Nan-Chang Chiu

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.

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.

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.

Comparison of hemocytometer leukocyte counts and standard urinalyses for predicting urinary tract infections in febrile infants.

Objectives. To compare the accuracy of standard and hemocytometer white blood cell (WBC) counts and urinalyses for predicting urinary tract infection (UTI) in febrile infants. Methods. Enrolled were 230 febrile infants <12 months of age. All urine specimens were obtained by suprapubic bladder aspiration and microscopically analyzed by the standard urinalysis (UA) and by hemocytometer WBC counts simultaneously, and quantitative urine cultures were performed. Receiver‐operating characteristic (ROC) curves were constructed for each method of UA. The optimal cutoff point of the UA test in predicting UTI was determined by ROC analysis. Results. There were 37 positive urine cultures of at least 1000 CFU/ml. Of these 37 patients, 9 females and 28 males, 1 had a positive blood culture (Escherichia coli). Thirty (81%) of the positive urine cultures had a bacterial colony count ≧100 000 colony‐forming units/ml, whereas the remaining had between 1000 and 50 000 colony‐forming units/ml. The area under the ROC curve for standard UA was 0.790 ± 0.053, compared with 0.900 ± 0.039 for hemocytometer WBC counts (P < 0.05). For hemocytometer WBC counts, the presence of ≧10 WBC/&mgr;l appeared to be the most useful cutoff point, yielding a high sensitivity (83.8%) and specificity (89.6%). Standard UA, with a cutoff point of 5 WBC/high power field, had a lower sensitivity (64.9%) and similar specificity (88.1%). The hemocytometer WBC counts showed significantly greater sensitivity and positive predictive value (83.8 and 60.8%, respectively) than the standard urinalysis (64.9 and 51.1%, respectively) (P < 0.05). The accuracy, specificity and likelihood ratio of hemocytometer WBC counts were also greater than that of standard UA (88.7, 89.6 and 8.08%vs. 84.3, 88.1 and 5.44%). Conclusion. Hemocytometer WBC counts provide more valid and precise prediction of UTI in febrile infants than standard UA. The presence of ≧10 WBC/&mgr;l in suprapubic aspiration specimens is the optimum cutoff value for identifying febrile infants for whom urine culture is warranted.

High cytomegalovirus load and prolonged virus excretion in breast milk increase risk for viral acquisition by very low birth weight infants.

Background: Breast milk is the main source of postnatal human cytomegalovirus (HCMV) infection. The aim of this study was to assess the relationship between HCMV load in breast milk and viral transmission to very low birth weight (VLBW) infants. Methods: Breast-fed VLBW infants who were born to HCMV-seropositive mothers and who were managed in a neonatal intensive care unit were enrolled in the study. Blood from mothers and infants was tested for HCMV antibodies after birth. Breast milk was collected for viral culture and HCMV load measurement. Urine from the babies was obtained for HCMV-DNA detection. Symptoms of HCMV infection were recorded and evaluated by neonatologists. Results: Of the 23 evaluated mothers during a 1-year period, 19 were HCMV seropositive; 17 of the women had detectable HCMV-DNA in their breast milk whey. Of the 23 infants born to the 19 seropositive mothers, 8 infants of 8 mothers had HCMV-DNA detected in the urine, indicating that they were infected, even though the breast milk was always frozen prior to feeding. Three infected infants had symptoms. At 4 weeks after delivery, the median viral load in breast milk from mothers of the 8 infected infants was significantly higher than that from mothers of the 15 noninfected infants (P = 0.04). HCMV was detectable in breast milk for a significantly longer period in mothers of infected infants (7.5 vs. 2.6 weeks P = 0.03). Conclusions: High HCMV load and prolonged virus excretion in breast milk are maternal risk factors for viral transmission to VLBW infants.

