Chia Yin Chong

Surveillance of Pneumococcal-Associated Disease among Hospitalized Children in Khanh Hoa Province, Vietnam

BACKGROUND To understand the epidemiology of childhood bacterial diseases, including invasive pneumococcal disease, prospective surveillance was conducted among hospitalized children in Nha Trang, Vietnam. METHODS From April 2005 through August 2006, pediatricians at the Khanh Hoa General Hospital used standardized screening criteria to identify children aged <5 years who had signs and symptoms of invasive bacterial disease. All cerebrospinal fluid (CSF) and blood specimens collected were tested by bacterial culture. Selected culture-negative specimens were tested for Streptococcus pneumoniae by antigen detection or for Haemophilus influenzae, Moraxella catarrhalis, Neisseria meningitidis, and S. pneumoniae by polymerase chain reaction (PCR). RESULTS A total of 987 children were enrolled (794 with pneumonia, 76 with meningitis, and 117 with other syndromes consistent with invasive bacterial disease); 84% of children were aged 0-23 months, and 57% were male. Seven (0.71%) of 987 blood cultures and 4 (15%) of 26 CSF cultures were positive for any bacterial pathogen (including 6 for H. influenzae type b and 1 for S. pneumoniae). Pneumococcal antigen testing and PCR identified an additional 16 children with invasive pneumococcal disease (12 by antigen testing and 4 by PCR). Among children aged <5 years who lived in Nha Trang, the incidence rate of invasive pneumococcal disease was at least 48.7 cases per 100,000 children (95% confidence interval, 27.9-85.1 cases per 100,000 children). CONCLUSIONS S. pneumoniae and H. influenzae type b were the most common causes of laboratory-confirmed invasive bacterial disease in children. PCR and antigen testing increased the sensitivity of detection and provided a more accurate estimate of the burden of invasive bacterial disease in Vietnam.

Outbreak of Zika virus infection in Singapore: an epidemiological, entomological, virological, and clinical analysis

BACKGROUND An outbreak of Zika virus infection was detected in Singapore in August, 2016. We report the first comprehensive analysis of a national response to an outbreak of Zika virus infection in Asia. METHODS In the first phase of the outbreak, patients with suspected Zika virus infection were isolated in two national referral hospitals until their serum tested negative for the virus. Enhanced vector control and community engagement measures were deployed in disease clusters, including stepped-up mosquito larvicide and adulticide use, community participation in source reduction (destruction of mosquito breeding sites), and work with the local media to promote awareness of the outbreak. Clinical and epidemiological data were collected from patients with confirmed Zika virus infection during the first phase. In the second phase, admission into hospitals for isolation was stopped but vector control efforts continued. Mosquitoes were captured from areas with Zika disease clusters to assess which species were present, their breeding numbers, and to test for Zika virus. Mosquito virus strains were compared with human strains through phylogenetic analysis after full genome sequencing. Reproductive numbers and inferred dates of strain diversification were estimated through Bayesian analyses. FINDINGS From Aug 27 to Nov 30, 2016, 455 cases of Zika virus infection were confirmed in Singapore. Of 163 patients with confirmed Zika virus infection who presented to national referral hospitals during the first phase of the outbreak, Zika virus was detected in the blood samples of 97 (60%) patients and the urine samples of 157 (96%) patients. There were 15 disease clusters, 12 of which had high Aedes aegypti breeding percentages. Captured mosquitoes were pooled into 517 pools for Zika virus screening; nine abdomen pools (2%) were positive for Zika virus, of which seven head and thorax pools were Zika-virus positive. In the phylogenetic analysis, all mosquito sequences clustered within the outbreak lineage. The lineage showed little diversity and was distinct from other Asian lineages. The estimated most recent common ancestor of the outbreak lineage was from May, 2016. With the deployment of vector control and community engagement measures, the estimated reproductive number fell from 3·62 (95% CI 3·48-3·77) for July 31 to Sept 1, 2016, to 1·22 (95% CI 1·19-1·24) 4 weeks later (Sept 1 to Nov 24, 2016). INTERPRETATION The outbreak shows the ease with which Zika virus can be introduced and spread despite good baseline vector control. Disease surveillance, enhanced vector control, and community awareness and engagement helped to quickly curb further spread of the virus. These intensive measures might be useful for other countries facing the same threat. FUNDING National Medical Research Council Singapore, Centre for Infectious Disease Epidemiology and Research, and A*STAR Biomedical Research Council.

