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1.  A Novel Six Consecutive Monthly Doses of Palivizumab Prophylaxis Protocol for the Prevention of Respiratory Syncytial Virus Infection in High-Risk Preterm Infants in Taiwan 
PLoS ONE  2014;9(6):e100981.
Background
Respiratory syncytial virus (RSV) circulates year round in Taiwan. A novel six consecutive monthly doses of palivizumab for RSV prevention protocol has been approved for high risk preterm infants since December 2010. This study aimed to determine the clinical effectiveness and safety of this novel protocol for the prevention of RSV infection.
Methods
From April 2011 to March 2013, we enrolled infants born at ≤28 weeks gestation and infants born at ≤35 weeks gestation with chronic lung disease (CLD) who received palivizumab prophylaxis as study group and followed up for 12 months. Historic control, those who were born and followed up between July 2000 and June 2008, were retrieved for propensity score matching. Primary endpoint was RSV-related hospitalization, and secondary endpoints included the length of hospital stay and intensive care unit (ICU) care.
Results
We enrolled 127 infants (108 infants born at ≤28 weeks and 19 infants born at 29–35 weeks with CLD). They completed 6-dose palivizumab as scheduled. Among the study group, the RSV-related hospitalizations were 2 (1.6%) within 6 months and 5 (3.9%) within 12 months after discharge. We matched 127 infants in the control group with 127 infants in the study group by propensity score matching. The reduction of RSV-related hospitalization rates were 86% (10.2% vs 1.6%, p = 0.002) within 6 months after discharge and 78% (15.7% vs 3.9%, p = 0.004) within 12 months after discharge. Compared to the control group, the rate of ICU care significantly decreased from 7.1% to 0.8% (p = 0.024) within 6 months after discharge and from 7.9% to 0.8% (p = 0.014) within 12 months after discharge. Adverse events were recorded in 6.4% injections.
Conclusions
Six monthly intramuscular administration of palivizumab is effective for prevention of RSV hospitalization in regions with no single seasonal peak of RSV infection such as Taiwan.
doi:10.1371/journal.pone.0100981
PMCID: PMC4074126  PMID: 24971565
2.  Molecular Epidemiology and Phylodynamics of the Human Respiratory Syncytial Virus Fusion Protein in Northern Taiwan 
PLoS ONE  2013;8(5):e64012.
Background and Aims
The glycoprotein (G protein) and fusion protein (F protein) of respiratory syncytial virus (RSV) both show genetic variability, but few studies have examined the F protein gene. This study aimed to characterize the molecular epidemiology and phylodynamics of the F protein gene in clinical RSV strains isolated in northern Taiwan from 2000–2011.
Methods
RSV isolates from children presenting with acute respiratory symptoms between July 2000 and June 2011 were typed based on F protein gene sequences. Phylogeny construction and evaluation were performed using the neighbor-joining (NJ) and maximum likelihood (ML) methods. Phylodynamic patterns in RSV F protein genes were analyzed using the Bayesian Markov Chain Monte Carlo framework. Selection pressure on the F protein gene was detected using the Datamonkey website interface.
Results
From a total of 325 clinical RSV strains studied, phylogenetic analysis showed that 83 subgroup A strains (RSV-A) could be further divided into three clusters, whereas 58 subgroup B strains (RSV-B) had no significant clustering. Three amino acids were observed to differ between RSV-A and -B (positions 111, 113, and 114) in CTL HLA-B*57- and HLA-A*01-restricted epitopes. One positive selection site was observed in RSV-B, while none was observed in RSV-A. The evolution rate of the virus had very little change before 2000, then slowed down between 2000 and 2005, and evolved significantly faster after 2005. The dominant subtypes of RSV-A in each epidemic were replaced by different subtypes in the subsequent epidemic.
Conclusions
Before 2004, RSV-A infections were involved in several small epidemics and only very limited numbers of strains evolved and re-emerged in subsequent years. After 2005, the circulating RSV-A strains were different from those of the previous years and continued evolving through 2010. Phylodynamic pattern showed the evolutionary divergence of RSV increased significantly in the recent 5 years in northern Taiwan.
doi:10.1371/journal.pone.0064012
PMCID: PMC3667090  PMID: 23734183
3.  The correlation between the presence of viremia and clinical severity in patients with enterovirus 71 infection: a multi-center cohort study 
BMC Infectious Diseases  2014;14(1):417.
Background
Enterovirus 71 (EV71) is a great disease burden across the whole world, particularly in Southeast Asia. However, in recent decades, the pathogenesis of severe EV71 infection was not well understood. This study was aimed to investigate the correlation between the presence of viremia and the clinical severity of EV71 infection.
Methods
We organized a prospective cohort study and enrolled laboratory-confirmed EV71 cases in six tertiary care hospitals in Taiwan during the EV71 epidemic from 2011 to 2012. Blood samples were collected once in the acute stage, on the first day of admission. We used real-time RT-PCR to detect EV71 viremia. Demographical and clinical data were collected and the clinical severity was categorized into four grades. Data analysis was performed to identify the risk factors of viremia and the correlation between viremia and clinical severity of EV71 infection.
