"Risk factors for tuberculosis among close IGRA-negative contacts of persons with infectious tuberculosis in Singapore".

BACKGROUND: Contacts of infectious TB cases testing positive on Interferon-Gamma Release Assay (IGRA) are followed up to exclude active disease. However, factors that predispose IGRA-negative contacts to TB could improve screening and follow-up strategies in a medium TB burden country like Singapore. METHODS: We conducted a retrospective study of IGRA-negative contacts aged ≥2 years identified during contact investigation between January 2014 and December 2022. We examined the risk factors associated with developing active TB among contacts previously testing IGRA-negative, using univariate and multivariable logistic regression and odds ratios (OR) with 95% confidence intervals (CI). RESULTS: Of 60,377 IGRA-negative contacts, 150 developed TB disease and half were notified within 23 months of index diagnosis. IGRA-negative contacts of a smear-positive index were more likely to develop TB. Independent risk factors for TB were being over 50, Malay, having Diabetes or End-Stage Renal Failure, a "family" relationship with the index or exposure in a dormitory or nursing home. CONCLUSION: Certain risk factors could help optimize follow-up strategies and preventive treatment in IGRA-negative individuals. The incidence of TB in this group was 150/100,000 population, substantially higher than in the community, with a median 92 weeks to develop disease. Findings suggest that follow-up be extended to 24 months for contacts with these risk factors.

The yield of tuberculosis contact investigation on relapsed TB patients and analysis of associated risk factors: Singapore's experience.

The yield of contact investigation on relapsed tuberculosis (TB) cases can guide strategies and resource allocation in the TB control programme. We conducted a retrospective cohort study to review the yield of contact investigation in relapsed TB cases and identify factors associated with TB infection (TBI) among close contacts of relapsed TB cases notified between 2018 and 2022 in Singapore. TB infection positivity was higher among contacts of relapsed cases which were culture-positive for Mycobacterium tuberculosis complex compared to those who were only polymerase chain reaction (PCR)-positive (14.8% vs. 12.3%). On multivariate analysis, after adjusting for age and gender of the index, gender, and existing comorbidities of contacts, factors independently associated with TBI were culture and smear positivity of the index (AOR 1.41, 95%CI 1.02-1.94), higher odds with every 10 years of increase in age compared to contacts below aged 30, contacts who were not Singapore residents (AOR 2.09, 95%CI 1.46-2.97), and household contacts (AOR 2.19, 95%CI 1.44-3.34). Although the yield of screening was higher for those who were culture-positive compared to only PCR-positive relapsed cases, contact tracing for only PCR-positive cases may still be important in a country with moderate TB incidence, should resources allow.

Implementation of national whole-genome sequencing of Mycobacterium tuberculosis, National Public Health Laboratory, Singapore, 2019-2022.

The National Tuberculosis Programme (NTBP) monitors the occurrence and spread of tuberculosis (TB) and multidrug-resistant TB (MDR-TB) in Singapore. Since 2020, whole-genome sequencing (WGS) of Mycobacterium tuberculosis isolates has been performed at the National Public Health Laboratory (NPHL) for genomic surveillance, replacing spoligotyping and mycobacterial interspersed repetitive unit-variable number tandem repeats analysis (MIRU-VNTR). Four thousand three hundred and seven samples were sequenced from 2014 to January 2023, initially as research projects and later developed into a comprehensive public health surveillance programme. Currently, all newly diagnosed culture-positive cases of TB in Singapore are prospectively sent for WGS, which is used to perform lineage classification, predict drug resistance profiles and infer genetic relationships between TB isolates. This paper describes NPHL's operational and technical experiences with implementing the WGS service in an urban TB-endemic setting, focusing on cluster detection and genomic drug susceptibility testing (DST). Cluster detection: WGS has been used to guide contact tracing by detecting clusters and discovering unknown transmission networks. Examples have been clusters in a daycare centre, housing apartment blocks and a horse-racing betting centre. Genomic DST: genomic DST prediction (gDST) identifies mutations in core genes known to be associated with TB drug resistance catalogued in the TBProfiler drug resistance mutation database. Mutations are reported with confidence scores according to a standardized approach referencing NPHL's internal gDST confidence database, which is adapted from the World Health Organization (WHO) TB drug mutation catalogue. Phenotypic-genomic concordance was observed for the first-line drugs ranging from 2959/2998 (98.7 %) (ethambutol) to 2983/2996 (99.6 %) (rifampicin). Aspects of internal database management, reporting standards and caveats in results interpretation are discussed.

