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Background: The use of a squalene-containing (AS03) pandemic vaccine for high-risk groups in England allowed vaccine effectiveness (VE) of such novel oil-in-water adjuvanted vaccine to be evaluated.Methods: Cases of laboratory-confirmed pandemic (H1N1)2009 influenza in England between November 2009 and January 2010 were followed up for history of pandemic (H1N1)2009 or 2009/10 seasonal influenza vaccination and relevant comorbidities. Controls were patients similarly tested but negative for the virus. We estimated pandemic (H1N1)2009 VE from the relative reduction in the odds of confirmed pandemic (H1N1)2009 infection between vaccinated and unvaccinated individuals after adjustment for confounders.Results: A total of 933 cases and 1220 controls were analyzed. VE from ≥ 14 days was 62% (95% CI 33% to 78%) with protection from 7 to 13 days post-vaccination (59%, 95% CI 12% to 81%). VE from ≥ 14 days differed by age (P = .03) being 77% (11% to 94%) in children <10 years, 100% (80% to 100%) in 10-24-year olds, 22% (-153% to 76%) in 25-49-year olds, and 41% (-71% to 80%) in 50-plus-year-olds.Conclusion: Use of oil-in-water adjuvant contributed to a high VE with reduced antigen dosage in children and young adults. Our VE estimate supports the serological correlates of protection used for licensure in these age groups. However, the immunological basis of disappointing VE in older adults merits investigation. [ABSTRACT FROM AUTHOR]

Background: Hybrid immunity to SARS-CoV-2, resulting from both vaccination and natural infection, remains insufficiently understood in paediatric populations, despite increasing rates of breakthrough infections among vaccinated children., Methods: We conducted a prospective longitudinal study to investigate the magnitude, specificity, and cytokine profile of antigen-specific T cell responses elicited by breakthrough SARS-CoV-2 infection in a cohort of mRNA-vaccinated children (n = 29) aged 5-11. This longitudinal analysis involved six distinct time points spanning a 16-month period post-vaccination, during which we analysed a total of 159 blood samples. All children who were followed for at least 12 months (n = 26) experienced a breakthrough infection. We conducted cytokine release assays using minimal blood samples, and we verified the cellular origin of these responses through intracellular cytokine staining., Findings: After breakthrough infection, children who had received mRNA vaccines showed enhanced Th1 responses specific to Spike peptides. Additionally, their Spike-specific T cells exhibited a distinctive enrichment of CD4+ IFN-γ+IL10+ cells, a characteristic akin to adults with hybrid immunity. Importantly, vaccination did not impede the development of multi-specific T cell responses targeting Membrane, Nucleoprotein, and ORF3a/7/8 antigens., Interpretation: Children, previously primed with a Spike-based mRNA vaccine and experiencing either symptomatic or asymptomatic breakthrough infection, retained the ability to enhance and diversify Th1/IL-10 antigen-specific T cell responses against multiple SARS-CoV-2 proteins. These findings mirror characteristics associated with hybrid cellular immunity in adults, known to confer resistance against severe COVID-19., Funding: This study was funded by the National Medical Research Council (NMRC) Singapore (COVID19RF-0019, MOH-000019, MOH-000535, OFLCG19May-0034 and MOH-OFYIRG19nov-0002)., Competing Interests: Declaration of interests MQ: none; SH: none; SKH: none; JZ: none; CWT: none; CYC: none; JGL: none; LW: none; AB and NLB: report a pending patent for a method to monitor virus-specific T cells in biological samples and are co-founders of T Cell Diagnostic (TCD) Ltd., a biotech company developing T cell diagnostic for viral infections. CFY: reports honoraria and funding to attend conferences from Sanofi, Pfizer and Takeda., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: There is a paucity of information on remdesivir (RDV) use in severe pediatric coronavirus disease 2019 (COVID-19). We aimed to explore the effectiveness of RDV as the cumulative proportion of pediatric COVID-19 patients deescalated from Day 5 of high dependency or intensive care unit (HD/ICU)., Methods: All children ≤18 years admitted to Singapore's largest pediatric hospital from January 1, 2020 to March 18, 2022 were reviewed retrospectively. Patients were included if they were positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on reverse transcriptase polymerase chain reaction, required oxygen, and HD/ICU care. The characteristics and outcomes of those who received RDV or not (no-RDV) were compared., Results: We reviewed 15 children with a median age of 2.5 years (interquartile range [IQR]: 0.8-11.0), of which 7 (46.7%) received RDV. There was no difference in cumulative proportion of children deescalated from Day 5 of HD/ICU care in the RDV versus the no-RDV group (5/7, 70% vs. 7/8, 87.5%, p  = 0.57). The RDV versus no-RDV group had higher disease severity, that is, WHO Ordinal Scale scores (median 6, IQR: 5-7 vs. 5, IQR: 4-5, p  = 0.03), higher procalcitonin levels (ug/L) (median 4.31, IQR: 0.8-24.2 vs. 0.12, IQR: 0.09-0.26, p  = 0.02), and longer HD/ICU care days (median 5, IQR: 4-9, vs. 1, IQR: 1-4, p  = 0.01). There was no significant difference in hospitalization days. There were no adverse events directly attributable to RDV. None died from COVID-19 infection., Conclusion: Our observational analysis was unable to detect any clear benefit of RDV in terms of reducing duration in HD/ICU. RDV was well-tolerated in children with severe COVID-19., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Multiple Omicron sub-lineages have emerged, with Omicron XBB and XBB.1.5 subvariants becoming the dominant variants globally at the time of this study. The key feature of new variants is their ability to escape humoral immunity despite the fact that there are limited genetic changes from their preceding variants. This raises the question of whether Omicron should be regarded as a separate serotype from viruses serologically clustered with the ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus. Here, we present cross-neutralization data based on a pseudovirus neutralization test using convalescent sera from naïve individuals who had recovered from primary infection by SARS-CoV-1 and SARS-CoV-2 strains/variants including the ancestral virus and variants Beta, Delta, Omicron BA.1, Omicron BA.2 and Omicron BA.5. The results revealed no significant cross-neutralization in any of the three-way testing for SARS-CoV-1, ancestral SARS-CoV-2 and SARS-CoV-2 Omicron subvariants. The data argue for the assignment of three distinct serotypes for the currently known human-infecting SARS-related coronaviruses., Competing Interests: DECLARATION OF COMPETING INTERESTS The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Importance: Infants younger than 6 months are at risk of severe SARS-CoV-2 infection. Data are lacking on the optimum timing for maternal vaccination and estimated effectiveness against Omicron variants, including XBB, for infants., Objective: To investigate maternal vaccination against Omicron variants, including XBB, and the association of vaccination timing during pregnancy vs prior to pregnancy and risks of SARS-CoV-2 infection among infants aged 6 months or younger., Design, Setting, and Participants: This population-based cohort study was conducted between January 1, 2022, and March 31, 2023. Singapore's national dataset was used to study infants born at greater than 32 weeks' gestation between January 1, 2022, and September 30, 2022. The study included infants whose parents had a confirmed SARS-CoV-2 infection from the date of birth up to 6 months of age. Of 21 609 infants born during this period, 7292 (33.7%) had at least 1 parent infected with SARS-CoV-2 before the age of 7 months. Statistical analysis was performed from April to July 2023., Exposure: Infants' mothers were unvaccinated, vaccinated prior to pregnancy, or vaccinated with a messenger RNA (mRNA) SARS-CoV-2 vaccine during pregnancy., Main Outcome and Measure: Infants were considered infected if they had a positive polymerase chain reaction test., Results: Among 7292 infants included in this study, 4522 (62.0%) had mothers who were Chinese, 527 (7.2%) had mothers who were Indian, 2007 (27.5%) had mothers who were Malay, and 236 (3.2%) had mothers who were other ethnicity; 6809 infants (93.4%) were born at full term, and 1272 infants (17.4%) were infected during the study period. There were 7120 infants (97.6%) born to mothers who had been fully vaccinated or boosted as of 14 days prior to delivery. The crude incidence rate was 174.3 per 100 000 person-days among infants born to mothers who were unvaccinated, 122.2 per 100 000 person-days among infants born to mothers who were vaccinated before pregnancy, and 128.5 per 100 000 person-days among infants born to mothers who were vaccinated during pregnancy. The estimated vaccine effectiveness (VE) was 41.5% (95% CI, 22.8% to 55.7%) among infants born to mothers vaccinated during pregnancy. Infants of mothers who received vaccination prior to pregnancy did not have a lower risk for infection (estimated VE, 15.4% [95% CI, -17.6% to 39.1%]). A lower risk for Omicron XBB infection was only observed among mothers vaccinated with the third (booster) dose antenatally (estimated VE, 76.7% [95% CI, 12.8% to 93.8%])., Conclusions and Relevance: In this population-based cohort study, maternal mRNA vaccination was associated with a lower risk of Omicron SARS-CoV-2 infection among infants up to 6 months of age only if the vaccine was given during the antenatal period. These findings suggest that mRNA vaccination during pregnancy may be needed for lower risk of SARS-CoV-2 infection among newborns.