Early impact of pneumococcal conjugate vaccine on invasive pneumococcal disease in Singapore children, 2005 through 2010

BACKGROUND In a previous study covering the period 1998-2004, we estimated the incidence of invasive pneumococcal disease (IPD) in Singapore to be 13.6 per 10(5) children aged <5 years, and determined that the 7-valent pneumococcal conjugate vaccine (PCV-7) would provide 78.1% serotype coverage for children aged <5 years. In the present study we sought to determine whether incidence and serotype trends have changed and to estimate pneumococcal vaccine coverage. METHODS We retrospectively reviewed IPD cases from 2005 to 2010 and calculated separate serotype proportions and population-based incidence rates for 2005-2007 (early PCV period) and 2008-2010 (late PCV period). PCV-7 coverage was obtained from the National Immunisation Registry, and patients with PCV-7 vaccine-type IPD (VT IPD) and non-vaccine-type IPD (non-VT IPD) were compared. RESULTS One hundred and eighteen patients, with a mean age of 46 months, were identified during 2005-2010. The incidence rate of IPD increased to 14.8 (for 2005-2007) and 15.2 (for 2008-2010) per 10(5) children <5 years, despite a gradual increase in PCV-7 coverage to approximately 45% of the birth cohort receiving one or more doses of PCV-7. Although IPD due to serotypes 6B and 19A increased, there was a concomitant reduction in other serotypes. Coverage by PCV-7 progressively declined from 78.6% in 2005-2007 to 64.4% in 2008-2010 for children aged <5 years. CONCLUSIONS Although population coverage with PCV-7 has risen, it remains suboptimal and the incidence of IPD remains unchanged. Furthermore, significant serotype changes (especially increases in 19A) have occurred. We need to adopt newer PCVs with broader serotype coverage and increase the number of children vaccinated as a matter of urgency.

Characteristics of Zika Virus Disease in Children: Clinical, Hematological, and Virological Findings from an Outbreak in Singapore

In the first reported pediatric case series of virologically confirmed Zika virus (ZIKV) infections from Southeast Asia, ZIKV infection was generally mild. Routine screening of children with suspected ZIKV infection for dengue virus coinfection should be considered in dengue-endemic countries.

Severe Pediatric Adenovirus 7 Disease in Singapore Linked to Recent Outbreaks across Asia

During November 2012–July 2013, a marked increase of adenovirus type 7 (Ad7) infections associated with severe disease was documented among pediatric patients in Singapore. Phylogenetic analysis revealed close genetic links with severe Ad7 outbreaks in China, Taiwan, and other parts of Asia.

Teacher led school-based surveillance can allow accurate tracking of emerging infectious diseases - evidence from serial cross-sectional surveys of febrile respiratory illness during the H1N1 2009 influenza pandemic in Singapore

