Fu-Yuan Huang

Two new susceptibility loci for Kawasaki disease identified through genome-wide association analysis

To find new candidate loci predisposing individuals to Kawasaki disease, an acute vasculitis that affects children, we conducted a genome-wide association study in 622 individuals with Kawasaki disease (cases) and 1,107 controls in a Han Chinese population residing in Taiwan, with replication in an independent Han Chinese sample of 261 cases and 550 controls. We report two new loci, one at BLK (encoding B-lymphoid tyrosine kinase) and one at CD40, that are associated with Kawasaki disease at genome-wide significance (P < 5 × 10−8). Our findings may lead to a better understanding of the role of immune activation and inflammation in Kawasaki disease pathogenesis.

Clinical characteristics and survival of trisomy 18 in a medical center in Taipei, 1988–2004†

Trisomy 18 is the second most common autosomal trisomy in newborns. The birth prevalence of this disorder is approximately 1 in 3,000 to 1 in 8,000, and the life span of the majority of patients is less than 1 year. As information regarding outcome in trisomy 18 is rather fragmentary in the literature, this study is aimed at investigating the survival and natural history of trisomy 18. We also evaluated the survival age and management of trisomy 18 in two different periods, before and after the implementation of National Health Insurance (NHI) program. Thirty‐nine cases of trisomy 18 were collected in Mackay Memorial Hospital in a 17‐year period, from 1988 to 2004. Delivery data, survival age, management before and after the implementation of NHI program, structural defects, image findings and cytogenetic results were analyzed by medical and nurses records. The diagnosis of trisomy 18 was based on the prenatal amniocentesis or postnatal chromosome analysis. Three patients had trisomy 18 mosaicism. Since cardiovascular and central nervous systems are the most common organ systems involved in this disorder, 31 patients received brain ultrasonography and heart ultrasonography for evaluation of their multiple anomalies after admission. All patients except one died in their first year due to severe malformations of the cardiovascular or central nervous systems. The median survival age was 6 days. We found a longer survival with female patients than with male patients (P < 0.05). Implementation of NHI program in the more recent decade of this study period was associated with longer survival of trisomy 18 (P < 0.05). The three most common structural defects were clenched hands (95%), rocker bottom feet (90%), and low set or malformed ears (90%). Low birth weight was present in 90%. By cardiac ultrasonography, the top four heart defects were ventricular septal defect (94%), patent ductus arteriosus (77%) and atrial septal defect (68%). However, ten cases (32%) had complex congenital heart defects. By brain ultrasonography, the most common brain lesion was cerebellar hypoplasia (32%), followed by brain edema (29%), enlarged cisterna magna (26%) and choroid plexus cysts (19%). Although most patients with trisomy 18 die within the first few weeks after birth, it is important to recognize that a small but notable percentage of these patients will survive the first year. When prenatal or postnatal decisions need to be made, the possibility of long‐term survival should be included in any discussion to enable families to make the most appropriate decision.

Influenza Pandemics: Past, Present and Future

Influenza A virus is well known for its capability for genetic changes either through antigen drift or antigen shift. Antigen shift is derived from reassortment of gene segments between viruses, and may result in an antigenically novel virus that is capable of causing a worldwide pandemic. As we trace backwards through the history of influenza pandemics, a repeating pattern can be observed, namely, a limited wave in the first year followed by global spread in the following year. In the 20th century alone, there were three overwhelming pandemics, in 1918, 1957 and 1968, caused by H1N1 (Spanish flu), H2N2 (Asian flu) and H3N2 (Hong Kong flu), respectively. In 1957 and 1968, excess mortality was noted in infants, the elderly and persons with chronic diseases, similar to what occurred during interpandemic periods. In 1918, there was one distinct peak of excess death in young adults aged between 20 and 40 years old; leukopenia and hemorrhage were prominent features. Acute pulmonary edema and hemorrhagic pneumonia contributed to rapidly lethal outcome in young adults. Autopsies disclosed multiple-organ involvement, including pericarditis, myocarditis, hepatitis and splenomegaly. These findings are, in part, consistent with clinical manifestations of human infection with avian influenza A H5N1 virus, in which reactive hemophagocytic syndrome was a characteristic pathologic finding that accounted for pancytopenia, abnormal liver function and multiple organ failure. All the elements of an impending pandemic are in place. Unless effective measures are implemented, we will likely observe a pandemic in the coming seasons. Host immune response plays a crucial role in disease caused by newly emerged influenza virus, such as the 1918 pandemic strain and the recent avian H5N1 strain. Sustained activation of lymphocytes and macrophages after infection results in massive cytokine response, thus leading to severe systemic inflammation. Further investigations into how the virus interacts with the hosts immune system will be helpful in guiding future therapeutic strategies in facing influenza pandemics.

Transmission of cytomegalovirus from mothers to preterm infants by breast milk.