Introduction: Information on the quality of health of children and younger persons (CYPs) after SARS-COV-2 infection remains scarce, especially from Asia. In this study, we utilised an online survey to investigate Long COVID prevalence in CYPs in Singapore., Method: The study was an anonymised online survey of physical and functional symptoms, made available from 14 October 2022 to 15 January 2023. Caregivers of CYPs aged 0 to 18 years were invited to complete the survey on behalf of their CYPs. Participants provided demographic information and their history of SARS-CoV-2 infection status to allow classification into cases and controls for analysis., Results: A total of 640 completed responses were analysed, 471 (73.6%) were cases and 169 (26.4%) were controls. The prevalence of Long COVID ≥3 months post-infection was 16.8%. This decreased to 8.7% ≥6 months post-infection. Cases had higher odds of developing Long COVID (odds ratio [OR] 2.42, 95% confidence interval [CI] 1.31-4.74). The most common symptoms of Long COVID were persistent cough (7.4%), nasal congestion (7.6%) and fatigue (3.0%). Male gender was significantly associated with higher odds of Long COVID (adjusted OR 1.71 [1.04-2.83]). Vaccinated CYPs had lower odds of Long COVID but this was not statically significant (adjusted OR 0.65, 95% CI 0.34-1.25)., Conclusion: About 1 in 6 CYPs in Singapore developed Long COVID with persistence of 1 or more symptoms ≥3 months post-infection, and approximately half will recover by 6 months. Male gender was associated with higher odds of Long COVID, and vaccination could potentially be protective against Long COVID in CYPs., Competing Interests: The authors have no conflict of interest to disclose.

There is little information on BNT162b2 vaccine-induced variant-specific immunogenicity, safety data and dynamics of breakthrough infections in pediatric populations. We addressed these questions using a prospective two dose BNT162b2 (10 mcg) vaccination cohort study of healthy children 5-11 years in Singapore. Follow up included blood samples at scheduled visits, daily vaccination symptom diary and confirmation of SARS-CoV-2 infection. Surrogate virus neutralization test (sVNT) and spike-specific T cell responses against SARS-CoV-2 variants were performed. The mean age of 127 participants was 8.27 years (SD 1.95) and 51.2% were males. The median sVNT level against original variant after 1 dose and 2 dose vaccination was 61.4% and 95.1% respectively (p < 0.0001). Neutralizing antibodies against the Omicron variant was the lowest, median 22.4% (IQR 16.5-30.8). However, T cell IFN-γ cytokine response against Omicron variant was high and remained so about 4 months after vaccination. Fever rate increased significantly from 4% (dose 1) to 11.5% (dose 2). The risk of Omicron breakthrough infection decreased by 7.8% for every 1% increase in sVNT inhibition level measured after dose 2 vaccination. BNT162b2 vaccines were safe, induced good T cell responses but poor neutralizing antibodies against Omicron in children. Low neutralizing antibody levels post-vaccination was predictive of subsequent breakthrough infection., (© 2023. Springer Nature Limited.)

Poliomyelitis, or polio, is a highly infectious disease and can result in permanent flaccid paralysis of the limbs. Singapore was certified polio-free by the World Health Organization (WHO) on 29 October 2000, together with 36 other countries in the Western Pacific Region. The last imported case of polio in Singapore was in 2006. Fortunately, polio is vaccine-preventable-the world saw the global eradication of wild poliovirus types 2 and 3 achieved in 2015 and 2019, respectively. However, in late 2022, a resurgence of paralytic polio cases from vaccine-derived poliovirus (VDPV) was detected in countries like Israel and the US (specifically, New York); VDPV was also detected during routine sewage water surveillance with no paralysis cases in London, UK. Without global eradication, there is a risk of re-infection from importation and spread of wild poliovirus or VDPV, or new emergence and circulation of VDPV. During the COVID-19 pandemic, worldwide routine childhood vaccination coverage fell by 5% to 81% in 2020-2021. Fortunately, Singapore has maintained a constantly high vaccination coverage of 96% among 1-year-old children as recorded in 2021. All countries must ensure high poliovirus vaccination coverage in their population to eradicate poliovirus globally, and appropriate interventions must be taken to rectify this if the coverage falters. In 2020, WHO approved the emergency use listing of a novel oral polio vaccine type 2 for countries experiencing circulating VDPV type 2 outbreaks. Environmental and wastewater surveillance should be implemented to allow early detection of "silent" poliovirus transmission in the population, instead of relying on clinical surveillance of acute flaccid paralysis based on case definition alone.