Epidemiological, Clinical, and Phylogenetic Characteristics of the First SARS-CoV-2 Transmission in a Nursing Home of Singapore: A Prospective Observational Investigation.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission has resulted in a significant burden among nursing home facilities globally. This prospective observational cohort study aims to define the potential sources of introduction and characteristics of SARS-CoV-2 transmission of the first nursing home facility in Singapore. An epidemiological serial point-prevalence survey of SARS-CoV-2 was conducted among 108 residents and 56 healthcare staff (HCS). In the current study, 14 (13%) residents and two (3.6%) HCS were diagnosed with coronavirus disease 2019 (COVID-19), with a case fatality rate (CFR) of 28.6% (4/14) among the residents. The median age of the infected residents was 86.5 [interquartile range (IQR) 78.5-88] and 85.7% were women. Five residents were symptomatic (35.7%) and the others were asymptomatic (64.3%). A higher proportion of residents who succumbed to COVID-19 had hypertension than those who recovered. The SARS-CoV-2 whole-genome sequencing showed lineage B.6 which is rare globally but common regionally during the early phase of the pandemic. Household transmission is a potential source of introduction into the nursing home, with at least six epidemiologically linked secondary cases. Male residents were less implicated due to the staff segregation plan by block. Among residents, a higher proportion of the non-survivors were asymptomatic and had hypertension compared with survivors.

Assessment of the risk posed to Singapore by the emergence of artemisinin-resistant malaria in the Greater Mekong Subregion.

OBJECTIVE: To assess the public health risk to Singapore posed by the emergence of artemisinin-resistant (ART-R) malaria in the Greater Mekong Subregion (GMS). METHODS: We assessed the likelihood of importation of drug-resistant malaria into Singapore and the impact on public health of its subsequent secondary spread in Singapore. Literature on the epidemiology and contextual factors associated with ART-R malaria was reviewed. The epidemiology of malaria cases in Singapore was analysed. The vulnerability and receptivity of Singapore were examined, including the connectivity with countries reporting ART-R malaria, as well as the preparedness of Singaporean health authorities. Sources of information include international journals, World Health Organization guidelines, data from the Singapore Ministry of Health and National Public Health Laboratory of the National Centre for Infectious Diseases, and the International Air Transport Association. RESULTS: The importation of ART-R malaria into Singapore is possible given the close proximity and significant travel volume between Singapore and the GMS countries reporting artemisinin resistance. Singapore's vulnerability is further enhanced by the presence of foreign workers from neighbouring endemic countries. Nonetheless, the overall likelihood of such an event is low based on the rarity and decreasing trend of imported malaria incidence.​: With the presence of Anopheles vectors in Singapore, imported cases of drug-resistant malaria could cause secondary transmission. Nevertheless, the risk of sustained spread is likely to be mitigated by the comprehensive surveillance and control system in place for both infected vectors and human cases. DISCUSSION: This risk assessment highlights the need for a continued high degree of vigilance of ART-R malaria locally and globally to minimize the risk and public health impact of drug-resistant malaria in Singapore.

The Effect of School Closure on Hand, Foot, and Mouth Disease Transmission in Singapore: A Modeling Approach.

