Epidemiology of extrapulmonary tuberculosis in Brunei Darussalam: a retrospective cohort study.

OBJECTIVES: We reported the incidence and associated factors of extrapulmonary tuberculosis (EPTB). DESIGN: A retrospective cohort study. SETTING: Brunei Darussalam, an intermediate tuberculosis (TB)-burden country with stagnating annual TB rates. PARTICIPANTS: All active TB cases identified in the country between January 2001 and December 2018 (18 years). PRIMARY AND SECONDARY OUTCOME MEASURES: Annual proportions of EPTB (overall and specific) were calculated. Multiple logistic regression was done to investigate factors associated with developing EPTB, when compared with pulmonary TB (PTB). Χ2 trend test was used to determine any trends during the 18-year study period. RESULTS: We identified 3916 TB cases, among which 743 (19.0%) were EPTB cases. Lymphatic (44.8%) and pleural (19.4%) EPTB were most common. The main modes of diagnosis were tissue biopsy (73.6%) and radiological assessment (18.3%). Treatment success and mortality rate were 79.7% and 7.0%, respectively. Associations with specific EPTB types varies with age-group and gender. Younger age-group (adjusted OR (aOR)≥1.94) and women (aOR: 2.45 (95% CI: 1.94 to 3.11)) had higher adjusted odds of developing lymphatic EPTB, but had lower adjusted odds of developing pleural EPTB (younger age-group (aOR≤0.54) and women (aOR: 0.41 (95% CI: 0.17 to 0.90)). When compared to foreign residents, locals had higher adjusted odds of skeletal (aOR: 4.44 (95% CI: 2.04 to 11.69)), gastrointestinal (aOR: 3.91 (95% CI: 1.84 to 9.66)) and other types of EPTB (aOR: 3.42 (95% CI: 1.53 to 9.14)). No significant trend differences were observed for overall and specific EPTB types. CONCLUSION: Despite being generally non-infectious and less recognised than PTB, understanding EPTB epidemiology is important as it also contributes to the overall TB burden in a country. Examining EPTB cases by their specific anatomical site would provide more information on risk factors. Raising public awareness on the EPTB symptoms and that TB affects lungs and other parts of the body could promote early health seeking behaviour and early EPTB diagnosis.

Contact investigation of tuberculosis in Brunei Darussalam: Evaluation and risk factor analysis.

INTRODUCTION: We evaluated the yield of tuberculosis (TB) contact investigation in Brunei Darussalam, and identified the associated factors for latent TB infection (LTBI) diagnosis, as well as for initiating and completing LTBI treatment. METHODS: Data were extracted and digitalised for all close contacts of pulmonary TB (PTB) cases at the National TB Coordinating Centre from January 2009 to December 2018. Generalising estimating equations logistic regression models were used to determine the associated factors. Manual matching against electronic health records system was done to identify contacts who had progressed to active TB disease. RESULTS: Among 10 537 contacts, 9.9% (n=1047) were diagnosed as LTBI, out of which 43.0% (n=450) initiated LTBI treatment. Among those who initiated, 74.0% (n=333) completed LTBI treatment. Contact factors associated with LTBI diagnosis include being male (adjusted OR (aOR)=1.18 (95% CI 1.03 to 1.34)), local (aOR=0.70 (95% CI 0.56 to 0.88)) and a household contact (aOR=1.59 (95% CI 1.26 to 1.99)). Contacts of index cases who were <60 years old and diagnosed as smear positive PTB (aOR=1.62 (95% CI 1.19 to 2.20)) had higher odds of being diagnosed with LTBI. Local LTBI cases had higher odds of initiating LTBI treatment (aOR=1.86 (95% CI 1.26 to 2.73)). Also, LTBI cases detected from local (aOR=2.32 (95% CI 1.08 to 4.97)) and smear positive PTB index cases (aOR=2.23 (95% CI 1.09 to 4.55)) had higher odds of completing LTBI treatment. Among 1047 LTBI cases, 5 (0.5%) had progressed to active PTB within 1-8 years post-LTBI diagnosis. DISCUSSION: LTBI burden is disproportionately high towards foreign nationals, with higher odds of LTBI diagnosis but lower odds of treatment initiation. Determining the reasons of not initiating LTBI treatment will be useful to help improve LTBI treatment uptake. Establishing digital databases and building TB laboratory capacity for molecular typing would be useful to determine the contribution of LTBI or reactivation towards TB incidence in Brunei.