Introduction: Children infected with COVID-19 are susceptible to severe manifestations. We aimed to develop and validate a predictive model for severe/ critical pediatric COVID-19 infection utilizing routinely available hospital level data to ascertain the likelihood of developing severe manifestations., Methods: The predictive model was based on an analysis of registry data from COVID-19 positive patients admitted to five tertiary pediatric hospitals across Asia [Singapore, Malaysia, Indonesia (two centers) and Pakistan]. Independent predictors of severe/critical COVID-19 infection were determined using multivariable logistic regression. A training cohort (n = 802, 70%) was used to develop the prediction model which was then validated in a test cohort (n = 345, 30%). The discriminative ability and performance of this model was assessed by calculating the Area Under the Curve (AUC) and 95% confidence interval (CI) from final Receiver Operating Characteristics Curve (ROC)., Results: A total of 1147 patients were included in this analysis. In the multivariable model, infant age group, presence of comorbidities, fever, vomiting, seizures and higher absolute neutrophil count were associated with an increased risk of developing severe/critical COVID-19 infection. The presence of coryza at presentation, higher hemoglobin and platelet count were associated with a decreased risk of severe/critical COVID-19 infection. The AUC (95%CI) generated for this model from the training and validation cohort were 0.96 (0.94, 0.98) and 0.92 (0.86, 0.97), respectively., Conclusion: This predictive model using clinical history and commonly used laboratory values was valuable in estimating the risk of developing a severe/critical COVID-19 infection in hospitalized children. Further validation is needed to provide more insights into its utility in clinical practice., Competing Interests: The authors have declared that no competing interests exist.

We present a country specific method to calculate the COVID-19 vaccination coverage needed for herd immunity by considering age structure, age group-specific contact patterns, relative infectivity and susceptibility of children to adults, vaccination effectiveness and seroprevalence prior to vaccination. We find that across all six countries, vaccination of adults age 60 and above has little impact on R eff and this is could be due to the smaller number of contacts between this age group and the rest of the population according to the contact matrices used. If R 0 is above 6, herd immunity by vaccine alone is unattainable for most countries either if vaccination is only available for adults or that vaccine effectiveness is lower at 65% against symptomatic infections. In this situation, additional control measures, booster shots, if they improve protection against infection, or the extension of vaccination to children, are required. For a highly transmissible variant with R 0 up to 8, herd immunity is possible for all countries and for all four scenarios of varying relative infectivity and susceptibility of children compared to adults, if vaccine effectiveness is very high at 95% against symptomatic infections and that high vaccination coverage is achieved for both adults and children. In addition, we show that the effective reproduction number will vary between countries even if the same proportion of the population is vaccinated, depending on the demographics, the contact rates and the previous pre-vaccination seroprevalence in the country. This therefore means that care must be taken in extrapolating population level impacts of certain vaccine coverages from one country to another., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

There is a scarcity of population-level data of pediatric COVID-19 infection from Southeast Asia. This study aims to describe and compare epidemiological, clinical, laboratory and outcome data among pediatric COVID-19 cases versus controls in two neighboring countries, Singapore and Malaysia. We used a test-negative case-control study design recruiting all suspected COVID-19 cases (defined by either clinical or epidemiological criteria) from January 2020 to March 2021 admitted to two main pediatric centers in Singapore and Malaysia. Data were collected using a standardized registry (Pediatric Acute and Critical Care COVID-19 Registry of Asia). The primary outcome was laboratory-confirmed COVID-19. Univariate and multivariable logistic regression analysis was used to determine factors associated with COVID-19. This study included 923 children with median age of 4 (interquartile range 2-9) years. Of these, 35.3% were COVID-19 cases. Children with COVID-19 were more likely to be asymptomatic compared with controls (49.4 versus 18.6%; P < 0.0001). They were also less likely to develop respiratory complications, such as bronchitis or pneumonia, or organ dysfunction. Four (1.2%) of our COVID-19 patients required respiratory support compared with 14.2% of controls needing respiratory support. COVID-19 cases tended to have lower neutrophil count but higher hemoglobin compared with controls. There were no reported deaths of COVID-19 infection; in contrast, 0.7% of the control group died. In the multivariable analysis, older age, travel history, and close contact with an infected household member were associated with COVID-19 infection. This study shows that the majority of pediatric COVID-19 cases were of lesser severity compared with other community acquired respiratory infections.

Kawasaki disease (KD, typical/atypical/partial) admissions (n = 644) were surveyed from 2017 to 2020 and compared to urinary tract infection (UTI) admissions and COVID-19 in 2020. KD admissions decreased by 27% and median KD age decreased in 2020, whereas UTI admissions remained steady. KD admissions showed a seasonality with a peak in April and nadir in February-March. All KD/KD-related pediatric intensive care unit cases tested negative for COVID-19, and no multisystem inflammatory syndrome in children was found., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

There is a scarcity of data regarding coronavirus disease 2019 (COVID-19) infection in children from southeast and south Asia. This study aims to identify risk factors for severe COVID-19 disease among children in the region. This is an observational study of children with COVID-19 infection in hospitals contributing data to the Pediatric Acute and Critical Care COVID-19 Registry of Asia. Laboratory-confirmed COVID-19 cases were included in this registry. The primary outcome was severity of COVID-19 infection as defined by the World Health Organization (WHO) (mild, moderate, severe, or critical). Epidemiology, clinical and laboratory features, and outcomes of children with COVID-19 are described. Univariate and multivariable logistic regression models were used to identify risk factors for severe/critical disease. A total of 260 COVID-19 cases from eight hospitals across seven countries (China, Japan, Singapore, Malaysia, Indonesia, India, and Pakistan) were included. The common clinical manifestations were similar across countries: fever (64%), cough (39%), and coryza (23%). Approximately 40% of children were asymptomatic, and overall mortality was 2.3%, with all deaths reported from India and Pakistan. Using the multivariable model, the infant age group, presence of comorbidities, and cough on presentation were associated with severe/critical COVID-19. This epidemiological study of pediatric COVID-19 infection demonstrated similar clinical presentations of COVID-19 in children across Asia. Risk factors for severe disease in children were age younger than 12 months, presence of comorbidities, and cough at presentation. Further studies are needed to determine whether differences in mortality are the result of genetic factors, cultural practices, or environmental exposures.

An accurate depiction of the convalescent COVID-19 immunome will help delineate the immunological milieu crucial for disease resolution and protection. Using mass cytometry, we characterized the immune architecture in patients recovering from mild COVID-19. We identified a virus-specific immune rheostat composed of an effector T (T eff ) cell recall response that is balanced by the enrichment of a highly specialized regulatory T (T reg ) cell subset. Both components were reactive against a peptide pool covering the receptor binding domain (RBD) of the SARS-CoV-2 spike glycoprotein. We also observed expansion of IFNγ + memory CD4 + T cells and virus-specific follicular helper T (T FH ) cells. Overall, these findings pinpoint critical immune effector and regulatory mechanisms essential for a potent, yet harmless resolution of COVID-19 infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Yeo, Leong, Tay, Nadua, Anderson, Lim, Ng, Poh, Guo, Yaung, Kumar, Wasser, Hazirah, Sutamam, Chua, Qui, Foo, Gamage, Yeo, Ramakrishna, Arkachaisri, Young, Lye, Wang, Chong, Tan, Li, Kam, Ginhoux, Thoon, Chan, Yung and Albani.)