Results
Of the total 224 enrolled patients, 59 (26%) patients were confirmed to have viremia. Two-thirds (68%) of viremic cases were detected within the first three days of infection. Viremia occurred more frequently in children under the age of one year old (odds ratios [OR] 4.82, p < 0.001) but the association between the presence of viremia and complicated EV71 infection was not found (OR 1.02, p = 0.96). In the viremia group, patients had significantly more severe complications if viremia was detected after the third day of disease onset (26% vs. 5%, p = 0.03).
Conclusions
Viremia occurred more frequently in children under the age of one year and viremia detected beyond three days after the onset of disease correlated with more severe disease in EV71 patients.
doi:10.1186/1471-2334-14-417
PMCID: PMC4133623  PMID: 25069383
Enterovirus; Viremia; Severe EV71 infection
4.  Immunogenicity and safety of combined measles-mumps-rubella-varicella vaccine using new measles and rubella working seeds in healthy children in Taiwan and Singapore 
Human Vaccines & Immunotherapeutics  2013;9(6):1308-1315.
Aim: This study evaluated the immunogenicity and safety of tetravalent measles-mumps-rubella-varicella (MMRV) vaccine produced with measles and rubella monovalent bulks derived from a newly established working seed virus stock (MMRVnew WS) compared with the combined MMRV vaccine derived from the current seed virus stock, in Taiwanese and Singaporean children (NCT00892775).
Methods:Healthy children aged 11–22 mo were randomized to receive two doses of either the MMRV new WS vaccine or the MMRV vaccine. Antibody titers against measles, mumps and rubella were measured using ELISA and against varicella using an immunofluorescence assay. The primary objective was to demonstrate non-inferiority of MMRVnew WS to MMRV in terms of post-dose-1 seroconversion rates, defined as a group difference with a lower limit of the 95% confidence interval greater than -10% for each antigen. Parents/guardians recorded symptoms in diary cards for 43 d after each vaccine dose.
Results:Non-inferiority of MMRV new WS to MMRV was achieved for all vaccine antigens. The lower limits of the 95% confidence intervals for group differences (MMRVnew WS group vs. MMRV) for measles (99.4% vs 100%), mumps (89.7% vs 90.4%), rubella (99.7% vs 100%) and varicella (97.6% vs 92.9%) seroconversion rates were greater than -10%. Mild symptoms including a peak in fever between days 5 and 12, post-dose-1, was observed in both groups.
Conclusion:The immune responses elicited by the MMRV new WS vaccine were non-inferior to that elicited by the MMRV vaccine for all antigens. Both vaccines exhibited an acceptable safety profile in Taiwanese and Singaporean children.
doi:10.4161/hv.24035
PMCID: PMC3901822  PMID: 23425607
immunogenicity; MMRV vaccine; newly established working seed virus stock; safety; Singapore; Taiwan
5.  Autocrine CCL3 and CCL4 Induced by the Oncoprotein LMP1 Promote Epstein-Barr Virus-Triggered B Cell Proliferation 
Journal of Virology  2013;87(16):9041-9052.
Epstein-Barr virus (EBV) alters the regulation and expression of a variety of cytokines in its host cells to modulate host immune surveillance and facilitate viral persistence. Using cytokine antibody arrays, we found that, in addition to the cytokines reported previously, two chemotactic cytokines, CCL3 and CCL4, were induced in EBV-infected B cells and were expressed at high levels in all EBV-immortalized lymphoblastoid cell lines (LCLs). Furthermore, EBV latent membrane protein 1 (LMP1)-mediated Jun N-terminal protein kinase activation was responsible for upregulation of CCL3 and CCL4. Inhibition of CCL3 and CCL4 in LCLs using a short hairpin RNA approach or by neutralizing antibodies suppressed cell proliferation and caused apoptosis, indicating that autocrine CCL3 and CCL4 are required for LCL survival and growth. Importantly, significant amounts of CCL3 were detected in EBV-positive plasma from immunocompromised patients, suggesting that EBV modulates this chemokine in vivo. This study reveals the regulatory mechanism and a novel function of CCL3 and CCL4 in EBV-infected B cells. CCL3 might be useful as a therapeutic target in EBV-associated lymphoproliferative diseases and malignancies.
doi:10.1128/JVI.00541-13
PMCID: PMC3754032  PMID: 23760235
6.  Household Transmission of Pandemic (H1N1) 2009 Virus, Taiwan 
Emerging Infectious Diseases  2011;17(10):1928-1931.
During August–November 2009, to investigate disease transmission within households in Taiwan, we recruited 87 pandemic (H1N1) 2009 patients and their household members. Overall, pandemic (H1N1) 2009 virus was transmitted to 60 (27%) of 223 household contacts. Transmission was 4× higher to children than to adults (61% vs. 15%; p<0.001).
doi:10.3201/eid1710.101662
PMCID: PMC3310653  PMID: 22000374
influenza virus subtype H1N1; pandemic (H1N1) 2009; household transmission; outcome; virus; viruses; influenza; Taiwan; dispatch
7.  Serologic Status for Pandemic (H1N1) 2009 Virus, Taiwan 
Emerging Infectious Diseases  2011;17(1):76-78.