Objectives: To assess the risk of transmission of cytomegalovirus (CMV) by breast milk from CMV-seropositive mothers to their breast-fed preterm infants and to evaluate their outcome. Patients and Methods: The study population comprised breast-fed preterm infants with a birth weight of <1500 g and gestational age of <35 weeks. Venous blood samples from the mothers and infants were tested for CMV IgG and IgM antibodies on the 5th and 30th day after birth. Breast milk was obtained for CMV DNA detection by polymerase chain reaction and viral culture on the 5th day and on the 3rd, 6th and 12th week. Urine samples of the babies were collected at the same time for CMV culture. Neurodevelopmental assessment was done at 6 months of age, corrected for preterm birth. Results: Thirty-eight mothers and 42 infants (including 4 sets of twins) were enrolled in the study. A mother-infant pair was excluded because of inadequate breast milk collection. Thirty-six mothers (97.3%) were CMV-seropositive. CMV DNA of breast milk was detected in 35 seropositive mothers. Six infants of 5 mothers were infected (infected group) at a mean of 77 days after birth, and 34 infants of 31 mothers were not (noninfected group). In all the mothers of the infected group, CMV virus could be cultured from the milk whey. The average maternal CMV IgG on day 5 after delivery was higher in the infected than in the noninfected group. Sepsis-like symptoms and hyperbilirubinemia were more frequently noted in the infected infants than in the noninfected, but the difference was not statistically significant. Neurodevelopmental outcome did not significantly differ between the 2 groups. Conclusions: The risk of CMV infection in breast-fed premature infants was highest when the mothers shed viable virus in their breast milk. These mothers had high CMV IgG, which may help identify those mother-infant pairs at risk. Inactivation of the virus in milk by freezing may be a way of reducing the transmission of this virus via breast milk.

Screening Young Children with a First Febrile Urinary Tract Infection for High-grade Vesicoureteral Reflux with Renal Ultrasound Scanning and Technetium-99m-labeled Dimercaptosuccinic Acid Scanning

OBJECTIVE To evaluate the predictive value of renal ultrasound scanning and 99m-Technetium-dimercaptosuccinic acid (DMSA) scintigraphy for high-grade vesicoureteral reflux (VUR) in young children with a first urinary tract infection (UTI). STUDY DESIGN The medical records of children who had been examined with renal ultrasound scanning, DMSA scanning, and voiding cystourethrography (VCUG) were reviewed. The findings of renal ultrasound scanning, DMSA scanning, and their predictive values were evaluated. RESULTS Of 699 children, high-grade VUR (grades III-V) was diagnosed in 119 (17.0%). Signs of renal hypodysplasia (OR, 16.15), cyclic dilatation of pelvicaliceal system (OR, 11.73), hydroureter (OR, 4.00) with renal ultrasound scanning, and renal hypodysplasia (OR, 8.78), acute pyelonephritis (OR, 2.76) with DMSA scanning were associated with high-grade VUR. The sensitivities for high-grade VUR of ultrasound scanning alone (67.2%) or DMSA scanning alone (65.5%) were not as good as that of a both-test strategy, which had a sensitivity rate of 83.2%. The negative predictive value of the both-test strategy was 91.5%. CONCLUSION Renal ultrasound scanning and DMSA scanning both should be routinely performed in children with a first febrile UTI. VCUG is only indicated when abnormalities are apparent on either ultrasound scanning or DMSA scanning or both.

Sepsis during total parenteral nutrition : exploration of risk factors and determination of the effectiveness of peripherally inserted central venous catheters

BACKGROUND Sepsis is the most frequent serious complication during total parenteral nutrition (TPN), resulting in increased morbidity, mortality and health care costs. Existing reports have not documented the risk factors of sepsis during TPN. The objectives of this study were to determine the rate of sepsis in our practice and to explore the risk factors for sepsis during TPN. We also determined the role and efficacy of using peripherally inserted central venous catheters (PCVC) as insertion catheters to administer TPN. METHODS From October, 1994, to May, 1996, we administered TPN to 378 pediatric patients hospitalized at Mackay Memorial Hospital. We followed all cases for the occurrences of any complications while administering TPN. We studied all patients who had fever, a clinical presentation of sepsis and a positive blood culture during their course of TPN. RESULTS During the 20-month period 378 patients received TPN for a total of 6562 days. Fifty-six patients presented with clinical sepsis and positive blood cultures. Significant features in the sepsis group included longer duration of TPN, age < 3 months, usage of central venous catheters, gastrointestinal diseases as indication for TPN, low birth weight and short gestational age in prematurity. Seven patients died despite prompt antimicrobial therapy. One hundred eleven patients received TPN via PCVC for a mean duration of 17.1 days, significantly longer than 10.4 days in the peripheral intravenous catheter group but no difference between the sepsis rates. CONCLUSION Considering the high incidence of sepsis during TPN, every attempt should be made to minimize the length of TPN therapy and encourage early enteral feeding. We also recommend the use of PCVC in patients requiring prolonged nutritional support.