It is important to understand the temporal trend of the paediatric severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load to estimate the transmission potential of children in schools and communities. We determined the differences in SARS-CoV-2 viral load dynamics between nasopharyngeal samples of infected asymptomatic and symptomatic children. Serial cycle threshold values of SARS-CoV-2 from the nasopharynx of a cohort of infected children were collected for analysis. Among 17 infected children, 10 (58.8%) were symptomatic. Symptomatic children, when compared to asymptomatic children, had higher viral loads (mean cycle threshold on day 7 of illness 28.6 vs. 36.7, P = 0.02). Peak SARS-CoV-2 viral loads occurred around day 2 of illness in infected children. Although we were unable to directly demonstrate infectivity, the detection of significant amount of virus in the upper airway of asymptomatic children suggest that they have the potential to shed and transmit SARS-CoV-2. Our study highlights the importance of contact tracing and screening for SARS-CoV-2 in children with epidemiological risk factors regardless of their symptom status, in order to improve containment of the virus in the community, including educational settings.

Background: Coronavirus disease 2019 (COVID-19) has impacted the provision of health services in all specialties. We aim to study the impact of COVID-19 on the utilization of pediatric hospital services including emergency department (ED) attendances, hospitalizations, diagnostic categories and resource utilization in Singapore., Methods: We performed a retrospective review of ED attendances and hospital admissions among children < 18 years old from January 1st to August 8th 2020 in a major pediatric hospital in Singapore. Data were analyzed in the following time periods: Pre-lockdown (divided by the change in Disease Outbreak Response System Condition (DORSCON) level), during-lockdown and post-lockdown. We presented the data using proportions and percentage change in mean counts per day with the corresponding 95% confidence intervals (CIs)., Results: We attended to 58,367 children with a mean age of 5.1 years (standard deviation, SD 4.6). The mean ED attendance decreased by 331 children/day during lockdown compared to baseline (p < 0.001), attributed largely to a drop in respiratory (% change - 87.9, 95% CI - 89.3 to - 86.3, p < 0.001) and gastrointestinal infections (% change - 72.4, 95%CI - 75.9 to - 68.4, p < 0.001). Trauma-related diagnoses decreased at a slower rate across the same periods (% change - 40.0, 95%CI - 44.3 to - 35.3, p < 0.001). We saw 226 children with child abuse, with a greater proportion of total attendance seen post-lockdown (79, 0.6%) compared to baseline (36, 0.2%) (p < 0.001). In terms of ED resource utilization, there was a decrease in the overall mean number of procedures performed per day during the lockdown compared to baseline, driven largely by a reduction in blood investigations (% change - 73.9, 95%CI - 75.9 to - 71.7, p < 0.001)., Conclusions: We highlighted a significant decrease in infection-related presentations likely attributed to the lockdown and showed that the relative proportion of trauma-related attendances increased. By describing the impact of COVID-19 on health services, we report important trends that may provide guidance when planning resources for future pandemics.

The epidemiological target of lockdowns is to drive down the effective reproduction number (Rt) to less than 1. A key unknown is the duration that lockdowns need to be in place to achieve this and which lockdown measures are effective. Daily number of laboratory confirmed community coronavirus 2019 cases were extracted from regular reports from the Ministry of Health Singapore from 20 March 2020 to 4 May 2020. We generated daily Rt to estimate the time needed for these public health lockdown measures to control the spread of severe acute respiratory syndrome coronavirus 2 as demonstrated by Rt < 1. It took about 14 days of nationwide lockdown for the Rt trend to change and start falling. The upper limit of the 95% confidence interval for time to Rt < 1 was day 15 of lockdown. We have shown that it is possible to start 'bending the Rt curve' about 2 weeks after implementation of specific lockdown measures with strict compliance.

Background: Existing studies have suggested that internet-based participatory surveillance systems are a valid sentinel for influenza-like illness (ILI) surveillance. However, there is limited scientific knowledge on the effectiveness of mobile-based ILI surveillance systems. Previous studies also adopted a passive surveillance approach and have not fully investigated the effectiveness of the systems and their determinants., Objective: The aim of this study was to assess the efficiency of a mobile-based surveillance system of ILI, termed FluMob, among health care workers using a targeted surveillance approach. Specifically, this study evaluated the effectiveness of the system for ILI surveillance pertaining to its participation engagement and surveillance power. In addition, we aimed to identify the factors that can moderate the effectiveness of the system., Methods: The FluMob system was launched in two large hospitals in Singapore from April 2016 to March 2018. A total of 690 clinical and nonclinical hospital staff participated in the study for 18 months and were prompted via app notifications to submit a survey listing 18 acute respiratory symptoms (eg, fever, cough, sore throat) on a weekly basis. There was a period of study disruption due to maintenance of the system and the end of the participation incentive between May and July of 2017., Results: On average, the individual submission rate was 41.4% (SD 24.3%), with a rate of 51.8% (SD 26.4%) before the study disruption and of 21.5% (SD 30.6%) after the disruption. Multivariable regression analysis showed that the adjusted individual submission rates were higher for participants who were older (<30 years, 31.4% vs 31-40 years, 40.2% [P<.001]; 41-50 years, 46.0% [P<.001]; >50 years, 39.9% [P=.01]), ethnic Chinese (Chinese, 44.4% vs non-Chinese, 34.7%; P<.001), and vaccinated against flu in the past year (vaccinated, 44.6% vs nonvaccinated, 34.4%; P<.001). In addition, the weekly ILI incidence was 1.07% on average. The Pearson correlation coefficient between ILI incidence estimated by FluMob and that reported by Singapore Ministry of Health was 0.04 (P=.75) with all data and was 0.38 (P=.006) including only data collected before the study disruption. Health care workers with higher risks of ILI and influenza such as women, non-Chinese, allied health staff, those who had children in their households, not vaccinated against influenza, and reported allergy demonstrated higher surveillance correlations., Conclusions: Mobile-based ILI surveillance systems among health care workers can be effective. However, proper operation of the mobile system without major disruptions is vital for the engagement of participants and the persistence of surveillance power. Moreover, the effectiveness of the mobile surveillance system can be moderated by participants' characteristics, which highlights the importance of targeted disease surveillance that can reduce the cost of recruitment and engagement., (©May Oo Lwin, Jiahui Lu, Anita Sheldenkar, Chitra Panchapakesan, Yi-Roe Tan, Peiling Yap, Mark I Chen, Vincent TK Chow, Koh Cheng Thoon, Chee Fu Yung, Li Wei Ang, Brenda SP Ang. Originally published in JMIR mHealth and uHealth (http://mhealth.jmir.org), 07.12.2020.)

