Estimation of trajectory of protective efficacy in infectious disease prevention trials using recurrent event times.

In studies of infectious disease prevention, the level of protective efficacy of medicinal products such as vaccines and prophylactic drugs tends to vary over time. Many products require administration of multiple doses at scheduled times, as opposed to one-off or continual intervention. Accurate information on the trajectory of the level of protective efficacy over time facilitates informed clinical recommendations and implementation strategies, for example, with respect to the timing of administration of the doses. Based on concepts from pharmacokinetic and pharmacodynamic modeling, we propose a non-linear function for modeling the trajectory after each dose. The cumulative effect of multiple doses of the products is captured by an additive series of the function. The model has the advantages of parsimony and interpretability, while remaining flexible in capturing features of the trajectories. We incorporate this series into the Andersen-Gill model for analysis of recurrent event time data and compare it with alternative parametric and non-parametric functions. We use data on clinical malaria disease episodes from a trial of four doses of an anti-malarial drug combination for chemoprevention to illustrate, and evaluate the performance of the methods using simulation. The proposed method out-performed the alternatives in the analysis of real data in terms of Akaike and Bayesian Information Criterion. It also accurately captured the features of the protective efficacy trajectory such as the area under curve in simulations. The proposed method has strong potential to enhance the evaluation of disease prevention measures and improve their implementation strategies.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Modelling non-linear patterns of time-varying intervention effects on recurrent events in infectious disease prevention studies.

Protective efficacy of vaccines and pharmaceutical products for prevention of infectious diseases usually vary over time. Information on the trajectory of the level of protection is valuable. We consider a parsimonious, non-linear and non-monotonic function for modelling time-varying intervention effects and compare it with several alternatives. The cumulative effects of multiple doses of intervention over time can be captured by an additive series of the function. We apply it to the Andersen-Gill model for analysis of recurrent time-to-event data. We re-analyze data from a trial of intermittent preventive treatment for malaria to illustrate and evaluate the method by simulation.

Paediatric actinomycosis: A 16-year, single-institution retrospective review of cases.

AIM: Actinomycosis is a rare subacute to chronic granulomatous infection which can mimic other infectious or malignant diseases. This study examined the epidemiology and treatment outcome of actinomycosis in children. METHODS: A retrospective study on children admitted for actinomycosis in a tertiary paediatric hospital in Singapore, from January 2004 to December 2020. Clinical profile, therapeutic interventions and outcomes were examined. RESULTS: A total of 10 patients were identified; 7 were female. The median age at first presentation was 9.8 years (range 4.7-15.7). The most common presenting symptom was fever (n = 6, 60%), followed by facial or neck swelling (n = 3, 30%) and ear pain (n = 3, 30%). Actinomycosis occurred predominantly in the orocervicofacial region (n = 6, 60%). Four patients (40%) had preceding dental infections in the form of dental caries or gingivitis. One patient had poorly controlled insulin-dependent diabetes mellitus. Actinomycosis was confirmed via culture in four patients, histopathology in four patients and both methods in two patients. All except one patient (n = 9, 90%) underwent surgical procedures. All patients received ampicillin or amoxicillin/clavulanate or other beta-lactams, for a median duration of 6.5 months (range 1.5-14). Complications included osteomyelitis (n = 4, 40%), mastoiditis (n = 2, 20%), brain abscess (n = 1, 10%) and recurrent neck abscess (n = 1, 10%). There was no mortality and all patients achieved complete resolution. CONCLUSIONS: Paediatric actinomycosis was rare in our 16-year review, but had a high complication rate. It can occur in immunocompetent patients, and dental infection was the predominant risk factor identified. Prognosis was excellent after surgical intervention and appropriate antimicrobial therapy.

Effectiveness of Palivizumab Against Respiratory Syncytial Virus Hospitalization Among Preterm Infants in a Setting With Year-Round Circulation.

BACKGROUND: The year-round respiratory syncytial virus (RSV) circulation in tropical regions leads to different transmission patterns and burden of disease among infants born very preterm. METHODS: We conducted a retrospective cohort study to estimate the effectiveness of palivizumab in preventing RSV hospitalization at 6 and 12 months after discharge, among infants born at <32 weeks' gestation in our tropical setting. RESULTS: A total of 109 infants (26.3%) received palivizumab at discharge, of 415 who were eligible. All patients received ≥4 doses, with 105 infants (96.3%) completing 5 doses. Within 1 year after discharge, there were 35 RSV-associated admissions (3 [2.8%] in the palivizumab vs 32 [10.5%] in the nonpalivizumab group; P = .02). After adjustment for confounders, the effectiveness of palivizumab against RSV hospitalization was estimated to be 90% (95% confidence interval, 10%-99%) up to 6 months after discharge. The median time to RSV hospitalization was shorter in the nonpalivizumab than in the palivizumab group (median [range], 155 [15-358] vs 287 [145-359] days, respectively; P = .11). Five infants (14.3%), all from the nonpalivizumab group, required admission to the intensive care unit. CONCLUSIONS: In our setting with year-round RSV circulation, palivizumab prophylaxis was effective in reducing RSV hospitalization among high-risk preterm infants of <32 weeks' gestation within the initial 6 months after discharge.