Singapore implements a school closure policy for institutional hand, foot, and mouth disease (HFMD) outbreaks, but there is a lack of empirical evidence on the effect of closure on HFMD transmission. We conducted a retrospective analysis of 197,207 cases of HFMD over the period 2003-2012 at the national level and of 57,502 cases in 10,080 institutional outbreaks over the period 2011-2016 in Singapore. The effects of school closure due to 1) institutional outbreaks, 2) public holidays, and 3) school vacations were assessed using a Bayesian time series modeling approach. School closure was associated with a reduction in HFMD transmission rate. During public holidays, average numbers of secondary cases having onset the week after dropped by 53% (95% credible interval 44-62%), and during school vacations, the number of secondary cases dropped by 7% (95% credible interval 3-10%). Schools being temporarily closed in response to an institutional outbreak reduced the average number of new cases by 1,204 (95% credible interval 1,140-1,297). Despite the positive effect in reducing transmission, the effect of school closure is relatively small and may not justify the routine use of this measure.

Dengue in Singapore from 2004 to 2016: Cyclical Epidemic Patterns Dominated by Serotypes 1 and 2.

Singapore has experienced periodic dengue epidemics despite maintaining a low Aedes house index. Each epidemic was associated with a switch in the predominant serotype. We investigated the temporal dynamics of dengue fever and dengue virus (DENV) and analyzed the epidemiological and entomological patterns of dengue in Singapore from 2004 to 2016. The case surveillance is based on a mandatory notification system that requires all medical practitioners to report clinically suspected and laboratory-confirmed cases. Circulating (DENV) serotypes are monitored through a virus surveillance program. Entomological surveillance involves inspections for larval breeding and monitoring of adults using gravitraps. Singapore experienced a similar epidemic pattern during 2004-2007 and 2013-2016. The pattern involved a 2-year DENV-1 epidemic occurring after a switch in the predominant serotype from DENV-2 to DENV-1, followed by a "lull" year. Thereafter, the predominant serotype switched back to DENV-2, tailed by a small-scale epidemic. Across the years, the highest incidence group was in the 25-44 years age group. The incidence rate of those aged ≥ 55 years was about half of that of the 15-24 years age group during DENV-1 predominant years. However, it was almost equal to the younger age group in DENV-2 predominant years. Types of Aedes aegypti breeding habitats remained similar. Dengue incidence was significantly higher in areas with high breeding percentage (BP) than areas with low BP (P < 0.05). In conclusion, the oscillation of DENV-1 and DENV-2, throughout the 13-year period, led to a cyclical epidemic pattern and older adults were more affected by DENV-2 than DENV-1.

Epidemiological characteristics associated with uptake of pneumococcal vaccine among older adults living in the community in Singapore: Results from the National Health Surveillance Survey 2013.

AIMS: In Singapore, pneumococcal vaccination is recommended for the elderly (i.e. those ≥65 years of age) and people with chronic medical conditions. We investigated epidemiological characteristics associated with the uptake of pneumococcal vaccine based on a nationally representative cross-sectional sample of community-living adults aged ≥50 years. METHODS: The data were obtained from the National Health Surveillance Survey (NHSS) 2013. Associations between pneumococcal vaccination and sociodemographic and health-related variables were analysed using univariable and multivariable logistic regression models. RESULTS: Among 3672 respondents aged ≥50 years in the NHSS, 7.8% had taken the pneumococcal vaccination. A higher level of education and higher monthly household income were sociodemographic characteristics independently associated with pneumococcal vaccine uptake. Health-related characteristics predictive of pneumococcal vaccine uptake were better self-rated health and having a regular family doctor/general practitioner. Among those who responded to the two questions on vaccinations, 3.9% had been vaccinated against both seasonal influenza and pneumococcal infection, while 11.1% had taken only seasonal influenza vaccination in the past year. CONCLUSIONS: There is a need to boost pneumococcal vaccination coverage among community-dwelling older adults. These findings provide insights into reviewing and tailoring public-health strategies and programmes to increase vaccine uptake in at-risk population groups.