Meteorological drivers are known to affect transmissibility of respiratory viruses including respiratory syncytial virus (RSV), but there are few studies quantifying the role of these drivers. We used daily RSV hospitalization data to estimate the daily effective reproduction number (R t ), a real-time measure of transmissibility, and examined its relationship with environmental drivers in Singapore from 2005 through 2015. We used multivariable regression models to quantify the proportion of the variance in R t explained by each meteorological driver. After constructing a basic model for RSV seasonality, we found that by adding meteorological variables into this model we were able to explain a further 15% of the variance in RSV transmissibility. Lower and higher value of mean temperature, diurnal temperature range (DTR), precipitation and relative humidity were associated with increased RSV transmissibility, while higher value of maximum wind speed was correlated with decreased RSV transmissibility. We found that a number of meteorological drivers were associated with RSV transmissibility. While indoor conditions may differ from ambient outdoor conditions, our findings are indicative of a role of ambient temperature, humidity and wind speed in affecting RSV transmission that could be biological or could reflect indirect effects via the consequences on time spent indoors.

Background: Enterovirus (EV) outbreaks often coincide with seasonal peaks in the community. However, they may also sporadically occur in neonatal units. Identification of EV infection in neonates can be challenging, as they tend to present with mild or nonspecific symptoms. This study reports an EV outbreak in the Neonatal Unit at KK Women's and Children's Hospital, Singapore., Methods: This is a single-center, retrospective cohort study of neonates who had positive results for EV during the outbreak. Demographic characteristics, clinical presentations and outcomes were analyzed. Control measures used to limit the spread of infection are reported., Results: A total of 7 cases of EV infection were identified. Their median birth weight and gestational age were 1240 g (750 -2890 g) and 28 weeks (26-35 weeks), respectively. Symptoms occurred at a median age of 48 days (9-103 days). All cases presented initially with recurrent apnea and 4 needed assisted ventilator support with CPAP (2) and mechanical ventilation (2). Serious complications occurred in 3 infants (2 with necrotizing enterocolitis and 1 with meningitis) and none died. EV was detected from rectal swabs (n = 6), CSF (n = 2) and nasopharyngeal swabs (n = 2). Viral subtyping uniformly revealed echovirus 25. Surveillance of all exposed infants by nasopharyngeal swabs was implemented, along with strict contact precautions and cohorting measures., Conclusions: Premature infants with EV are more prone to serious complications, which can lead to significant morbidity. Thus, early recognition of symptoms, rapid diagnosis and prompt implementation of infection control measures are key to prevent further spread of infection., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Disseminated Bacillus Calmette-Guérin (BCG) disease (BCGosis) is a classical feature of children with primary immunodeficiency disorders (PIDs)., Methods: A 15-year retrospective review was conducted in KK Women's and Children's Hospital in Singapore, from January 2003 to October 2017., Results: Ten patients were identified, the majority male (60.0%). The median age at presentation of symptoms of BCG infections was 3.8 (0.8 - 7.4) months. All the patients had likely underlying PIDS - four with Severe Combined Immunodeficiency (SCID), three with Mendelian Susceptibility to Mycobacterial Diseases (MSMD), one with Anhidrotic Ectodermal Dysplasia with Primary Immunodeficiency (EDA-ID), one with combined immunodeficiency (CID), and one with STAT-1 gain-of-function mutation. Definitive BCGosis was confirmed in all patients by the identification of Mycobacterium bovis subsp BCG from microbiological cultures. The susceptibility profiles of Mycobacterium bovis subsp BCG are as follows: Rifampicin (88.9%), Isoniazid (44.47%), Ethambutol (100.0%), Streptomycin (100.0%), Kanamycin (100.0%), Ethionamide (25.0%), and Ofloxacin (100.0%). Four patients (40.0%) received a three-drug regimen. Five patients (50.0%) underwent hematopoietic stem cell transplant (HSCT), of which three (60%) have recovered. Overall mortality was 50.0%., Conclusion: Disseminated BCG disease (BCGosis) should prompt immunology evaluation to determine the diagnosis of the immune defect. A three-drug regimen is adequate for treatment if the patient undergoes early HSCT., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was detected from at least 1 buccal specimen in 9 of 11 coronavirus disease 2019 (COVID-19)-infected children (81.8%). Viral loads in buccal specimens were substantially lower than those in nasopharyngeal specimens. Buccal swabs are not good as COVID-19 screening specimens in children., (© The Author(s) 2020. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Serratia marcescens (S. marcescens) is associated with nosocomial infections with significant morbidity and mortality in the neonatal intensive care units (NICU). We describe the control of a multi-clonal S. marcescens infections outbreak in our tertiary-level NICU and the application of molecular typing using repetitive element palindromic PCR (rep-PCR) and next generation sequencing (NGS) in the investigation., Methods: Outbreak investigation was performed where clinical, spatial and epidemiologic links were established. Screening of all infants in the NICU and the environment was performed. Rep-PCR and NGS methods were used to identify potential environmental sources of infections and clustering among cases., Results: Eleven cases were detected during the outbreak period: mean gestational age 27 weeks (range: 24-32), predominantly male (82%), mean age of infection 24 days (range: 6-51). Six infants were treated for conjunctivitis and one for bacteraemia. Identification of colonized infant via a point prevalence survey and cohorting of all infected/colonized patients were implemented. We performed environmental swabbing of surfaces, water outlets, chlorhexidine hand wash solutions and hand hygiene hand rubs. Both rep-PCR and NGS classified the 11 case isolates into 5 types. No point source was identified except for a single positive environmental isolate from a sink which was clonally distinct from the cases., Conclusion: Identification and cohorting of infected/colonized patient was important in the control of S. marcescens outbreak in the NICU. The utility of rep-PCR was comparable to NGS in providing molecular information to develop S. marcescens outbreak control strategies., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Respiratory syncytial virus (RSV) is the most common cause of pediatric acute lower respiratory tract infection worldwide. Detailed data on the health and economic burden of RSV disease are lacking from tropical settings with year-round RSV transmission. We developed a statistical and economic model to estimate the annual incidence and healthcare cost of medically attended RSV disease among young children in Singapore, using Monte Carlo simulation to account for uncertainty in model parameters. RSV accounted for 708 hospitalizations in children <6 months of age (33.5/1,000 child-years) and 1,096 in children 6-29 months of age (13.2/1,000 child-years). The cost of hospitalization was SGD 5.7 million (US $4.3 million) at 2014 prices; patients bore 60% of the cost. RSV-associated disease burden in tropical settings in Asia is high and comparable to other settings. Further work incorporating efficacy data from ongoing vaccine trials will help to determine the potential cost-effectiveness of different vaccination strategies.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Background: The concurrent sampling design was developed for case-control studies of recurrent events. It involves matching for time. Standard conditional logistic-regression (CLR) analysis ignores the dependence among recurrent events. Existing methods for clustered observations for CLR do not fit the complex data structure arising from the concurrent sampling design., Methods: We propose to break the matches, apply unconditional logistic regression with adjustment for time in quintiles and residual time within each quintile, and use a robust standard error for observations clustered within persons. We conducted extensive simulation to evaluate this approach and compared it with methods based on CLR. We analysed data from a study of childhood pneumonia to illustrate the methods., Results: The proposed method and CLR methods gave very similar point estimates of association and showed little bias. The proposed method produced confidence intervals that achieved the target level of coverage probability, whereas the CLR methods did not, except when disease incidence was low., Conclusions: The proposed method is suitable for the analysis of case-control studies with recurrent events., (© The Author(s) 2020. Published by Oxford University Press on behalf of the International Epidemiological Association.)