We studied preexisting immunity to pandemic (H1N1) 2009 virus in persons in Taiwan. A total of 18 (36%) of 50 elderly adults in Taiwan born before 1935 had protective antibodies against currently circulating pandemic (H1N1) 2009 virus. Seasonal influenza vaccines induced antibodies that did not protect against pandemic (H1N1) 2009 virus.
doi:10.3201/eid1701.100014
PMCID: PMC3204618  PMID: 21192858
Pandemic (H1N1) 2009; viruses; influenza; neutralization assay; hemagglutination inhibition assay; serologic assays; vaccine; Taiwan; dispatch
8.  Strategy to Better Select HIV-Infected Individuals for Latent TB Treatment in BCG-Vaccinated Population 
PLoS ONE  2013;8(8):e73069.
Objective
To evaluate the T-SPOT.TB interferon-γ releasing assay and the tuberculin skin test (TST), for the diagnosis of latent tuberculosis infection(LTBI) and the development of subsequent active tuberculosis, in BCG-vaccinated HIV-infected individuals.
Methods
HIV-infected individuals without clinical suspicion of active TB or a past history of TB were enrolled from 1 January 2008 to 30 November 2010. Both T-SPOT.TB test and TST were offered to the participants whom were followed up prospectively until April 30, 2012 for development of TB.
Results
Among the 909 participants, 25% had positive TST reactions with cut-off point of 5 mm and 15% had positive T-SPOT.TB results. After a median follow-up of 2.97 years, there were 5 cases developed culture-confirmed active TB (all had dual positive TST and T-SPOT.TB results), and the incidence was 0.17 per 100 person-years. The relative risks (RRs) for subsequent active TB in HIV-infected individuals with positive TST results, positive T-SPOT.TB results and dual positive results compared with the risk for individuals with negative results were 40.6 (95% CI 2.1–767.9), 73.9 (95% CI 3.9–1397.7) and 226.5 (95% CI 12.0–4284), respectively. The number needed to treat to prevent one subsequent TB case among patients with a positive TST, a positive T-SPOT.TB and dual positive results was 35, 22 and 8 respectively.
Conclusions
Adopting positive results of the TST and T-SPOT.TB to screen LTBI among BCG-vaccinated HIV-infected individuals might be feasible. Number needed to treat for isoniazid preventive therapy could be reduced significantly by using dual positive strategy.
doi:10.1371/journal.pone.0073069
PMCID: PMC3754919  PMID: 24015285
9.  Immunogenicity and Safety of an Inactivated Quadrivalent Influenza Vaccine Candidate: A Phase III Randomized Controlled Trial in Children 
The Journal of Infectious Diseases  2013;208(4):544-553.
Background. Mismatch between circulating influenza B viruses (Yamagata and Victoria lineages) and vaccine strains occurs frequently.
Methods. In a randomized controlled trial, immunogenicity and safety of an inactivated quadrivalent influenza vaccine candidate (QIV) versus trivalent inactivated influenza vaccine (TIV)-Victoria(Vic) and TIV-Yamagata(Yam) in children 3–17 years of age was evaluated. In an open-label study arm, QIV only was assessed in children 6–35 months of age.
Results. A total of 3094 children (932 QIV, 929 TIV-Vic, 932 TIV-Yam, and 301 QIV only) were vaccinated. QIV was noninferior to the TIVs for shared strains (A/H3N2 and A/H1N1) based on hemagglutination-inhibition (HI) antibodies 28 days after last vaccination, and superior for the unique B strains Victoria and Yamagata (geometric mean titer ratios 2.61, 3.78; seroconversion rate differences 33.96%, 44.63%). Among children in the randomized trial, adverse event rates were similar except for injection site pain (dose 1: 65.4% QIV, 54.6% TIV-Vic, 55.7% TIV-Yam).
Conclusion. QIV elicited superior HI responses to the added B strains compared to TIV controls, potentially improving its effectiveness against influenza B. HI responses were similar between QIV and TIV controls for the shared strains. QIV had an acceptable safety profile relative to TIVs.
Clinical Trials Registration. NCT01198756.
doi:10.1093/infdis/jit263
PMCID: PMC3719910  PMID: 23847058
influenza vaccine; immunogenicity; children
10.  Cellular Protein HAX1 Interacts with the Influenza A Virus PA Polymerase Subunit and Impedes Its Nuclear Translocation 
Journal of Virology  2013;87(1):110-123.