BackgroundSchools are important foci of influenza transmission and potential targets for surveillance and interventions. We compared several school-based influenza monitoring systems with clinic-based influenza-like illness (ILI) surveillance, and assessed the variation in illness rates between and within schools.MethodsDuring the initial wave of pandemic H1N1 (pdmH1N1) infections from June to Sept 2009 in Singapore, we collected data on nation-wide laboratory confirmed cases (Sch-LCC) and daily temperature monitoring (Sch-DTM), and teacher-led febrile respiratory illness reporting in 6 sentinel schools (Sch-FRI). Comparisons were made against age-stratified clinic-based influenza-like illness (ILI) data from 23 primary care clinics (GP-ILI) and proportions of ILI testing positive for pdmH1N1 (Lab-ILI) by computing the fraction of cumulative incidence occurring by epidemiological week 30 (when GP-ILI incidence peaked); and cumulative incidence rates between school-based indicators and sero-epidemiological pdmH1N1 incidence (estimated from changes in prevalence of A/California/7/2009 H1N1 hemagglutination inhibition titers ≥ 40 between pre-epidemic and post-epidemic sera). Variation in Sch-FRI rates in the 6 schools was also investigated through a Bayesian hierarchical model.ResultsBy week 30, for primary and secondary school children respectively, 63% and 79% of incidence for Sch-LCC had occurred, compared with 50% and 52% for GP-ILI data, and 48% and 53% for Sch-FRI. There were 1,187 notified cases and 7,588 episodes in the Sch-LCC and Sch-DTM systems; given school enrollment of 485,723 children, this represented 0.24 cases and 1.6 episodes per 100 children respectively. Mean Sch-FRI rate was 28.8 per 100 children (95% CI: 27.7 to 29.9) in the 6 schools. We estimate from serology that 41.8% (95% CI: 30.2% to 55.9%) of primary and 43.2% (95% CI: 28.2% to 60.8%) of secondary school-aged children were infected. Sch-FRI rates were similar across the 6 schools (23 to 34 episodes per 100 children), but there was widespread variation by classrooms; in the hierarchical model, omitting age and school effects was inconsequential but neglecting classroom level effects led to highly significant reductions in goodness of fit.ConclusionsEpidemic curves from Sch-FRI were comparable to GP-ILI data, and Sch-FRI detected substantially more infections than Sch-LCC and Sch-DTM. Variability in classroom attack rates suggests localized class-room transmission.

Pertussis--an under-diagnosed disease with high morbidity in Singapore children.

UNLABELLED Since the introduction of the pertussis vaccine into the standard immunization program, very few cases of pertussis have been detected. In 2007, it was felt that the number of cases being admitted for pertussis had increased and this was verified on a retrospective review done from 2004 to 2007 of children diagnosed with pertussis in KK Womens and Childrens Hospital. AIM To review the cases diagnosed with pertussis, the demographic profile and the outcome of these patients. METHODS A retrospective review was done of patients diagnosed with pertussis from 2004 to 2007. The patients were identified from records of the positive results obtained from the microbiology laboratory. RESULTS In the preceding years, only 1-2 cases/year were reported with pertussis but this increased to 33 cases in 2007. 45 confirmed cases were analysed. Most infections were in infants below 6 months old (mean age 4.1 months) and almost all were not vaccinated. The average length of stay was 4.96 days (Range 2-14 days, SD 2.55). Children under 6 months had more severe disease in terms of ICU admissions (6% vs. 0%, p=0.70) and average length of stay (5.1 vs. 3.5 days, p=0.25) as compared to those above 6 months of age. Exposure to a symptomatic adult was documented in 64%, mainly parents (45%), older siblings (29%). Healthcare workers may also be a source of infection as one child had symptoms as early as the first week of life and none of the family members were coughing. CONCLUSION There is a resurgence of pertussis in recent years with high morbidity in children who have not been vaccinated. A booster with Tdap vaccine should be considered for young adults and healthcare workers looking after children.

Investigations into an outbreak of suppurative lymphadenitis with BCG vaccine SSI® in Singapore