Severe haze episodes originating from biomass burning are common in Southeast Asia. However, there is a paucity of data on the personal exposure and characteristics of Particulate Matter (PM) present in ambient air during haze and non-haze periods. Aims of this study were to monitor 24 h ambulatory exposure to PM among school children in Singapore; characterize haze and non-haze PM for their physicochemical properties, cytotoxicity and inflammatory potential, using bronchial epithelial cell culture model (BEAS-2B). Forty-six children had ambulatory PM exposure monitored using portable Aethalometer and their hourly activity recorded. The mean (±SE) PM exposure on a typical school day was 3343 (±174.4) ng/m 3 /min. Higher PM exposure was observed during haze periods and during commuting to and from the school. Characterization of PM collected showed a drastic increase in the proportion of ultrafine particle (UFP) in haze PM. These PM fraction showed higher level of sulphur, potassium and trace metals in comparison to those collected during non-haze periods. Dose dependent increases in abiotic reactive oxygen species generation, activation of NF-κB and cytotoxicity were observed for both haze and non-haze PM. Generally, haze PM induced significantly higher release of IL-6, IL-8 and TNFα by BEAS-2B cells in comparison to non-haze PM. In summary, this study provides experimental evidence for higher PM exposure during haze period which has the potential to elicit oxidative stress and pro-inflammatory cytokine release from airway epithelial cells., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Introduction: In tropical Singapore, influenza occurs all year-round. This study of influenza-confirmed hospitalized pediatric patients compared clinical characteristics and complications by age-group and differences between influenza A and B., Methods: This was a retrospective study of pediatric inpatients from January 2013 to December 2014. Patients were grouped into: <6 months, 6 months to <5 years, 5- to <10-year and ≥10 years. Complications were classified into neurologic, pulmonary, and other. We also calculated the incidence of hospitalized influenza cases per 100 000 age-related population., Results: There were a total of 1272 patients with a median age of 37 months. The highest hospitalization rates were in the <6 months age-group. Majority (75.2%) had no comorbidity; 25.6% had complications: neurologic 11.9%, pulmonary 9.6%, other 4.1%. Patients with other complications were older, male, and had the highest influenza B rates and the longest length of stay. Influenza A comprised 76.9% of cases and had higher complication rates especially neurologic, compared to influenza B. Influenza B patients were older and were more likely to develop other complications. The 6-month to <5-year-age-group had the highest complication rate (30.6%), especially neurologic. However, ≥10 years old had the highest other complications, ICU/ high-dependency admissions and influenza B Victoria rates., Conclusions: Infants <6 months had the highest hospitalization rates for influenza. The 6-month to <5-year-age-group had the highest complication rate especially neurologic. Influenza A patients were younger, had higher seizure rates and complications compared to influenza B., (© 2019 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

Kawasaki disease (KD) is a systemic vasculitis mainly affecting young children and the leading cause of acquired heart disease in developed countries. We performed a self-controlled case series analysis to investigate the association between PCV13 and KD. All hospitalized KD cases <2 y old from our hospital in Singapore from 2010 to 2014 were included. Complete KD cases were classified based on the definitions of the American Heart Association. During the study period, 288 KD cases were identified. A total of 21 KD cases (12 were classified as Complete KD) had date of onset within the risk interval of day 1 to day 28 post PCV13. The age-adjusted Relative Incidence (RI) for KD following PCV13 dose 1, dose 2 and dose 3 were 1.40 (95%CI, 0.72 to 2.71), 1.23 (95% CI, 0.62 to 2.44) and 0.34 (95% CI, 0.08 to 1.40) respectively. There were seven Complete KD cases with onset during the risk interval after dose 1 of PCV13 (age-adjusted RI 2.59, 95%confidence interval (CI), 1.16 to 5.81). We did not detect a significant increased risk for overall KD among PCV13 recipients. However, a significant association between PCV13 and Complete KD was noted following receipt of the first dose of PCV13.

Objectives: Elizabethkingia meningoseptica is a multi-drug-resistant organism that is associated with high mortality and morbidity in newborn and immunocompromised patients. This study aimed to identify the best antimicrobial therapy for treating this infection., Methods: A retrospective descriptive study was conducted from 2010 to 2017 in a tertiary paediatric hospital in Singapore. Paediatric patients aged 0 to 18 years old with a positive culture for E. meningoseptica from any sterile site were identified from the hospital laboratory database. The data collected included clinical characteristics, antimicrobial susceptibility and treatment, and clinical outcomes., Results: Thirteen cases were identified in this study. Combination therapy with piperacillin/tazobactam and trimethoprim/sulfamethoxazole or a fluoroquinolone resulted in a cure rate of 81.8  %. The mortality rate was 15.4  % and neurological morbidity in patients with bacteraemia and meningitis remained high (75 %)., Conclusions: Treatment with combination therapy of piperacillin/tazobactam and trimethoprim/sulfamethoxazole or a fluroquinolone was effective in this study, with low mortality rates being observed.

Background: Pregnant women are at increased risk of influenza-related complications. The World Health Organisation recommends influenza vaccination to this high-risk population as highest priority. However, achieving high influenza vaccine coverage among pregnant women remains challenging. We conducted a cross-sectional survey to estimate the coverage and determinants of influenza vaccination among pregnant women in Singapore., Methods: Between September and November 2017, pregnant women aged ≥21 years were recruited at two public hospitals in Singapore. Participants completed an anonymous, self-administered online questionnaire assessing participants' influenza vaccination uptake, knowledge of and attitudes towards influenza and the influenza vaccine, vaccination history, willingness to pay for the influenza vaccine, and external cues to vaccination. We estimated vaccine coverage and used multivariable Poisson models to identify factors associated with vaccine uptake., Results: Response rate was 61% (500/814). Only 49 women (9.8, 95% Confidence Interval (CI): 7.3-12.7%) reported receiving the vaccine during their current pregnancy. A few misconceptions were identified among participants, such as the belief that influenza can be treated with antibiotics. The most frequent reason for not being vaccinated was lack of recommendation. Women who were personally advised to get vaccinated against influenza during pregnancy were 7 times more likely to be vaccinated (prevalence ratio (PR) = 7.11; 95% CI: 3.92-12.90). However, only 12% of women were personally advised to get vaccinated. Other factors associated with vaccine uptake were vaccination during a previous pregnancy (PR = 2.51; 95% CI: 1.54-4.11), having insurance to cover the cost of the vaccine (PR = 2.32; 95% CI: 1.43-3.76), and higher vaccine confidence (PR = 1.62; 95% CI: 1.30-2.01)., Conclusions: Influenza vaccination uptake among pregnant women in Singapore is low. There is considerable scope for improving vaccination coverage in this high-risk population through vaccination recommendations from healthcare professionals, and public communication targeting common misconceptions about influenza and influenza vaccines.