Transcription and replication of the influenza A virus RNA genome occur in the nucleus through the viral RNA-dependent RNA polymerase consisting of PB1, PB2, and PA. Cellular factors that associate with the viral polymerase complex play important roles in these processes. To look for cellular factors that could associate with influenza A virus PA protein, we have carried out a yeast two-hybrid screen using a HeLa cell cDNA library. We identified six cellular proteins that may interact with PA. We focused our study on one of the new PA-interacting proteins, HAX1, a protein with antiapoptotic function. By using glutathione S-transferase pulldown and coimmunoprecipitation assays, we demonstrate that HAX1 specifically interacts with PA in vitro and in vivo and that HAX1 interacts with the nuclear localization signal domain of PA. Nuclear accumulation of PA was increased in HAX1-knockdown cells, and this phenotype could be reversed by reexpression of HAX1, indicating that HAX1 can impede nuclear transport of PA. As a consequence, knockdown of HAX1 resulted in a significant increase in virus yield and polymerase activity in a minigenome assay, and this phenotype could be reversed by reexpression of HAX1, indicating that HAX1 can inhibit influenza A virus propagation. Together, these results not only provide insight into the mechanism underlying nuclear transport of PA but also identify an intrinsic host factor that restricts influenza A virus infection.
doi:10.1128/JVI.00939-12
PMCID: PMC3536397  PMID: 23055567
11.  Seroprevalence of Hepatitis E Virus Infection among Swine Farmers and the General Population in Rural Taiwan 
PLoS ONE  2013;8(6):e67180.
Objectives
Hepatitis E virus (HEV) is an emerging pathogen. We evaluated the seroprevalence of HEV infection among swine farmers and the general population in Taiwan, a nonendemic country.
Methods
We conducted a cross-sectional seroepidemiologic study in rural Taiwan in 2012 and 2013. The study included swine farmers, health examination attendees, pregnant women, and students. A commercial enzyme-linked immunosorbent assay was used to detect immunoglobulin G (IgG) and IgM against HEV. Pertinent information was collected using a questionnaire.
Results
In total, 660 participants were enrolled in the study, including 156 swine farmers, 314 health examination attendees, 100 pregnant women, and 90 students. IgG anti-HEV was detected in 29.5% of swine farmers, 11.5% of health examination attendees, 2% of pregnant women, and 1.1% of students. Two subjects were positive for IgM anti-HEV. Logistic regression analysis revealed that swine farmers had an approximately 3.5-fold increased risk (odds ratio [OR], 3.46; 95% confidence interval [CI], 1.91–6.27; p<0.0001) for being seropositive for IgG anti-HEV as compared to the general population. Age was positively associated with seropositive rate (OR, 1.07 per year; 95% CI, 1.05–1.09; p<0.0001).
Conclusion
HEV infection is prevalent in Taiwan. The seroprevalence of HEV infection is high in swine farmers and in the elderly population.
doi:10.1371/journal.pone.0067180
PMCID: PMC3694024  PMID: 23840620
12.  Atypical hand-foot-mouth disease in children: a hospital-based prospective cohort study 
Virology Journal  2013;10:209.
Background
In 2010, we observed children with atypical presentations of hand-foot-mouth disease (HFMD), such as rashes on earlobes and faces, or bullae on trunks and bilateral limbs. Hyperpigmentation later developed as the bullous lesions crusted. Thus, we intended to study the etiology of the illness and the phylogeny of the pathogens.
Method
Patients were prospectively enrolled in a tertiary medical center in Taipei, Taiwan. The definition of atypical HFMD includes symptoms of acute viral infection with either of the following presentations: (1) maculopapular rashes presenting on the trunks, buttocks or facial areas, or (2) large vesicles or bullae on any sites of the body. Patients were classified into two groups according to vesicle sizes by two pediatricians at different points in time. The large vesicle group was defined as having vesciculobullous lesions ≥ 1 cm in diameter; the small rashes group had maculopapular rashes < 1cm in diameter. Two throat swabs were collected from each patient for virus isolation and reverse transcription polymerase chain reactions.
Results
We enrolled 101 patients between March and December 2010. The mean age of the participants was 3.3 ± 3.0 years (median age: 2.5 years, range: 21 days-13.5 years). The ratio of males to females was 1.8 to 1. All samples were enterovirus-positive, including coxsackievirus A6 (80%), coxsackievirus A16 (6%), enterovirus 71 (1%), coxsackievirus A5 (1%) and 12 non-typable enterovirus (12%). Bullous fluid aspirated from 2 patients also grew coxsackievirus A6. Among the patients infected with coxsackievirus A6, 54% (45/81) had bullae, compared to 25% (5/20) of those having non-coxsackievirus A6 infections (P=0.02). Fourteen cases had myoclonic jerks and one boy was diagnosed with febrile convulsions. None had complications or sequelae. Phylogenetic analysis showed the strains in Taiwan in 2010 shared more commonality with strains from Finland in 2009 (GenBank: FJ870502-FJ870508), and were close to those circulating in Japan in 2011 (GenBank: AB649286-AB649291).