Influenza-Associated Hospitalizations for Cardiovascular Diseases in the Tropics.

Influenza is a major cause of mortality and morbidity. We aimed to examine the influenza-associated hospitalization rates and proportions for cardiovascular disease (CVD) in tropical Singapore. Hospital admissions for ischemic heart disease (IHD), congestive heart failure (CHF), and overall CVD were obtained from the national inpatient database for the period of 2010-2014. We used, as the key indicator of influenza virus activity, the overall proportion of specimens from outpatients with influenza-like illness in the community that tested positive for influenza as part of the national influenza surveillance program. The annual influenza-associated hospitalization rates per 100,000 person-years ranged from 9.5 to 12.2 for IHD, 7.7 to 9.1 for CHF, and 15.8 to 19.2 for overall CVD. The influenza-associated hospitalization rates increased with increasing age. Influenza was significantly associated with excess hospitalizations in elderly persons aged ≥80 years, with an excess hospitalization rate per 100,000 person-years of 242.7 for IHD (P = 0.02), 271.8 for CHF (P = 0.01), and 497.2 for overall CVD (P < 0.001). In the tropics, influenza accounts for excess cardiovascular-related hospitalizations, especially in the elderly.

The inevitable colonisation of Singapore by Zika virus.

Singapore is endemic for Dengue virus, with approximately 10,000 to 20,000 annual cases reported in recent years. In 2012, Chikungunya was introduced, although the numbers of cases reported is much fewer. The current Zika virus pandemic originating in Brazil represents a threat to all regions with Aedes mosquitoes, particularly those well connected by travellers. In this respect, it was felt inevitable that Singapore would eventually realise its third endemic flavivirus. In late August 2016, a primary care practitioner observed a cluster of geographically linked patients attending with fever and rash. This resulted in the first identification of locally transmitted Zika in Singapore on August 27, 2016. This prompted a robust response in an attempt to stop further spread, which continued for approximately 10 days until a large number of laboratory-confirmed cases were found as a result of active case finding. Surprisingly, the strain was later identified to be of Asian lineage and distinct from that originating in the Americas, prompting speculation over the epidemiology of this under recognised virus in Asia.

Group B Streptococcus Serotype III Sequence Type 283 Bacteremia Associated with Consumption of Raw Fish, Singapore.

We conducted a retrospective study of 40 case-patients and 58 controls as part of a nationwide investigation of a group B Streptococcus outbreak in Singapore in 2015. Eating a Chinese-style raw fish dish (yusheng) was a major risk factor for bacteremia, particularly caused by serotype III sequence type 283.

Epidemic resurgence of dengue fever in Singapore in 2013-2014: A virological and entomological perspective.

BACKGROUND: Dengue resurged in Singapore during 2013-14, causing an outbreak with unprecedented number of cases in the country. In the present study, we summarise the epidemiological, virological and entomological findings gathered through the dengue surveillance programme and highlight the drivers of the epidemic. We also describe how the surveillance system facilitated the preparedness to moderate epidemic transmission of dengue in the country. METHODS: The case surveillance was based on a mandatory notification system that requires all medical practitioners to report clinically-suspected and laboratory-confirmed cases within 24 hours. The circulating Dengue virus (DENV) populations were monitored through an island wide virus surveillance programme aimed at determining the serotypes and genotypes of circulating virus strains. Entomological surveillance included adult Aedes surveillance as well as premise checks for larval breeding. RESULTS: A switch in the dominant serotype from DENV-2 to DENV-1 in March 2013 signalled a potential spike in cases, and the alert was corroborated by an increase in average Aedes house index. The alert triggered preparedness and early response to moderate the impending outbreak. The two-year outbreak led to 22,170 cases in 2013 and 18,338 in 2014, corresponding to an incidence rate of 410.6 and 335.0 per 100,000 population, respectively. DENV-1 was the dominant serotype in 2013 (61.7 %, n = 5,071) and 2014 (79.2 %, n = 5,226), contributed largely by a newly-introduced DENV-1 genotype III strain. The percentage of houses with Ae. aegypti breeding increased significantly (p < 0.001) from 2012 (annual average of 0.07 %) to 2013 (annual average of 0.14 %), followed by a drop in 2014 (annual average of 0.10 %). Aedes breeding data further showed a wide spread distribution of Ae. aegypti in the country that corresponded with the dengue case distribution pattern in 2013 and 2014. The adult Aedes data from 34 gravitrap sentinel sites revealed that approximately 1/3 of the monitored sites remained at high risk of DENV transmission in 2013. CONCLUSIONS: The culmination of the latest epidemic is likely to be due to a number of demographic, social, virological, entomological, immunological, climatic and ecological factors that contribute to DENV transmission. A multi-pronged approach backed by the epidemiological, virological and entomological understanding paved way to moderate the case burden through an integrated vector management approach.