INTRODUCTION From 2011 to 2012, we received an unexpectedly high number of reports of suppurative lymphadenitis following administration of a BCG vaccine used in our childhood vaccination programme in Singapore. We sought to determine the local incidence rates of BCG-associated suppurative lymphadenitis across the 2009 to 2012 vaccinated cohorts, and to analyse the potential factors contributing to this outbreak. METHODS Reports of lymphadenitis following BCG vaccination from an AEFI active surveillance system at the KK Womens and Childrens Hospital (KKH) and passive surveillance data from other healthcare institutions were reviewed. All valid reports received from January 2009 to December 2013 involving neonates vaccinated with the BCG vaccine in 2009 to 2012 that met case definitions were included in our analysis. Details of the demographics and vaccination history of the child, and statistics from the local vaccination programme were also obtained. Potential contributory factors were selected for further investigation based on a literature review of similar outbreaks overseas. RESULTS We identified 283 cases of lymphadenitis, of which 76% were suppurative. A spike in suppurative lymphadenitis cases was seen in the 2011 vaccinated cohort, with an incidence rate of 3.16 per 1000 vaccinees, as compared to 0.71 to 0.85 per 1000 in the 2009, 2010 and 2012 cohorts. Our investigations identified the likely cause of the outbreak to be batch-related, arising from manufacturing issues encountered by the manufacturer, after ruling out vaccine administration-related and host-related factors. CONCLUSIONS The three-fold spike in BCG-associated suppurative lymphadenitis cases observed in the 2011 vaccinated cohort, possibly due to batch-to-batch variation of the vaccine, highlights that manufacturing controls can continue to be a challenge. Development of a more sensitive assay to test the reactogenicity of the BCG vaccine may help reduce the occurrence of such outbreaks and improve public confidence in the nations vaccination programme.

Near disappearance of childhood invasive Haemophilus influenzae type b disease in Singapore

BACKGROUND Haemophilus influenzae type b (Hib) conjugate vaccines have significantly limited Hibs disease impact in every country where it was introduced. We previously estimated invasive Hib disease incidence in Singapore at ∼4.4 per 100,000 children <5 years (from 1994 to 2003, period 1), but the vaccine was not included in the national childhood immunization schedule until May 2013 (although it was available privately). The current study aims to describe changes in Hib disease incidence and vaccine coverage prior to the introduction of the vaccine. METHODOLOGY We retrospectively reviewed all invasive Hib cases from January 2004 to December 2012 (period 2) and estimated population-based incidence rates. Vaccine coverage was estimated from vaccine sales for 1994-2003, and from National Immunisation Registry for 2004-2010. RESULTS There were 8 cases of invasive Hib disease in period 2, of whom 5 were <5 years. Invasive Hib incidence for period 2 was 0.57 per 100,000 children <5 years, representing an 86.4% reduction compared to period 1 (rate ratio 0.14, 95% confidence interval 0.06-0.26). However, for the later part of period 2 (2008-2012), incidence was 0.2 per 100,000 children <5 years; this represented a 95% reduction from period 1 (rate ratio 0.05, 95% confidence interval 0.01-0.18). Between periods 1 and 2, national Hib vaccine coverage rose from 22% to >80%, with >99% of children receiving combination Hib-containing vaccines. CONCLUSIONS Childhood invasive Hib disease has nearly disappeared from Singapore, despite the absence of universal mass vaccination. We believe this is likely due to excellent uptake of combination vaccines.

Cytokine and Chemokine Profiling in Patients with Hand, Foot and Mouth Disease in Singapore and Malaysia

Hand, foot and mouth disease (HFMD) is a prevalent contagious childhood disease typically associated with fever, oral lesions and limb exanthema. While HFMD is caused by a plethora of serotypes of viruses under the genus Enterovirus within the Picornaviridae family, Coxsackievirus A16 (CV-A16) and Enterovirus 71 (EV-A71) are considered the main etiological agents. In recent years however, other viruses have also been isolated in considerable numbers from infected individuals in many regions, joining the legion commonly associated with HFMD. The present study investigated the cytokine and chemokine profiles of HFMD patients from Singapore and Malaysia for the first time. Comparative cohort studies of EV-A71-associated HFMD cases revealed that the Malaysia cohort had a distinct profile from the Singapore cohort, and this could be partly attributed by different EV-A71 genotypes. As the isolation of CV-A6, instead of CV-A16, had become prevalent in the Singapore cohort, it was also of particular interest to study the differential cytokine and chemokine profiles. Our data revealed that overlapping as well as unique profiles exist between the two major causative clinical isolates in the Singapore cohort. Having a better understanding of the respective immunological profiles could be useful for more accurate HFMD diagnosis, which is imperative for disease transmission control until multi-valent vaccines and/or broad-spectrum anti-viral drugs become available.