Association of CTLA4 gene A–G polymorphism with type 1 diabetes in Chinese children†

The CTLA4 (cytotoxic T lymphocyte associated antigen‐4) gene encodes the T cell receptor involved in the control of T cell proliferation and mediates T cell apoptosis. Thus it is a strong candidate gene for T cell‐mediated autoimmune disease. There is polymorphism at position 49 in exon 1 of the CTLA4 gene, providing a A–G exchange. This polymorphism is reportedly associated with type 1 diabetes in Caucasians but not in a small data set of Chinese. We wished to test this polymorphism in a larger and more homogeneous data set of Chinese children with type 1 diabetes and normal adult controls.

T-antigen activation for prediction of pneumococcus-induced hemolytic uremic syndrome and hemolytic anemia.

Background: Among the most severe complications of invasive pneumococcal infection are hemolytic uremic syndrome (P-HUS) and hemolytic anemia (P-HA), which occur when the Thomsen-Freidenreich antigen (TA) is exposed on erythrocytes, platelets and glomeruli. Methods: To determine the positive predictive value, sensitivity, and specificity of early TA activation testing for P-HUS or P-HA and to compare the microbiologic features of pneumococcus isolates associated or not associated with TA activation. The case records for 36 patients with invasive pneumococcal infection who had been tested for TA activation were retrospectively reviewed. Clinical and laboratory data were compared between patients with and without TA activation. Results: Positive TA activation was 86% sensitive and 57% specific for P-HUS or P-HA. The positive predictive value was 76%. There were no between-group differences in antibiotic susceptibility of the pneumococcal isolates. Pneumococcal serotype 14 was the most frequent (5/10 isolates tested) serotype causing P-HUS. Of the 36 patients, 13 required packed red blood cell transfusion, 3 died, and 2 required extracorporeal membrane oxygenation. No patient had long-term renal sequelae. Conclusions: TA activation is a reasonable predictor of P-HUS or P-HA and could be useful if tested soon after invasive pneumococcal disease is first diagnosed.

Polymorphism of Transmembrane Region of MICA Gene and Kawasaki Disease

Kawasaki disease is a febrile disease of children complicated with vasculitis of the coronary arteries and potential aneurysm formation. It has been recognized worldwide and appears to be increasing in frequency. Studies have found that Kawasaki disease is associated with major histocompatibility complex (MHC) class I B antigens. The MHC-class-I-chain-related gene A (MICA) is located near HLA-B. It has a triplet repeat microsatellite polymorphism in the transmembrane region. We investigated the microsatellite polymorphism in children with Kawasaki disease and controls. Seventy children (46 boys), age at diagnosis 1.68 ± 1.69 years, with Kawasaki who were treated with aspirin as well as intravenous gamma-globulin were enrolled. Control subjects consisted of 154 children (87 boys), age 2.81 ± 2.12 years. Phenotype frequency of allele A4 in patients with aneurysm formation was significantly lower than in patients without aneurysms [relative risk (RR) = 0.06, 95% confidence interval (CI) = 0.01–0.48, p = 0.00469, pc = 0.0232] and showed a similar tendency when compared with controls. Gene frequency of allele A4 was also significantly lower in patients who developed aneurysms than in patients who did not (RR = 0.07, 95% CI = 0.01–0.57, p = 0.0057, pc = 0.0282). Gene frequency of allele A5 showed a tendency to be higher in patients who developed aneurysms than in controls (RR = 2.35, 95% CI = 0.98–5.63, p = 0.0486, pc = 0.220). Allele A5.1 tended to be negatively associated with Kawasaki disease (RR = 0.57, 95% CI = 0.35–0.93, p = 0.022, pc = 0.105). Our study showed that allele A4 was negatively associated with coronary aneurysm formation in Kawasaki disease. This suggests that allele A4 protects the children with Kawasaki disease from developing coronary aneurysms after aspirin and gamma globulin therapy.

Pancreatitis in children - experience with 43 cases

Pancreatitis in children is not common and can be associated with severe morbidity and mortality. We encountered 43 children, ranging in age from 2 to 18 years, with pancreatitis over the past 10 years. The diagnosis of pancreatitis was made in those patients who showed: (1) significant intra-operative pathology or; (2) clinical findings of pancreatic inflammation and laboratory confirmation. More than one third (16 cases) of the cases were due to trauma, other causes included systemic disease (10), structural disease (8), and toxins or drugs (4). Five cases were classified as idiopathic. Most of the patients presented with abdominal pain (95%) and vomiting (56%). Jaundice was found in 7 patients and an abdominal mass in 2. Morbidity included pseudocyst (10), relapse (4), hyperglycaemia (4) and miscellaneous problems. Eight (50%) of the patients with trauma and 6 (86%) of the patients with structural diseases required surgery. Other patients were managed conservatively with bowel rest, gastric decompression, intravenous fluid and total parenteral nutrition. One case had a fatal outcome. All the survivors did well in long term follow up. Relevant literature has been reviewed and the sensitivity of various diagnostic modalities compared and discussed. A lesser known association between pancreatitis and structural anomalies such as choledochal cyst is discussed. To our knowledge, the present review is the first on pancreatitis in Chinese children.ConclusionPancreatitis can occur from a wide variety of causes and may result in severe complications. Early diagnosis, close monitoring and aggressive intervention are mandatory to reduce morbidity and mortality.