Characterization of influenza activity based on virological surveillance of influenza-like illness in tropical Singapore, 2010-2014.

Singapore is situated in the tropics where the seasonality of influenza is not as well defined as that of temperate countries. We examined the circulation of influenza viruses in the community in terms of the characteristics of influenza activity. We reviewed laboratory-confirmed virological data collected between 2010 and 2014 under the national influenza surveillance programme. Influenza activity was measured by the proportion of specimens from outpatients with influenza-like illness tested positive for influenza virus based on 4-weekly moving interval. Seasonal epidemics occurred around the end of previous year or the beginning and middle of the year. Increases in influenza positivity were more pronounced when there was a change in the predominant circulating influenza virus type/subtype to influenza A(H3N2). Influenza epidemics lasted about 12 weeks on average, with longer duration when there was a change in the predominant influenza type/subtype and especially when it was associated with influenza A(H3N2). Continuous influenza surveillance is important as it could provide early warning of imminent surges in virus transmission, and allow for timely implementation of public health prevention and control interventions to minimize influenza-associated disease burden. J. Med. Virol. 88:2069-2077, 2016. © 2016 Wiley Periodicals, Inc.

Temporal Patterns of Influenza A and B in Tropical and Temperate Countries: What Are the Lessons for Influenza Vaccination?

INTRODUCTION: Determining the optimal time to vaccinate is important for influenza vaccination programmes. Here, we assessed the temporal characteristics of influenza epidemics in the Northern and Southern hemispheres and in the tropics, and discuss their implications for vaccination programmes. METHODS: This was a retrospective analysis of surveillance data between 2000 and 2014 from the Global Influenza B Study database. The seasonal peak of influenza was defined as the week with the most reported cases (overall, A, and B) in the season. The duration of seasonal activity was assessed using the maximum proportion of influenza cases during three consecutive months and the minimum number of months with ≥80% of cases in the season. We also assessed whether co-circulation of A and B virus types affected the duration of influenza epidemics. RESULTS: 212 influenza seasons and 571,907 cases were included from 30 countries. In tropical countries, the seasonal influenza activity lasted longer and the peaks of influenza A and B coincided less frequently than in temperate countries. Temporal characteristics of influenza epidemics were heterogeneous in the tropics, with distinct seasonal epidemics observed only in some countries. Seasons with co-circulation of influenza A and B were longer than influenza A seasons, especially in the tropics. DISCUSSION: Our findings show that influenza seasonality is less well defined in the tropics than in temperate regions. This has important implications for vaccination programmes in these countries. High-quality influenza surveillance systems are needed in the tropics to enable decisions about when to vaccinate.

Seroprevalence of past dengue virus infection among children and adolescents in Singapore.