Conclusions
Coxsackievirus A6 infections may cause atypical manifestations of HFMD, including vesicles or papules on faces or bullae on trunks. These features could provide valuable information to distinguish this versatile enterovirus infection from other virus-induced vesiculobullous diseases.
doi:10.1186/1743-422X-10-209
PMCID: PMC3717056  PMID: 23800163
Hand-foot-mouth disease; Onychomadesis; Vesiculobullous rash; Large vesicles; Enterovirus; Pigmentation; Phylogenetic analysis
13.  A randomized controlled study to evaluate the immunogenicity of a trivalent inactivated seasonal influenza vaccine at two dosages in children 6 to 35 months of age 
Human Vaccines & Immunotherapeutics  2013;9(9):1978-1988.
The trivalent inactivated influenza vaccine Fluarix™ is licensed in the US for adults and children from 3 years old. This randomized observer-blind study (NCT00764790) evaluated Fluarix™ at two doses; 0.25 ml (Flu-25) and 0.5 ml (Flu-50) in children aged 6–35 months. The primary objective was to demonstrate immunogenic non-inferiority vs. a control vaccine (Fluzone®; 0.25 ml). Children received Flu-25 (n = 1107), Flu-50 (n = 1106) or control vaccine (n = 1104) at Day 0 and for un-primed children, also on Day 28. Serum hemagglutination-inhibition titers were determined pre-vaccination and at Day 28 (primed) or Day 56 (un-primed). Non-inferiority was assessed by post-vaccination geometric mean titer (GMT) ratio, (upper 95% confidence interval [CI] ≤ 1.5) and difference in seroconversion rate (upper 95% CI ≤ 10%). Reactogenicity/safety was monitored. The immune response to Flu-50 met all regulatory criteria. Indicated by adjusted GMT ratios [with 95% CI], the criteria for non-inferiority of Flu-50 vs. control vaccine were reached for the B/Florida strain (1.13 [1.01–1.25]) but not for the A/Brisbane/H1N1 (1.74 [1.54–1.98]) or A/Uruguay/H3N2 (1.72 [1.57–1.89]) strains. In children aged 18–35 months similar immune responses were observed for Flu-50 and the control vaccine. Flu-50 induced a higher response than Flu-25 for all strains. Temperature (≥ 37.5°C) was reported in 6.2%, 6.4%, and 6.6% of the Flu-25, Flu-50, and control group, respectively. Reactogenicity/safety endpoints were within the same range for all vaccines.
In children aged 6–35 months, immune responses with Flu-50 fulfilled regulatory criteria but did not meet the pre-defined criteria for non-inferiority vs. control. This appeared to be due to differences in immunogenicity in children aged < 18 months.
doi:10.4161/hv.25363
PMCID: PMC3906365  PMID: 23782962
influenza; vaccine; children; immunogenicity; trivalent inactivated
14.  Clinical features and phylogenetic analysis of Coxsackievirus A9 in Northern Taiwan in 2011 
Background
Coxsackievirus A9 (CA9) was one of the most prevalent serotype of enteroviral infections in Taiwan in 2011. After several patient series were reported in the 1960s and 1970s, few studies have focused on the clinical manifestations of CA9 infections. Our study explores and deepens the current understanding of CA9.
Methods
We analyzed the clinical presentations of 100 culture-proven CA9-infected patients in 2011 by reviewing their medical records and depicted the CA9 phylogenetic tree.
Results
Of the 100 patients with culture-proven CA9 infections, the mean (SD) age was 4.6 (3.4) years and the male to female ratio was 1.9. For clinical manifestations, 96 patients (96%) had fever and the mean (SD) duration of fever was 5.9 (3.4) days. Sixty one patients (61%) developed a skin rash, and the predominant pattern was a generalized non-itchy maculopapular rash without vesicular changes. While most patients showed injected throat, oral ulcers were found in only 19 cases (19%), among whom, 6 were diagnosed as herpangina. Complicated cases included: aseptic meningitis (n=8), bronchopneumonia (n=6), acute cerebellitis (n=1), and polio-like syndrome (n=1). Phylogenetic analysis for current CA9 strains is closest to the CA9 isolate 27-YN-2008 from the border area of mainland China and Myanmar.
Conclusions
The most common feature of CA9 during the 2011 epidemic in Taiwan is generalized febrile exanthema rather than herpangina or hand, foot, and mouth disease. Given that prolonged fever and some complications are possible, caution should be advised in assessing patients as well as in predicting the clinical course.
doi:10.1186/1471-2334-13-33
PMCID: PMC3565879  PMID: 23347781
Coxsackievirus A9; Enterovirus; Viral exanthema; Phylogenetic tree
15.  Adenovirus Serotype 3 and 7 Infection with Acute Respiratory Failure in Children in Taiwan, 2010–2011 
PLoS ONE  2013;8(1):e53614.
Objective
Increased incidence of adenovirus infection in children was noticed since September 2010 in Taiwan and severe cases requiring intensive care were noted later. We did this study to find the clinical characteristics and risk factors associated with severe adenovirus infection.
Patients and Methods
We collected cases of severe adenovirus infection between November 2010 and June 2011 to analyze their clinical characteristics in two medical centers in northern Taiwan. Severe adenovirus infection was defined as laboratory-confirmed adenovirus cases with required intensive care. Hexon gene sequencing was performed for molecular genotyping.