Deep Neck Infections in Different Age Groups of Children

BACKGROUND/PURPOSE Deep neck infections (DNIs) can cause significant morbidity in children. This study analyzes the clinical presentations, diagnostic clues, and age relationship of DNI in pediatric patients. METHODS Pediatric patients admitted to our hospital from January 1996 to December 2007 with a diagnosis of DNIs were reviewed retrospectively. Diseases were categorized according to the site of infection: peritonsillar, parapharyngeal, and retropharyngeal spaces. Patients were divided into two groups: children (aged < 10 years) and adolescents (aged 10-18 years). RESULTS Fifty pediatric patients were enrolled, including nine with DNI in the retropharyngeal space, 17 in the parapharyngeal, 21 in the peritonsillar and three with mixed type abscesses. A total of 21 patients belonged to the child group, and 29 were adolescents. All retropharyngeal abscesses occurred in children; whereas most peritonsillar abscesses (81%) were found in adolescents. Most retropharyngeal and parapharyngeal abscesses were associated with fever (100% and 65%, respectively) and neck masses (67% and 94%, respectively); while odynophagia was the most common symptom in peritonsillar abscess (100%). Thirty-two abscess cultures were obtained and seven grew mixed pathogens, followed by Streptococcus pyogenes (n = 5), and normal flora (n = 5). Complications of airway obstruction arose in one patient with parapharyngeal abscess, and mediastinitis in another two patients with retropharyngeal abscesses. Recurrent DNIs were observed in six patients; three had congenital bronchogenic cysts. CONCLUSION The location of the DNI appears to vary in different pediatric age groups. Its insidious presentation, with a potentially complicated course, warrants careful inspection in children with fever and neck masses, especially young children.

ITPKC gene SNP rs28493229 and Kawasaki disease in Taiwanese children

Kawasaki disease (KD) is a systemic vasculitis caused by unknown infectious agents, host immune dysregulation and genetic susceptibility in children. Coronary artery lesions (CALs) complicate 15-25% of cases of untreated KD. The aim of this study was to investigate if the single-nucleotide polymorphism (SNP) rs28493229 of the ITPKC gene is associated with susceptibility to KD or with CALs in Taiwanese children. A total of 385 unrelated Taiwanese children (222 boys and 163 girls) with KD were included, 140 of whom had CALs. Mean age at diagnosis was 1.9 +/- 1.7 (0.1-10.2) years. Rs28493229 was genotyped in children with KD and 1158 ethnically matched healthy controls using the TaqMan Allelic Discrimination Assay. In 184 families with KD, both biological parents were available, constituting 184 trios with their children. They were assessed in a family-based study by means of a transmission/disequilibrium test (TDT). No significant differences in genotype (P = 0.29 and P = 0.29, respectively), allele (P = 0.14 and P = 0.22, respectively) and carrier (P = 0.22 and P = 0.25, respectively) frequencies of the SNP were found between healthy controls and children with KD or those with CALs. TDT in the 184 family trios and in 69 trios where the child had CALs did not reveal significant overtransmittion of the C allele. In conclusion, we did not find a statistically significant association between the ITPKC gene SNP rs28493229 and KD or CALs in Taiwanese children.

A psychometric study of the Bayley Scales of Infant and Toddler Development - 3rd Edition for term and preterm Taiwanese infants

The Bayley Scales of Infant and Toddler Development - 3rd Edition (Bayley-III) was updated to enhance its usefulness for contemporary child developmental assessment. However, recent data in Western countries have implicated the overestimation of child development by the new instrument. This study aimed to investigate the psychometric features of the Bayley-III for term and preterm infants in Taiwan. Forty-seven term infants and 167 preterm infants were prospectively examined with the Bayley Scales of Infant Development - 2nd Edition (BSID-II) and the Bayley-III at 6, 12, 18, and 24 months of age (corrected for prematurity). The psychometric properties examined included reliability, construct validity, and known-group validity. The intra- and inter-rater reliabilities of the Bayley-III were good to excellent. The correlations between the BSID-II and Bayley-III raw scores were good to excellent for the cognitive and motor items and low to excellent for the language items. Term infants achieved higher composite scores than preterm infants on all of the Bayley-III scales (p<0.05). However, their rates of developmental delay were lower than the previously established prevalence estimates. The Bayley-III cut-off composite score was adjusted 10-20, 1-13, and 12-24 points higher than 70 for optimal prediction of cognitive, language, and motor delay, respectively, as defined by the BSID-II index score<70. The Bayley-III is a reliable instrument that extends its previous edition, especially in early language assessment. However, the upward adjustment of its cut-off score is recommended for the accurate identification of developmental delay in term and preterm Taiwanese infants.