Association between climate variables and pulmonary tuberculosis incidence in Brunei Darussalam.

We investigated the association between climate variables and pulmonary tuberculosis (PTB) incidence in Brunei-Muara district, Brunei Darussalam. Weekly PTB case counts and climate variables from January 2001 to December 2018 were analysed using distributed lag non-linear model framework. After adjusting for long-term trend and seasonality, we observed positive but delayed relationship between PTB incidence and minimum temperature, with significant adjusted relative risk (adj.RR) at 25.1 °C (95th percentile) when compared to the median, from lag 30 onwards (adj.RR = 1.17 [95% Confidence Interval (95% CI): 1.01, 1.36]), suggesting effect of minimum temperature on PTB incidence after 30 weeks. Similar results were observed from a sub-analysis on smear-positive PTB case counts from lag 29 onwards (adj.RR = 1.21 [95% CI: 1.01, 1.45]), along with positive and delayed association with total rainfall at 160.7 mm (95th percentile) when compared to the median, from lag 42 onwards (adj.RR = 1.23 [95% CI: 1.01, 1.49]). Our findings reveal evidence of delayed effects of climate on PTB incidence in Brunei, but with varying degrees of magnitude, direction and timing. Though explainable by environmental and social factors, further studies on the relative contribution of recent (through primary human-to-human transmission) and remote (through reactivation of latent TB) TB infection in equatorial settings is warranted.

Reasons for non-attendance to cervical cancer screening and acceptability of HPV self-sampling among Bruneian women: A cross-sectional study.

OBJECTIVE: Uptake for cervical cancer screening remains well below the 80% target as recommended by Brunei's National Cervical Cancer Prevention and Control plan. We conducted a pilot study to determine the reasons for non-attendance and explore their acceptance of human papillomavirus (HPV) self-sampling as an alternative to the Pap test. METHODS: A cross-sectional study was conducted at a primary healthcare center in Brunei, from January to December 2019. We recruited screening non-attendees, defined as women who were eligible for Pap test but who either never, or did not have one within the recommended screening interval of 3 years. This recruitment was done conveniently among women attending outpatient care and/or child health services at the primary healthcare center. Participants were first asked to complete a self-administered paper-based questionnaire on their reasons for screening non-attendance, and then invited for HPV self-sampling. Among those who agreed to participate in HPV self-sampling, they were asked to complete a second questionnaire on the self-sampling procedure and their samples were tested for high-risk HPV (hr-HPV). Results were analyzed using descriptive and inferential statistics. RESULT: We enrolled 174 screening non-attendees, out of which 97 (55.7%) also participated in HPV self-sampling. The main reasons for not attending Pap test screening were fear of bad results (16.1%, n = 28); embarrassment (14.9%, n = 26) and lack of time due to home commitments (10.3%, n = 18). When compared to those who agreed to participate in HPV self-sampling, those who declined were significantly older (p = 0.002) and less likely to agree that they are susceptible to cervical cancer (p = 0.023). They preferred to receive Pap test-related information from healthcare workers (59.0%, n = 155), social messaging platforms (28.7%, n = 51) and social media (26.4%, n = 47). HPV self-sampling kits were positively received among the 97 participants, where > 90% agreed on its ease and convenience. Nine (9.3%) tested positive for hr-HPV, out of which eight were non-16/18 HPV genotypes. CONCLUSION: Our findings suggest that promoting awareness on cervical cancer, clarifying any misconceptions of Pap test results, and highlighting that the disease is preventable and that early detection through screening can facilitate successful treatment would help increase screening uptake among Bruneian non-attendees. Response to HPV self-sampling was highly positive, suggesting the possibility of implementing this strategy in the local setting. Our high detection of non-16/18 HPV genotypes suggest high prevalence of other hr-HPV genotypes in Brunei. Larger studies should be conducted to further validate our findings.