Novel Coronavirus 2019 Transmission Risk in Educational Settings.

Transmission risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in schools is unknown. Our investigations, especially in preschools, could not detect SARS-CoV-2 transmission despite screening of symptomatic and asymptomatic children. The data suggest that children are not the primary drivers of SARS-CoV-2 transmission in schools and could help inform exit strategies for lifting of lockdowns.

Respiratory viral infections in hospitalised paediatric patients in the tropics.

AIM: Respiratory viruses are a huge disease burden globally. An understanding of the seasonal trends and the ability to predict peak periods of respiratory virus disease incidence is useful for clinical care. METHODS: This is a retrospective analysis of paediatric hospitalizations of laboratory-confirmed viral respiratory tract infections in KK Women's and Children's Hospital, Singapore, from 1 January 2011 to 31 December 2016. Standard direct immunofluorescence was used to detect respiratory syncytial virus (RSV), influenza A and B viruses, parainfluenza 1, 2 and 3 viruses, metapneumovirus and adenovirus. RESULTS: A total of 97 840 specimens were analysed with a positive detection rate of 23.8%. RSV made up the largest proportion (42% of the total positive results), predominating between May to September. Influenza A had two peaks, June to July and December to January. Type 3 was the most common parainfluenza virus and showed annually recurring peaks. In contrast, parainfluenza 1 and 2, metapneumovirus and adenovirus had a biennial pattern. The test of seasonality detected identifiable seasonality for RSV and parainfluenza 3 virus. CONCLUSIONS: In conclusion, respiratory viruses have different and overlapping seasonality in tropical Singapore. Respiratory virus testing for patients admitted for acute respiratory infection is useful to target antiviral therapies and appropriate infection control practices.

Universal Face Masking Reduces Respiratory Viral Infections Among Inpatient Very-Low-Birthweight Neonatal Infants.

We reviewed the impact of a universal face masking policy on respiratory viral infections (RVIs) among admitted very-low-birthweight infants in our neonatal department. There was a significant decrease in RVI incidence, specifically in our step-down level 2 unit, with respiratory syncytial virus and parainfluenza virus being the most common viruses isolated.

A Well Infant With Coronavirus Disease 2019 With High Viral Load.

A well 6-month-old infant with coronavirus disease 2019 (COVID-19) had persistently positive nasopharyngeal swabs up to day 16 of admission. This case highlights the difficulties in establishing the true incidence of COVID-19, as asymptomatic individuals can excrete the virus. These patients may play important roles in human-to-human transmission in the community.

Burden and Cost of Hospitalization for Respiratory Syncytial Virus in Young Children, Singapore.

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.

Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 from Adults to Children.

Knowledge of transmission dynamics of severe acute respiratory syndrome coronavirus 2 from adults to children in household settings is limited. We found an attack rate among 213 children in 137 households to be 6.1% in households with confirmed adult 2019 novel coronavirus disease index case(s). Transmission from adult to child occurred in only 5.2% of households. Young children <5 years old were at lowest risk of infection (1.3%). Children were most likely to be infected if the household index case was the mother.

Impact of COVID-19 on pediatric emergencies and hospitalizations in Singapore.

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.

Timeliness of Childhood Vaccination Coverage: the Growing Up in Singapore Towards Healthy Outcomes Study.

Studies investigating timeliness for childhood vaccination are limited especially in Asia. We examined the timeliness of vaccine administration and associated factors among infant and young children in Singapore. A total of 782 children born between November 2009 and July 2011 from a prospective cohort in Singapore were studied. Vaccination records from birth to 24 months of age were obtained from the National Immunization Registry of Singapore. Multivariable logistic regression models were performed. By 2 years of age, 92.8% of children in our cohort experienced a delay in receiving 1 or more vaccine doses according to the recommended national immunization schedule. When vaccinations were reviewed by series for each vaccine, 15.6% received all vaccine series outside the recommended age ranges. Factors associated with receiving vaccination series outside the recommended ages included maternal aged ≤ 35 years (OR 2.00; 95% CI 1.09, 3.66), Malay (1.71; 1.01, 2.89) or Indian ethnicity (2.06; 1.19, 3.59), low monthly household income (1.91; 1.14, 3.18), having at least four children (3.46; 1.62, 7.38) and private (3.42; 1.80, 6.48) and multiple vaccination providers (3.91; 1.23, 12.48). These findings show an unacceptably high proportion of children experienced a delay in the receipt of their vaccinations. The identification of several demographic, socioeconomic, health-seeking behavioural and vaccine provider factors provides opportunities for targeted interventions to enhance the timeliness of childhood vaccination in Singapore.

Semiannual Versus Annual Influenza Vaccination in Older Adults in the Tropics: An Observer-blind, Active-comparator-controlled, Randomized Superiority Trial.

