investigate the markers of vascular endothelial cell injuries and dysfunction that might be used as early predictors of the subsequent manifestation of DSS. Methods: The blood samples from 111 patients with dengue fever, DHF and other febrile illness (OFI) were collected daily from the day of admission until discharge and at convalescent stage. The sample from the day of defervescence was defined as day 0, 1 day before defervescence was defined as day –1 and so on. Also, 1 day after defervescence was defined as day +1 and so on. Results: Increased soluble thrombomodulin (sTM) was demonstrated in dengue-infected patients via an enzyme-linked immunosorbent assay. Patients with DSS (DHF grades III and IV) had higher concentrations of sTM than those with dengue fever, DHF grade I, II and OFIs from day –3 until day +2. Increased circulating endothelial cells were detected from day 0 until day +2 in DSS patients as compared with other groups. In addition, increased soluble vascular cell adhesion molecule-1, soluble intercellular adhesion molecule-1 and soluble E-selectin were also found in dengue virus-infected patients as compared with OFIs. Conclusion: Blood sTM may be useful as an early predictor of DSS in dengue infected patients in the febrile stage. However, a further evaluation in a large prospective series is needed.

Alteration of cytokines and chemokines during febrile episodes associated with endothelial cell damage and plasma leakage in dengue hemorrhagic fever.

Background: The leakage of plasma during febrile episodes in dengue-infected patients is a severe condition leading to dengue shock syndrome. Alteration of cytokines/chemokines is suspected to be a major cause of endothelial cell damage in these patients. The study was designed to demonstrate the alteration of cytokines and chemokines in dengue-infected patients during febrile episodes. Methods: The blood samples from 164 patients with dengue fever, dengue hemorrhagic fever and other febrile illnesses were collected daily from the day of hospitalization until discharge and also in the convalescent stage. The levels of cytokines/chemokines were determined using a sandwich chemiluminescent immunoassay, and the hematological parameters were examined by the ADVIA hematological analyzer. Results: Two patterns of cytokines/chemokines alteration were detected at different time points during the febrile episode. The increased factors included interleukin (IL)-4, IL-6, IL-8, IL-10, tumor necrosis factor-&agr;, interferon-&ggr; and monocyte chemoattractant protein-1 whereas IL-1&bgr;, IL-2, vascular endothelial growth factor and epidermal growth factor were decreased. Several cytokines were correlated with disease severity especially in dengue hemorrhagic fever/dengue shock syndrome patients. Conclusions: The alteration in the cytokine/chemokine kinetics during a febrile episode can be used as a predictor for severe dengue infection. The increased and decreased levels at different time points can indicate the disease progression related to vascular leakage in dengue hemorrhagic fever/dengue shock syndrome patients.