Prevalence and associated factors of diabetes mellitus among tuberculosis patients in Brunei Darussalam: A 6-year retrospective cohort study.

OBJECTIVES: To determine the prevalence and associated factors of diabetes mellitus (DM) among tuberculosis (TB) cases in Brunei Darussalam. METHODS: We conducted a retrospective cohort study among all TB patients registered between 2013 and 2018. Collected data include sociodemographics, comorbidities, and information related to their TB diagnosis and treatment outcomes. Associated factors of having DM among TB patients were investigated using logistic regression analyses. RESULTS: We identified a total of 1362 TB patients, among which 462 (33.9% [95%CI: 31.4%,36.5%]) also have DM. 70.6% (n = 326) were diagnosed with DM at least six months prior to their TB diagnosis. The incidence of newly diagnosed DM among TB patients was 74.2 per 1000 population. Significant factors of having TB and DM comorbidity were age (adjusted OR (adj. OR) = 1.04 [95%CI: 10.3,1.05]), classified as smear-positive pulmonary TB (adj. OR = 5.77 [95%CI: 3.71,9.22]), having the following underlying conditions: hypertension/heart disease (adj. OR = 24.05 [95%CI: 5.80,100.05]), renal disease (adj. OR = 7.34 [95%CI: 2.88,20.22]) and chronic obstructive pulmonary disease/asthma (adj. OR = 0.38 [95%CI: 0.22,0.64]). CONCLUSION: About one-third of TB cases in Brunei were also diagnosed with DM. Bi-directional screening could be a good strategy to facilitate early detection and treatment of both diseases.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Setting-specific Transmission Rates: A Systematic Review and Meta-analysis.

BACKGROUND: Understanding the drivers of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission is crucial for control policies, but evidence of transmission rates in different settings remains limited. METHODS: We conducted a systematic review to estimate secondary attack rates (SARs) and observed reproduction numbers (Robs) in different settings exploring differences by age, symptom status, and duration of exposure. To account for additional study heterogeneity, we employed a beta-binomial model to pool SARs across studies and a negative-binomial model to estimate Robs. RESULTS: Households showed the highest transmission rates, with a pooled SAR of 21.1% (95% confidence interval [CI]:17.4-24.8). SARs were significantly higher where the duration of household exposure exceeded 5 days compared with exposure of ≤5 days. SARs related to contacts at social events with family and friends were higher than those for low-risk casual contacts (5.9% vs 1.2%). Estimates of SARs and Robs for asymptomatic index cases were approximately one-seventh, and for presymptomatic two-thirds of those for symptomatic index cases. We found some evidence for reduced transmission potential both from and to individuals younger than 20 years of age in the household context, which is more limited when examining all settings. CONCLUSIONS: Our results suggest that exposure in settings with familiar contacts increases SARS-CoV-2 transmission potential. Additionally, the differences observed in transmissibility by index case symptom status and duration of exposure have important implications for control strategies, such as contact tracing, testing, and rapid isolation of cases. There were limited data to explore transmission patterns in workplaces, schools, and care homes, highlighting the need for further research in such settings.

Analysis of SARS-CoV-2 Transmission in Different Settings, Brunei.

We report the transmission dynamics of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) across different settings in Brunei. An initial cluster of SARS-CoV-2 cases arose from 19 persons who had attended the Tablighi Jama'at gathering in Malaysia, resulting in 52 locally transmitted cases. The highest nonprimary attack rates (14.8%) were observed from a subsequent religious gathering in Brunei and in households of attendees (10.6%). Household attack rates from symptomatic case-patients were higher (14.4%) than from asymptomatic (4.4%) or presymptomatic (6.1%) case-patients. Workplace and social settings had attack rates of <1%. Our analyses highlight that transmission of SARS-CoV-2 varies depending on environmental, behavioral, and host factors. We identify red flags for potential superspreading events, specifically densely populated gatherings with prolonged exposure in enclosed settings, persons with recent travel history to areas with active SARS-CoV-2 infections, and group behaviors. We propose differentiated testing strategies to account for differing transmission risk.