Results
45 patients were included, 22 cases (49%) were infected with serotype 7, 19 (42%) with serotype 3, and 4 with serotype 2. The median age (range) was 2.75 years (0.08–15.43 years); 87% were below 5 years. Male to female ratio was 1.65 (28 to 17). Of these patients, 56% had underlying neurological diseases, 50% experienced fever higher than 40°C and 69% suffered fever longer than one week. The clinical diagnosis included pneumonia in 40 (89%) patients, bronchopneumonia in 5 (11%), and encephalitis in 7 (16%). At least 22 patients had pleural effusion. They had complications of respiratory failure (53%), acute respiratory distress syndrome (24%), hypotension (40%), and 6 (13%) patients needed extracorporeal membranous oxygenation. Ten (22%) patients died, all with underlying major systemic diseases and 7 (70%) infected with serotype 7.
Conclusions
Adenovirus serotype 7 and 3 can cause severe disease–even death–in children, especially those with underlying neurological diseases. Patients infected with adenovirus serotype 7 tended to have a higher case-fatality rate.
doi:10.1371/journal.pone.0053614
PMCID: PMC3542335  PMID: 23326469
16.  Serotype Competence and Penicillin Resistance in Streptococcus pneumoniae 
Emerging Infectious Diseases  2006;12(11):1709-1714.
Enhanced molecular surveillance of virulent clones with higher competence can detect serotype switching.
From 2003 to 2005, we prospectively collected 118 isolates of pneumococci belonging to 7 serotypes to investigate their competence under the influence of the synthetic competence-stimulating peptides. The degree of competence of the various serotypes differed significantly. Serotype 6B had the highest competence, followed by serotypes 14, 19F, 9V, 23F, 3, and 18C. Isolates belonging to serotype 6B had greater genetic diversity than isolates belonging to serotype 3, which has high genetic clustering. Isolates belonging to serotypes 3 and 18C that were 100% sensitive to penicillin were significantly less competent than isolates belonging to serotypes 6B, 14, 19F, 9V, and 23F, which were frequently resistant to penicillin. Under the 7-valent pneumococcal conjugate vaccine program, enhanced molecular surveillance of virulent clones with higher competence to detect serotype switching will become more important.
doi:10.3201/eid1211.060414
PMCID: PMC3372340  PMID: 17283621
Streptococcus pneumoniae; competence; serotype; antimicrobial resistance; research
17.  Community Outbreak of Adenovirus, Taiwan, 2011 
Emerging Infectious Diseases  2012;18(11):1825-1832.
Adenovirus type 7 caused a high proportion of severe infections.
In 2011, a large community outbreak of human adenovirus (HAdV) in Taiwan was detected by a nationwide surveillance system. The epidemic lasted from week 11 through week 41 of 2011 (March 14–October 16, 2011). Although HAdV-3 was the predominant strain detected (74%), an abrupt increase in the percentage of infections caused by HAdV-7 occurred, from 0.3% in 2008–2010 to 10% in 2011. Clinical information was collected for 202 inpatients infected with HAdV; 31 (15.2%) had severe infection that required intensive care, and 7 of those patients died. HAdV-7 accounted for 10%, 12%, and 41% of infections among outpatients, inpatients with nonsevere infection, and inpatients with severe infection, respectively (p<0.01). The HAdV-7 strain detected in this outbreak is identical to a strain recently reported in the People’s Republic of China (HAdV7-HZ/SHX/CHN/2009). Absence of circulating HAdV-7 in previous years and introduction of an emerging strain are 2 factors that caused this outbreak.
doi:10.3201/eid1811.120629
PMCID: PMC3559173  PMID: 23092602
adenovirus; surveillance; pneumonia; outbreak; viruses; Taiwan; severe infection; adenovirus type 7; HAdV; human adenovirus
18.  Longitudinal seroepidemiologic study of the 2009 pandemic influenza A (H1N1) infection among health care workers in a children's hospital 
Background
To probe seroepidemiology of the 2009 pandemic influenza A (H1N1) among health care workers (HCWs) in a children's hospital.
Methods
From August 2009 to March 2010, serum samples were drawn from 150 HCWs in a children's hospital in Taipei before the 2009 influenza A (H1N1) pandemic, before H1N1 vaccination, and after the pandemic. HCWs who had come into direct contact with 2009 influenza A (H1N1) patients or their clinical respiratory samples during their daily work were designated as a high-risk group. Antibody levels were determined by hemagglutination inhibition (HAI) assay. A four-fold or greater increase in HAI titers between any successive paired sera was defined as seroconversion, and factors associated with seroconversion were analyzed.
Results
Among the 150 HCWs, 18 (12.0%) showed either virological or serological evidence of 2009 pandemic influenza A (H1N1) infection. Of the 90 unvaccinated HCWs, baseline and post-pandemic seroprotective rates were 5.6% and 20.0%. Seroconversion rates among unvaccinated HCWs were 14.4% (13/90), 22.5% (9/40), and 8.0% (4/50) for total, high-risk group, and low-risk group, respectively. Multivariate analysis revealed being in the high-risk group is an independent risk factor associated with seroconversion.