BACKGROUND: Antibody titres and vaccine effectiveness decline within 6 months after influenza vaccination in older adults. Biannual vaccination may be necessary to provide year-round protection in the tropics, where influenza circulates throughout the year. METHODS: Tropical Influenza Control Strategies (TROPICS1) was a single-center, 1:1 randomized, observer-blinded, active-comparator-controlled, superiority study in 200 community-resident adults aged ≥65 years. Participants received a standard-dose trivalent inactivated influenza vaccination (IIV3) at enrollment, and either tetanus-diphtheria-pertussis vaccination or IIV3 6 months later. The primary outcome was the proportion of participants with haemagglutination-inhibition (HI) geometric mean titre (GMT) ≥1:40 1 month after the second vaccination (month 7). Secondary outcomes included GMTs to month 12, the incidence of influenza-like illness (ILI), and adverse reactions after vaccination. RESULTS: At month 7, the proportion of participants with an HI tire ≥1:40 against A/H1N1 increased by 21.4% (95% confidence interval [CI] 8.6-33.4) in the semiannual vaccination group. This proportion was not significantly higher for A/H3N2 (4.3, 95% CI -1.1-10.8) or B (2.1, 95% CI -2.0-7.3). Semiannual vaccination significantly increased GMTs against A/H1N1 and A/H3N2, but not B, at month 7. Participants receiving a repeat vaccination of IIV3 reported a significantly lower incidence of ILI in the 6 months after the second vaccination (relative vaccine effectiveness 57.1%, 95% CI 0.6-81.5). The frequency of adverse events was similar after the first and second influenza vaccinations. CONCLUSIONS: Semiannual influenza vaccination in older residents of tropical countries has the potential to improve serological measures of protection against infection. Alternative vaccination strategies should also be studied. CLINICAL TRIALS REGISTRATION: NCT02655874.

Coverage and determinants of influenza vaccine among pregnant women: a cross-sectional study.

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.

Burden, Etiology, and Risk Factors of Respiratory Virus Infections Among Symptomatic Preterm Infants in the Tropics: A Retrospective Single-Center Cohort Study.

Background: The burden of respiratory viral infections (RVIs) among preterm infants in the first few years of life, especially those living in the tropics with year-long transmissions of respiratory viruses, remains unknown. We aimed to describe the clinical epidemiology and associated risk factors for RVIs among symptomatic preterm infants ≤32 weeks up to 2 years of life. Methods: We performed a data linkage analysis of clinical and hospital laboratory databases for preterm infants born at KK Women's and Children's Hospital, Singapore, from 2005 to 2015. RVI episodes during initial admission and subsequent hospital readmissions were included. Results: Of 1854 infants in the study, 270 (14.5%) infants were diagnosed with at least 1 RVI. A total of 285 (85.3%) episodes were diagnosed postdischarge, with the highest risk for RVIs being from 3 to 5 months of age. The incidence of RVI in this population was 116 per 1000 infant-years and respiratory syncytial virus was the main overall causative pathogen. Infants with RVIs were more likely to be born at ≤27 weeks' gestational age (odds ratio [OR], 1.7; 95% confidence interval [CI], 1.2-2.3), to have received postnatal steroids (OR, 1.5; 95% CI, 1.0-2.1), and to be diagnosed with bronchopulmonary dysplasia (OR, 1.7; 95% CI, 1.2-2.4). Conclusions: The burden of RVIs is high in preterm infants in the tropics, affecting >1 of 10 infants born at ≤32 weeks' gestation before 2 years of age. Respiratory syncytial virus was the main causative pathogen identified. Risk factors for RVI included extremely low gestational age, receipt of postnatal steroids, and bronchopulmonary dysplasia.

Elizabethkingia anophelis and Association with Tap Water and Handwashing, Singapore.

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.

Effectiveness of Masks and Respirators Against Respiratory Infections in Healthcare Workers: A Systematic Review and Meta-Analysis.

This systematic review and meta-analysis quantified the protective effect of facemasks and respirators against respiratory infections among healthcare workers. Relevant articles were retrieved from Pubmed, EMBASE, and Web of Science. Meta-analyses were conducted to calculate pooled estimates. Meta-analysis of randomized controlled trials (RCTs) indicated a protective effect of masks and respirators against clinical respiratory illness (CRI) (risk ratio [RR] = 0.59; 95% confidence interval [CI]:0.46-0.77) and influenza-like illness (ILI) (RR = 0.34; 95% CI:0.14-0.82). Compared to masks, N95 respirators conferred superior protection against CRI (RR = 0.47; 95% CI: 0.36-0.62) and laboratory-confirmed bacterial (RR = 0.46; 95% CI: 0.34-0.62), but not viral infections or ILI. Meta-analysis of observational studies provided evidence of a protective effect of masks (OR = 0.13; 95% CI: 0.03-0.62) and respirators (OR = 0.12; 95% CI: 0.06-0.26) against severe acute respiratory syndrome (SARS). This systematic review and meta-analysis supports the use of respiratory protection. However, the existing evidence is sparse and findings are inconsistent within and across studies. Multicentre RCTs with standardized protocols conducted outside epidemic periods would help to clarify the circumstances under which the use of masks or respirators is most warranted.

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.