What do we know about SARS-CoV-2 transmission? A systematic review and meta-analysis of the secondary attack rate and associated risk factors.

INTRODUCTION: Current SARS-CoV-2 containment measures rely on controlling viral transmission. Effective prioritization can be determined by understanding SARS-CoV-2 transmission dynamics. We conducted a systematic review and meta-analyses of the secondary attack rate (SAR) in household and healthcare settings. We also examined whether household transmission differed by symptom status of index case, adult and children, and relationship to index case. METHODS: We searched PubMed, medRxiv, and bioRxiv databases between January 1 and July 25, 2020. High-quality studies presenting original data for calculating point estimates and 95% confidence intervals (CI) were included. Random effects models were constructed to pool SAR in household and healthcare settings. Publication bias was assessed by funnel plots and Egger's meta-regression test. RESULTS: 43 studies met the inclusion criteria for household SAR, 18 for healthcare SAR, and 17 for other settings. The pooled household SAR was 18.1% (95% CI: 15.7%, 20.6%), with significant heterogeneity across studies ranging from 3.9% to 54.9%. SAR of symptomatic index cases was higher than asymptomatic cases (RR: 3.23; 95% CI: 1.46, 7.14). Adults showed higher susceptibility to infection than children (RR: 1.71; 95% CI: 1.35, 2.17). Spouses of index cases were more likely to be infected compared to other household contacts (RR: 2.39; 95% CI: 1.79, 3.19). In healthcare settings, SAR was estimated at 0.7% (95% CI: 0.4%, 1.0%). DISCUSSION: While aggressive contact tracing strategies may be appropriate early in an outbreak, as it progresses, measures should transition to account for setting-specific transmission risk. Quarantine may need to cover entire communities while tracing shifts to identifying transmission hotspots and vulnerable populations. Where possible, confirmed cases should be isolated away from the household.

Epidemiological Investigation of the First 135 COVID-19 Cases in Brunei: Implications for Surveillance, Control, and Travel Restrictions.

Studies on the early introduction of SARS-CoV-2 in a naive population have important epidemic control implications. We report findings from the epidemiological investigation of the initial 135 COVID-19 cases in Brunei and describe the impact of control measures and travel restrictions. Epidemiological and clinical information was obtained for all confirmed COVID-19 cases, whose symptom onset was from March 9 to April 5, 2020. The basic reproduction number (R0), incubation period, and serial interval (SI) were calculated. Time-varying R was estimated to assess the effectiveness of control measures. Of the 135 cases detected, 53 (39.3%) were imported. The median age was 36 (range = 0.5-72) years. Forty-one (30.4%) and 13 (9.6%) were presymptomatic and asymptomatic cases, respectively. The median incubation period was 5 days (interquartile range [IQR] = 5, range = 1-11), and the mean SI was 5.4 days (SD = 4.5; 95% CI: 4.3, 6.5). The reproduction number was between 3.9 and 6.0, and the doubling time was 1.3 days. The time-varying reproduction number (Rt) was below one (Rt = 0.91; 95% credible interval: 0.62, 1.32) by the 13th day of the epidemic. Epidemic control was achieved through a combination of public health measures, with emphasis on a test-isolate-trace approach supplemented by travel restrictions and moderate physical distancing measures but no actual lockdown. Regular and ongoing testing of high-risk groups to supplement the existing surveillance program and a phased easing of physical distancing measures has helped maintain suppression of the COVID-19 outbreak in Brunei, as evidenced by the identification of only six additional cases from April 5 to August 5, 2020.

Global trends and gaps in research related to latent tuberculosis infection.