Conclusion
The infection rate of 2009 pandemic influenza A (H1N1) in HCWs was moderate and not higher than that for the general population. The majority of unvaccinated HCWs remained susceptible. Direct contact of influenza patients and their respiratory samples increased the risk of infection.
doi:10.1186/1471-2334-12-89
PMCID: PMC3364885  PMID: 22498010
Influenza; Pandemic; H1N1; Health care workers; Children
19.  Emerged HA and NA Mutants of the Pandemic Influenza H1N1 Viruses with Increasing Epidemiological Significance in Taipei and Kaohsiung, Taiwan, 2009–10 
PLoS ONE  2012;7(2):e31162.
The 2009 influenza pandemic provided an opportunity to observe dynamic changes of the hemagglutinin (HA) and neuraminidase (NA) of pH1N1 strains that spread in two metropolitan areas -Taipei and Kaohsiung. We observed cumulative increases of amino acid substitutions of both HA and NA that were higher in the post–peak than in the pre-peak period of the epidemic. About 14.94% and 3.44% of 174 isolates had one and two amino acids changes, respective, in the four antigenic sites. One unique adaptive mutation of HA2 (E374K) was first detected three weeks before the epidemic peak. This mutation evolved through the epidemic, and finally emerged as the major circulated strain, with significantly higher frequency in the post-peak period than in the pre-peak (64.65% vs 9.28%, p<0.0001). E374K persisted until ten months post-nationwide vaccination without further antigenic changes (e.g. prior to the highest selective pressure). In public health measures, the epidemic peaked at seven weeks after oseltamivir treatment was initiated. The emerging E374K mutants spread before the first peak of school class suspension, extended their survival in high-density population areas before vaccination, dominated in the second wave of class suspension, and were fixed as herd immunity developed. The tempo-spatial spreading of E374K mutants was more concentrated during the post–peak (p = 0.000004) in seven districts with higher spatial clusters (p<0.001). This is the first study examining viral changes during the naïve phase of a pandemic of influenza through integrated virological/serological/clinical surveillance, tempo-spatial analysis, and intervention policies. The vaccination increased the percentage of E374K mutants (22.86% vs 72.34%, p<0.001) and significantly elevated the frequency of mutations in Sa antigenic site (2.36% vs 23.40%, p<0.001). Future pre-vaccination public health efforts should monitor amino acids of HA and NA of pandemic influenza viruses isolated at exponential and peak phases in areas with high cluster cases.
doi:10.1371/journal.pone.0031162
PMCID: PMC3273476  PMID: 22328930
20.  Epidemiological characteristics of varicella from 2000 to 2008 and the impact of nationwide immunization in Taiwan 
BMC Infectious Diseases  2011;11:352.
Background
Varicella has an important impact on public health. Starting in 2004 in Taiwan, nationwide free varicella vaccinations were given to 1-year-old children.
Methods
Our study investigated the epidemiological characteristics of varicella from 2000 to 2008, and assessed the change of varicella epidemiology after the mass varicella immunization. ICD-9-CM codes related to varicella or chickenpox (052, 052.1, 052.2, 052.7, 052.8, 052.9) were analyzed for all young people under 20 years of age through the National Health Insurance database of Taiwan from 2000 to 2008.
Results
Case numbers of varicella or chickenpox significantly declined after the nationwide immunization in 2004. Winter, particularly January, was the epidemic season of varicella. We found a significant post-vaccination decrease in incidence among preschool children, especially 3 to 6 year-old children-- the peak incidence was 66 per thousand for 4 and 5 year-old children before the nationwide immunization (2000 to 2003), and the peak incidence was 23 per thousand for 6 year-old children in 2008 (p < 0.001). Varicella-related hospitalization also significantly decreased in children younger than 6 years after the nationwide immunization.
Conclusion
The varicella annual incidence and varicella-related hospitalization markedly declined in preschool children after nationwide varicella immunization in 2004.
doi:10.1186/1471-2334-11-352
PMCID: PMC3265566  PMID: 22176638
varicella; chickenpox; epidemiology; incidence; vaccine; prevention
21.  Recombinant Trimeric HA Protein Immunogenicity of H5N1 Avian Influenza Viruses and Their Combined Use with Inactivated or Adenovirus Vaccines 
PLoS ONE  2011;6(5):e20052.
Background
The highly pathogenic avian influenza (HPAI) H5N1 virus continues to cause disease in poultry and humans. The hemagglutinin (HA) envelope protein is the primary target for subunit vaccine development.
Methodology/Principal Findings
We used baculovirus-insect cell expression to obtain trimeric recombinant HA (rHA) proteins from two HPAI H5N1 viruses. We investigated trimeric rHA protein immunogenicity in mice via immunizations, and found that the highest levels of neutralizing antibodies resulted from coupling with a PELC/CpG adjuvant. We also found that the combined use of trimeric rHA proteins with (a) an inactivated H5N1 vaccine virus, or (b) a recombinant adenovirus encoding full-length HA sequences for prime-boost immunization, further improved antibody responses against homologous and heterologous H5N1 virus strains. Data from cross-clade prime-boost immunization regimens indicate that sequential immunization with different clade HA antigens increased antibody responses in terms of total IgG level and neutralizing antibody titers.