Acute suppurative thyroiditis in children.

Background. Acute suppurative thyroiditis in children is rare and is often related to a pyriform sinus fistula or thyroglossal duct remnant, especially when it is recurrent. Methods. From January, 1985, through December, 2000, 15 children with acute suppurative thyroiditis were treated. Their clinical, laboratory and radiologic findings were reviewed and analyzed. Results. There were 8 girls and 7 boys, with a mean age at diagnosis of 6.1 ± 2.9 years (range, 1.5 to 9.8). A thyroid mass was present on the left in 13 and on the right in 2 (P < 0.05). Fever, neck pain and swelling were the most common symptoms and signs. Seven patients (46.7%) had recurrent disease. Needle aspiration for Gram stain and bacterial cultures were done, and pathogenic organisms were identified on culture in 8 patients but were found only on Gram stain in 2 patients. In one-half of the patients with positive cultures, mixed pathogens were found. The most common organisms isolated were streptococcal species (50%). Barium esophagography was performed in all patients, and 5 (33.3%) had a pyriform sinus fistula on the left. Only 1 of the recurrent patients had a fistula. Thyroid scans were performed in 13 patients, of whom 12 (92.3%) had decreased radioactive uptake. Thyroid function tests were normal in all 15. Conclusions. Acute suppurative thyroiditis is usually caused by oropharyngeal flora, resulting in mixed pathogens on culture. Broad spectrum antibiotics should be given once cultures have been obtained. Imaging studies might be helpful in the diagnosis of acute suppurative thyroiditis.

The Changing Face of Early-onset Neonatal Sepsis After the Implementation of a Maternal Group B Streptococcus Screening and Intrapartum Prophylaxis Policy—A Study in One Medical Center

BACKGROUND Early-onset sepsis (EOS) is the major cause of neonatal morbidity and mortality. Maternal group B Streptococcus (GBS) screening and intrapartum antibiotic prophylaxis (IAP) were implemented in our hospital in 2004. Our aim was to evaluate the effectiveness of the program and changes in pathogens and antibiotic susceptibility. METHODS The medical charts of mothers and infants with EOS between January 2001 and November 2008 were retrospectively reviewed. EOS was defined as sepsis occurring within 72 hours of birth. Data were pooled and compared for January 2001 through September 2004 (Period 1, without GBS screening) and October 2004 through November 2008 (Period 2, with GBS screening and IAP). RESULTS The GBS screening rate increased from 10.11% in 2004 to 65% in 2008 and the IAP rate increased from 40% in 2004 to 90% in 2008. The most common EOS pathogen in Period 1 was GBS (45.4%), which decreased to 20% in Period 2 (p=0.081; trend p=0.009). The percentage of EOS because of Escherichia coli in Period 1 was 40.9% but increased to 70% in Period 2 (p=0.059). E coli EOS increased in extremely low birth weight premature babies weighing 500-1000g from Period 1 to Period 2 (p=0.031). The incidence of ampicillin-resistant E coli EOS was relatively high, but no significant change (88.9% vs. 92.9%) after implementation of GBS screening and IAP was noted. CONCLUSION GBS screening plus IAP is effective in decreasing the incidence of GBS EOS; however, an increase in EOS caused by E coli was noted. Monitoring of pathogens causing EOS is important for effective treatment.