We conducted a pediatric seroprevalence study of dengue virus (DENV) infection in Singapore, a dengue endemic city-state. Residual sera from 1,200 Singapore residents aged 1-17 years seen in two hospitals between 2008 and 2010 were tested for anti-DENV IgG antibodies. The overall seroprevalence was 10.4% (95%CI: 8.7-12.1%). There had been a marked decline in seroprevalence in the 15-19-year age group over the last three decades, while the prevalence in the 1-5-year olds (12.6%) was significantly higher than that of the 1996-1997 pediatric survey (0.8%). The overall dengue seroprevalence in children and adolescents remained low.

Seroepidemiology of Coxsackievirus A6, Coxsackievirus A16, and Enterovirus 71 Infections among Children and Adolescents in Singapore, 2008-2010.

Coxsackieviruses A6 (CV-A6) and A16 (CV-A16) and Enterovirus 71 (EV-A71) have caused periodic epidemics of hand, foot and mouth disease (HFMD) among children in Singapore. We conducted a cross-sectional study to estimate the seroprevalence of these enteroviruses among Singapore children and adolescents. The study was conducted between August 2008 and July 2010. It involved 700 Singapore residents aged 1-17 years whose residual sera were obtained following the completion of routine biochemical investigations in two public acute-care hospitals. The levels of neutralizing antibodies (NtAb) against CV-A6, CV-A16 and EV-A71 were analyzed by the microneutralization test. The age-specific geometric mean titer (GMT) of antibodies against each of the three enteroviruses and the 95% confidence intervals (CI) were calculated. The seroprevalence of CV-A6 and CV-A16 was high at 62.7% (95% CI: 59.1-66.2%) and 60.6% (95% CI: 56.9-64.1%), respectively. However, the seroprevalence of EV-A71 was significantly lower at 29.3% (95% CI: 26.0-32.8%). About 89.7% of the children and adolescents had been infected by at least one of the three enteroviruses by 13-17 years of age. About half (52.3%) were seropositive for two or all three enteroviruses, while only 16.1% had no NtAb against any of the three enteroviruses. High NtAb levels were observed in the younger age groups. CV-A6 and CV-A16 infections are very common among Singapore children and adolescents, while EV-A71 infections are less common. Infection is continually acquired from early childhood to adolescent age.

An epidemiological assessment towards elimination of rubella and congenital rubella syndrome in Singapore.

OBJECTIVE: In line with regional and global goals for the elimination of rubella and congenital rubella syndrome (CRS), we reviewed the epidemiological situation in Singapore, based on surveillance reports on rubella and CRS, national immunization coverage and seroprevalence surveys. The aim of our review was to identify current gaps and steps taken to achieve the targets set by the World Health Organization (WHO) Western Pacific Regional Office (WPRO). METHODS: Epidemiological data on clinical and laboratory-confirmed rubella cases, including CRS, notified to the Communicable Diseases Division, Ministry of Health, Singapore, from 2003 to 2013 were collated and analyzed. Vaccination coverage against rubella was obtained from the National Immunization Registry and School Health Services of the Health Promotion Board. The changing prevalence of rubella was determined from periodic serological surveys. FINDINGS: The incidence of indigenous rubella cases per million population decreased from 37.2 in 2008 to 7.6 in 2013 and there had been no indigenous case of CRS in 2012 and 2013. Therapeutic abortions performed due to rubella infections had become uncommon. The annual measles, mumps, and rubella (MMR) vaccination coverage in childhood population remained high ranging from 93% to 96%. The overall susceptibility to rubella in women aged 18-44 years had reduced significantly from 15.8% in 2004 to 11.0% in 2010. The prevalence of IgG antibody against rubella among Singapore children aged 1-17 years was maintained at 87.3% in 2008-2010. CONCLUSION: All available data indicated that Singapore has made good progress towards the elimination of rubella and CRS. It has attained the targets set by the WHO WPRO for 2015. In preparation for verification of rubella elimination, an enhanced surveillance system has been implemented to ensure that all reported cases are laboratory confirmed, and genotyping of rubella virus strains isolated is carried out to provide evidence for interruption of endemic transmission.