We report an Elizabethkingia anophelis case cluster associated with contaminated aerators and tap water in a children's intensive care unit in Singapore in 2017. We demonstrate a likely transmission route for E. anophelis to patients through acquisition of the bacteria on hands of healthcare workers via handwashing.

Introduction: We report the results of a rapid assessment of Zika virus awareness among key clinical specialties in Singapore., Methods: Between June 6 and June 19, 2016 we conducted an online survey of doctors working in obstetrics and gynaecology, neonatology and paediatrics in Singapore. The survey included 15 multiple choice questions to measure respondents' knowledge of Zika virus in four domains covering clinical and public health., Results: A total of 110 survey responses (15% response rate) were obtained, 82% of respondents worked in the public sector. Overall, the median respondent score was 9.4 (Max score=15), with substantial variation (range: 3.5 - 14.7). Microcephaly and Guillain-Barré syndrome were recognised as causal complications of Zika virus infection by 99% and 50% of respondents respectively.  Clinical features which could help differentiate Zika from Dengue were less well understood with 50% and 68% correctly identifying conjunctivitis and low grade fever respectively. Worryingly, 14% favoured non-steroidal anti-inflammatory drugs as part of treatment, without first excluding dengue as a diagnosis. Also, only 36% of respondents were aware of the current recommendation for preventing sexual transmission of Zika virus. Fewer than 50% were aware of the need for ophthalmological evaluation as part of congenital Zika virus infection., Discussion: Our assessment demonstrates that there is good awareness of the clinical manifestation of Zika virus disease among key specialty doctors, but confusion with Dengue disease remains. It also highlights knowledge gaps in the prevention of sexually-transmitted Zika virus infection and the clinical management of congenital Zika virus infection in newborns. Our study identified strategic areas to improve communication to front-line doctors during public health response to the Zika epidemic.

Singapore is a hotspot for emerging infectious diseases and faces a constant risk of pandemic outbreaks as a major travel and health hub for Southeast Asia. With an increasing penetration of smart phone usage in this region, Singapore's pandemic preparedness framework can be strengthened by applying a mobile-based approach to health surveillance and control, and improving upon existing ideas by addressing gaps, such as a lack of health communication. FluMob is a digitally integrated syndromic surveillance system designed to assist health authorities in obtaining real-time epidemiological and surveillance data from health-care workers (HCWs) within Singapore, by allowing them to report influenza incidence using smartphones. The system, integrating a fully responsive web-based interface and a mobile interface, is made available to HCW using various types of mobile devices and web browsers. Real-time data generated from FluMob will be complementary to current health-care- and laboratory-based systems. This paper describes the development of FluMob, as well as challenges faced in the creation of the system.

Background: The seasonal influenza vaccine is less effective in older people and a single dose is unlikely to provide the year-round protection necessary for tropical climates which have year-round influenza virus activity. This study aims to assess the effect of a trivalent inactivated influenza vaccine (IIV3) booster at 180 days on haemagglutination-inhibition (HI) antibody titres for each of the influenza strains present in the administered vaccine in older people aged 65 years or above in Singapore., Methods/design: This is a single-centre, randomised, observer-blind, active-comparator controlled, parallel-group, phase IV trial in 200 adults aged 65 years or older. Study participants will be assigned to one of two groups in a 1:1 ratio and followed for 1 year, with five scheduled visits. The control group will receive IIV3 at day 1, and an active comparator (Tetanus-diphtheria-pertussis vaccine) at day 180. Participants in the experimental group will receive IIV3 containing the same strains at day 1 and day 180. Endpoints are immunological, and include measures of HI titres, microneutralisation titres (MN) and cell-mediated immunity from first vaccination up to day 360., Discussion: If superiority of 6-monthly influenza vaccination is demonstrated, this study could form the basis for a larger clinical trial with influenza infection as the primary endpoint., Trial Registration: ClinicalTrials.gov, ID: NCT02655874 . Registered on 12 January 2016.

Background: Understanding changes in the ecology and epidemiology of dengue is important to ensure resource intensive control programmes are targeted effectively as well as to inform future dengue vaccination strategies., Methods: We analyzed data from a multicentre longitudinal prospective study of fever in adults using a nested test negative case control approach to identify epidemiological risk factors for dengue disease in Singapore. From April 2005 to February 2013, adult patients presenting with fever within 72 h at selected public primary healthcare clinics and a tertiary hospital in Singapore were recruited. Acute and convalescent blood samples were collected and used to diagnose dengue using both PCR and serology methods. A dengue case was defined as having a positive RT-PCR result for DENV OR evidence of serological conversion between acute and convalescent blood samples. Similarly, controls were chosen from patients in the cohort who tested negative for dengue using the same laboratory methods., Results: The host epidemiological factors which increased the likelihood of dengue disease amongst adults in Singapore were those aged between 21 and 40 years old (2 fold increase) while in contrast, Malay ethnicity was protective (OR 0.57, 95%CI 0.35 to 0.91) against dengue disease. Spatial factors which increased the odds of acquiring dengue was residing at a foreign workers dormitory or hostel (OR 3.25, 95 % CI 1.84 to 5.73) while individuals living in the North-West region of the country were less likely to get dengue (OR 0.50, 95%CI 0.29 to 0.86). Other factors such as gender, whether one primarily works indoors or outdoors, general dwelling type or floor, the type of transportation one uses to work, travel history, as well as self-reported history of mosquito bite or household dengue/fever were not useful in helping to inform a diagnosis of dengue., Conclusions: We have demonstrated a test negative study design to better understand the epidemiological risk factors of adult dengue over multiple seasons. We were able to discount other previously speculated factors such as gender, whether one primarily works indoors or outdoors, dwelling floor in a building and the use of public transportation as having no effect on one's risk of getting dengue.

