Hsin Chi

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.

Identification of Novel Susceptibility Loci for Kawasaki Disease in a Han Chinese Population by a Genome-Wide Association Study

Kawasaki disease (KD) is an acute systemic vasculitis syndrome that primarily affects infants and young children. Its etiology is unknown; however, epidemiological findings suggest that genetic predisposition underlies disease susceptibility. Taiwan has the third-highest incidence of KD in the world, after Japan and Korea. To investigate novel mechanisms that might predispose individuals to KD, we conducted a genome-wide association study (GWAS) in 250 KD patients and 446 controls in a Han Chinese population residing in Taiwan, and further validated our findings in an independent Han Chinese cohort of 208 cases and 366 controls. The most strongly associated single-nucleotide polymorphisms (SNPs) detected in the joint analysis corresponded to three novel loci. Among these KD-associated SNPs three were close to the COPB2 (coatomer protein complex beta-2 subunit) gene: rs1873668 (p = 9.52×10−5), rs4243399 (p = 9.93×10−5), and rs16849083 (p = 9.93×10−5). We also identified a SNP in the intronic region of the ERAP1 (endoplasmic reticulum amino peptidase 1) gene (rs149481, pbest = 4.61×10−5). Six SNPs (rs17113284, rs8005468, rs10129255, rs2007467, rs10150241, and rs12590667) clustered in an area containing immunoglobulin heavy chain variable regions genes, with pbest-values between 2.08×10−5 and 8.93×10−6, were also identified. This is the first KD GWAS performed in a Han Chinese population. The novel KD candidates we identified have been implicated in T cell receptor signaling, regulation of proinflammatory cytokines, as well as antibody-mediated immune responses. These findings may lead to a better understanding of the underlying molecular pathogenesis of KD.

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.

Necrotizing fasciitis in southeast Taiwan: clinical features, microbiology, and prognosis

OBJECTIVES To determine the spectrum of microorganisms, clinical features, and risk factors of necrotizing fasciitis in southeast Taiwan. METHODS We retrospectively studied patients diagnosed with necrotizing fasciitis and fully treated in our hospital for the period January 1995 to December 2006. RESULTS The mean age of the patients was 58.2+/-14.2 years. The affected anatomical sites were primarily peripheral (91 patients, 85.8%). Sixty patients (56.6%) had a type 1 infection, 17 patients (16.0%) had type 2, and eight patients (7.5%) had type 3. Diabetes mellitus was the most common comorbidity. A single pathogen was identified as the infectious agent in 64 patients (60.4%), multiple pathogens were identified in 21 patients (19.8%), and no organism was identified in 21 patients (19.8%). Streptococcus pyogenes was the most common pathogen. The average hospital stay was 28.0+/-23.1 days. Patients received a mean of 2.3+/-1.2 debridements, and five patients (4.7%) eventually underwent an amputation. The overall mortality was 17.0%. Predictors of mortality included advanced age, class C liver cirrhosis, ascites, higher serum creatinine, and lower hemoglobin and platelet levels. CONCLUSIONS Monobacterial infections are more common in our patients. Accurate early diagnosis and extensive surgical debridement are essential for a favorable outcome.

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.

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.

Infections associated with indwelling ventriculostomy catheters in a teaching hospital.

BACKGROUND Ventriculostomy-associated infections are a serious complication of external ventricular drains. The objective of this study was to analyze the clinical features of and risk factors for such infections. METHODS We retrospectively collected demographic and clinical data on patients with indwelling ventriculostomy catheters hospitalized in a teaching hospital from July 2001 to June 2006, comparing those with and without ventriculostomy-associated infections. RESULTS A total of 197 drains (2910 catheter-days) placed in 155 patients were studied. Infections developed in 28 of the 197 (14.2%) drains. The duration from insertion to infection ranged from 7 to 36 days. The cut-off point of duration from insertion to infection was 15.5 days. Re-insertion because of catheter malfunction carried a high risk of infection (p<0.001). Patients with infections had a longer intensive care unit stay (p=0.001), longer duration of catheterization (p=0.002), and a higher incidence of concurrent sepsis (p=0.018), urinary tract infection (p=0.011) and pneumonia (p=0.004). Gram-negative bacilli were the leading pathogens (84%); Pseudomonas aeruginosa was the most common isolate. Polymicrobial infections occurred later than monomicrobial infections (p=0.003). CONCLUSIONS Repeated insertion and longer duration of drains are major risk factors for ventriculostomy-associated infections.

Epidemiology and clinical manifestations of children with macrolide‐resistant Mycoplasma pneumoniae pneumonia in Taiwan

Mycoplasma pneumoniae accounts for 10–30% of community‐acquired pneumonia (CAP) in children. This study reveals the epidemiology and clinical manifestations of children with macrolide‐resistant (MLr) M. pneumoniae pneumonia in Taiwan. Respiratory tract specimens were collected from children hospitalized with CAP for evaluation via PCR followed by DNA sequencing for several point mutations related to the MLr character. Of the 412 specimens collected during the study period, 60 (15%) were positive for M. pneumoniae, 14 (23%) of which presented point mutation (all A2063G) in 23S rRNA. Clinical symptoms and chest X‐ray findings between the MLs and MLr groups were not significantly different. However, the MLr group had longer mean duration of fever after azithromycin treatment (3.2 days vs. 1.6 days, P = 0.02) and significantly higher percentage of changing antibiotics for suspected MLr strain (42% vs. 13%, P = 0.04). Although 58% of children in the MLr group did not receive effective antibiotics, all children were discharged without sequelae. In conclusion, 15% of CAP in children is caused by M. pneumoniae and the macrolide‐resistance rate is 23% in Taiwan. Despite ineffective antibiotics, children with MLr M. pneumoniae pneumonia recover completely. Pediatr Pulmonol. 2013; 48:904–911.