Conclusion/Significance
Our findings suggest that the use of trimeric rHA in prime-boost vaccine regimens represents an alternative strategy for recombinant H5N1 vaccine development.
doi:10.1371/journal.pone.0020052
PMCID: PMC3104987  PMID: 21655326
22.  Identification of Novel Susceptibility Loci for Kawasaki Disease in a Han Chinese Population by a Genome-Wide Association Study 
PLoS ONE  2011;6(2):e16853.
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.
doi:10.1371/journal.pone.0016853
PMCID: PMC3033903  PMID: 21326860
23.  Inferring nonneutral evolution from contrasting patterns of polymorphisms and divergences in different protein coding regions of enterovirus 71 circulating in Taiwan during 1998-2003 
Background
Enterovirus (EV) 71 is one of the common causative agents for hand, foot, and, mouth disease (HFMD). In recent years, the virus caused several outbreaks with high numbers of deaths and severe neurological complications. Despite the importance of these epidemics, several aspects of the evolutionary and epidemiological dynamics, including viral nucleotide variations within and between different outbreaks, rates of change in immune-related structural regions vs. non-structural regions, and forces driving the evolution of EV71, are still not clear.
Results
We sequenced four genomic segments, i.e., the 5' untranslated region (UTR), VP1, 2A, and 3C, of 395 EV71 viral strains collected from 1998 to 2003 in Taiwan. The phylogenies derived from different genomic segments revealed different relationships, indicating frequent sequence recombinations as previously noted. In addition to simple recombinations, exchanges of the P1 domain between different species/genotypes of human enterovirus species (HEV)-A were repeatedly observed. Contrasting patterns of polymorphisms and divergences were found between structural (VP1) and non-structural segments (2A and 3C), i.e., the former was less polymorphic within an outbreak but more divergent between different HEV-A species than the latter two. Our computer simulation demonstrated a significant excess of amino acid replacements in the VP1 region implying its possible role in adaptive evolution. Between different epidemic seasons, we observed high viral diversity in the epidemic peaks followed by severe reductions in diversity. Viruses sampled in successive epidemic seasons were not sister to each other, indicating that the annual outbreaks of EV71 were due to genetically distinct lineages.
Conclusions
Based on observations of accelerated amino acid changes and frequent exchanges of the P1 domain, we propose that positive selection and subsequent frequent domain shuffling are two important mechanisms for generating new genotypes of HEV-A. Our viral dynamics analysis suggested that the importation of EV71 from surrounding areas likely contributes to local EV71 outbreaks.
doi:10.1186/1471-2148-10-294
PMCID: PMC2958165  PMID: 20868512
24.  Perinatal Tuberculosis in a 73-Day-Old Infant ▿  
Journal of Clinical Microbiology  2009;47(11):3785-3786.
A 73-day-old female infant presented with cough and fever. A chest roentgenogram showed a pneumonic patch, but empirical antibiotic treatment failed. The pathology of an excisional biopsy specimen confirmed pulmonary tuberculosis. We emphasize that tuberculosis should be considered for neonates or infants with unresponsive pneumonia because delayed diagnosis is associated with a fatal outcome.
doi:10.1128/JCM.00127-09
PMCID: PMC2772582  PMID: 19726601
25.  Determination of Human Rotavirus VP6 Genogroups I and II by Reverse Transcription-PCR▿ † 
Journal of Clinical Microbiology  2008;46(10):3330-3337.
Based on nucleotide sequence and phylogenetic analysis of the partial VP6 genes, group A rotaviruses can be mainly differentiated into two genogroups. In this study, a method employing reverse transcription-PCR (RT-PCR) and degenerate primers was established to assign the VP6 genogroup. VP6 genogroup I and genogroup II could be determined according to the sizes of the amplicons: 380 and 780 bp, respectively. The VP6 genogroup of human reference strains of G1 to G4 and G9 types and RotaTeq vaccine strains could be properly assigned by RT-PCR. Eighty rotavirus-positive fecal samples were subjected to enzyme-linked immunosorbent assay (ELISA), RT-PCR, and sequencing of the partial VP6 gene for subgroup and genogroup determination. The results correlated well among these three methods, except for seven samples whose subgroups could not be determined by ELISA. VP6 genogroups of another 150 rotavirus strains recovered between 1981 and 2005 were determined by RT-PCR and sequencing, and the same results were obtained by these two methods. Furthermore, an additional 524 rotavirus-positive fecal samples were tested by RT-PCR, and the VP6 genogroups could be easily determined. The RT-PCR assay developed here provided a reliable and convenient method for assigning the VP6 genogroups of human rotaviruses with a wide range of genetic variation.
doi:10.1128/JCM.00432-08
PMCID: PMC2566130  PMID: 18667595

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