Studies on serotype-specific features of dengue and disease severity on adults are limited. We prospectively recruited adult febrile patients without alternate diagnosis to dengue from April 2005 to December 2011. Outcomes were defined using both the World Health Organization (WHO) 1997 and 2009 criteria; Dengue hemorrhagic fever (DHF) and severe dengue (SD). Infecting serotype was identified in 469 dengue-confirmed patients comprising 22.0% dengue virus serotype 1 (DENV-1), 57.1% DENV-2, 17.1% DENV-3, and 3.8% DENV-4. Cases infected with DENV-1 were more likely to present with red eyes whereas presence of joint pain and lower platelet count was associated with DENV-2 cases. After adjusting for potential confounders, DENV-1 was associated with both DHF (adjusted Relative Risk [aRR] = 1.74) and SD (aRR = 2.1) whereas DENV-2 had a lower risk of DHF (aRR = 0.5). DENV-1 genotype 1 and DENV-2 cosmopolitan were the predominant genotypes identified. Infecting dengue serotype and possibly genotype may play an important role in disease severity among adult dengue patients in Singapore., (© The American Society of Tropical Medicine and Hygiene.)

Background: In 2009, the World Health Organization (WHO) proposed seven warning signs (WS) as criteria for hospitalization and predictors of severe dengue (SD). We assessed their performance for predicting dengue hemorrhagic fever (DHF) and SD in adult dengue., Method: DHF, WS and SD were defined according to the WHO 1997 and 2009 dengue guidelines. We analyzed the prevalence, sensitivity (Sn), specificity (Sp), positive predictive value (PPV) and negative predictive value (NPV) of WS before DHF and SD onset., Results: Of 1507 cases, median age was 35 years (5(th)-95(th) percentile, 17-60), illness duration on admission 4 days (5(th)-95(th) percentile, 2-6) and length of hospitalization 5 days (5(th)-95(th) percentile, 3-7). DHF occurred in 298 (19.5%) and SD in 248 (16.5%). Of these, WS occurred before DHF in 124 and SD in 65 at median of two days before DHF or SD. Three commonest warning signs were lethargy, abdominal pain/tenderness and mucosal bleeding. No single WS alone or combined had Sn >64% in predicting severe disease. Specificity was >90% for both DHF and SD with persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, clinical fluid accumulation, and any 3 or 4 WS. Any one of seven WS had 96% Sn but only 18% Sp for SD., Conclusions: No WS was highly sensitive in predicting subsequent DHF or SD in our confirmed adult dengue cohort. Persistent vomiting, hepatomegaly, hematocrit rise and rapid platelet drop, and clinical fluid accumulation, as well as any 3 or 4 WS were highly specific for DHF or SD.

In England, during pandemic 2009 H1N1, vaccine efficacy and immunogenicity population studies in priority groups were rolled out in parallel to evaluate the pandemic vaccination programme. This provided a unique opportunity to compare immunogenicity and clinical protection in the same population and thus provide insights into the correlates of protection for the pandemic H1N1 2009 vaccine in risk groups. While clinical protection from AS03-adjuvanted pandemic 2009 H1N1 vaccine was high in those aged <25 years and pregnant women, effectiveness in older adults with chronic conditions has been found to be surprisingly poor. Here we present results from the immunogenicity study derived from the same population. Individuals from priority groups eligible for pandemic vaccination attending participating general practices were recruited. Pre and post-vaccination blood samples were collected and HI antibody testing to assess immune response to vaccination performed. The final cohort consisted of 610 individuals: 60 healthy children aged <5 years; 32 healthy pregnant women; 518 individuals from risk groups. Seroconversion rate in healthy children aged <5 years (87%, 95% CI: 75% to 94%) was higher than that of risk groups combined (65%, 95% CI: 61% to 69%) (p<0.001). Multivariable analysis of risk groups showed that the size of response in those who did seroconvert was lower in those who received the 2009/10 seasonal TIV (Fold effect: 0.52, 0.35 to 0.78). Predicted immunological boosting from higher pre-vaccine titres after 2009 pandemic H1N1 vaccination only occurred in children (seroconversion rate = 92%) and not in individuals aged 10 to 39 from risk groups (seroconversion rate = 74%). The lack of clinical protection identified in the same population in older adults from risk groups could be attributed to these lower seroresponses. Current immunogenicity licensing criteria for pandemic influenza vaccine may not correlate with clinical protection in individuals with chronic disease or immunocompromised.

We analyzed data from hospital admissions and enhanced mumps surveillance to assess mumps complications during the largest mumps outbreak in England and Wales, 2004-2005, and their association with mumps vaccination. When compared with nonoutbreak periods, the outbreak was associated with a clear increase in hospitalized patients with orchitis, meningitis, and pancreatitis. Routine mumps surveillance and hospital data showed that 6.1% of estimated mumps patients were hospitalized, 4.4% had orchitis, 0.35% meningitis, and 0.33% pancreatitis. Enhanced surveillance data showed 2.9% of mumps patients were hospitalized, 6.1% had orchitis, 0.3% had meningitis, and 0.25% had pancreatitis. Risk was reduced for hospitalization (odds ratio [OR] 0.54, 95% confidence interval [CI] 0.43-0.68), mumps orchitis (OR 0.72, 95% CI 0.56-0.93) and mumps meningitis (OR 0.28, 95% CI 0.14-0.56) when patient had received 1 dose of measles, mumps, and rubella vaccine. The protective effect of vaccination on disease severity is critical in assessing the total effects of current and future mumps control strategies.

Background: Children with cancer have an increased susceptibility to influenza infection. The objective of this study was to assess the immunogenicity of pandemic (H1N1) 2009 vaccine in children with cancer., Methods: Children were recruited from the Royal Marsden Hospital, England, during November 2009. The vaccination schedule consisted of 2 doses of an AS03(B)-adjuvanted vaccine given at days 0 and 21. Serological analysis was performed on blood samples obtained at day 0 and day 42. The primary immunological end point was the seroconversion rate, which was defined as the proportion of subjects with an individual 4-fold increase in hemagglutination inhibition titer and a postvaccination hemagglutination inhibition titer ≥1:32., Results: Fifty-four children with a median age of 6.3 years (range, 1.4-16.6 years) were vaccinated and had samples taken for serological analysis. Twenty-four (44.4%) of 54 children demonstrated seroconversion. Seroconversion rates were 33.3% (9 of 27) among children with acute lymphoblastic leukemia, 36.4% (4 of 11) among those with lymphoma or other leukemias, 66.7% (6 of 9) among those with brain tumors, and 71.4% (5 of 7) among those with other solid tumors. Seroconversion occurred in 4 (28.6%) of 14 children receiving acute lymphoblastic leukemia maintenance therapy. Univariate analysis showed significantly higher responses among children with solid tumors, compared with those with hematological malignancies (11 [68.8%] of 16 vs 13 [34.2%] of 38; P = .03), and among those not receiving treatment, compared with those receiving treatment (7 [87.5%] of 8 vs 17 [37.0%] of 46; P = .02). Multivariable analysis showed that age, cancer type, and lymphopenia did not influence seroconversion rates., Conclusion: These data suggest that this AS03(B)-adjuvanted pandemic (H1N1) 2009 vaccine can induce limited but useful protective immune responses in children with cancer.