BACKGROUND: There is a global commitment to eliminating tuberculosis (TB). It is critical to detect and treat cases of latent TB infection (LTBI), the reservoir of new TB cases. Our study assesses trends in publication of LTBI-related research. METHODS: We used the keywords ("latent tuberculosis" OR "LTBI" OR "latent TB") to search the Web of Science for LTBI-related articles published 1995-2018, then classified the results into three research areas: laboratory sciences, clinical research, and public health. We calculated the proportions of LTBI-related articles in each area to three areas combined, the average rates of LTBI-related to all scientific and TB-related articles, and the average annual percent changes (AAPC) in rates for all countries and for the top 13 countries individually and combined publishing LTBI research. RESULTS: The proportion of LTBI-related articles increased over time in all research areas, with the highest AAPC in laboratory (38.2%/yr), followed by public health (22.9%/yr) and clinical (15.1%/yr). South Africa (rate ratio [RR] = 8.28, 95% CI 5.68 to 12.08) and India (RR = 2.53, 95% CI 1.74 to 3.69) had higher RRs of overall TB-related articles to all articles, but did not outperform the average of the top 13 countries in the RRs of LTBI-related articles to TB-related articles. Italy (RR = 1.95, 95% CI 1.45 to 2.63), Canada (RR = 1.73, 95% CI 1.28 to 2.34), and Spain (RR = 1.53, 95% CI 1.13 to 2.07) had higher RRs of LTBI-related articles to TB-related articles. CONCLUSIONS: High TB burden countries (TB incidence > 100 per 100,000 population) published more overall TB-related research, whereas low TB burden countries showed greater focus on LTBI. Given the potential benefits, high TB burden countries should consider increasing their emphasis on LTBI-related research.

Seasonality of Influenza and Respiratory Syncytial Viruses and the Effect of Climate Factors in Subtropical-Tropical Asia Using Influenza-Like Illness Surveillance Data, 2010 -2012.

INTRODUCTION: The seasonality of influenza and respiratory syncytial virus (RSV) is well known, and many analyses have been conducted in temperate countries; however, this is still not well understood in tropical countries. Previous studies suggest that climate factors are involved in the seasonality of these viruses. However, the extent of the effect of each climate variable is yet to be defined. MATERIALS AND METHODS: We investigated the pattern of seasonality and the effect of climate variables on influenza and RSV at three sites of different latitudes: the Eastern Visayas region and Baguio City in the Philippines, and Okinawa Prefecture in Japan. Wavelet analysis and the dynamic linear regression model were applied. Climate variables used in the analysis included mean temperature, relative and specific humidity, precipitation, and number of rainy days. The Akaike Information Criterion estimated in each model was used to test the improvement of fit in comparison with the baseline model. RESULTS: At all three study sites, annual seasonal peaks were observed in influenza A and RSV; peaks were unclear for influenza B. Ranges of climate variables at the two Philippine sites were narrower and mean variables were significantly different among the three sites. Whereas all climate variables except the number of rainy days improved model fit to the local trend model, their contributions were modest. Mean temperature and specific humidity were positively associated with influenza and RSV at the Philippine sites and negatively associated with influenza A in Okinawa. Precipitation also improved model fit for influenza and RSV at both Philippine sites, except for the influenza A model in the Eastern Visayas. CONCLUSIONS: Annual seasonal peaks were observed for influenza A and RSV but were less clear for influenza B at all three study sites. Including additional data from subsequent more years would help to ascertain these findings. Annual amplitude and variation in climate variables are more important than their absolute values for determining their effect on the seasonality of influenza and RSV.

Burden of Influenza and Respiratory Syncytial Virus Infection in Pregnant Women and Infants Under 6 Months in Mongolia: A Prospective Cohort Study.

BACKGROUND: Pregnant women and infants under 6 months are at risk of influenza-related complications. Limited information exists on their community burden of respiratory viruses. METHODS AND FINDINGS: This prospective, observational open cohort study was conducted in Baganuur district, Ulaanbaatar, Mongolia during 2013/14 and 2014/15 influenza seasons. Influenza-like illness (ILI) and severe acute respiratory infection (sARI) were identified by follow-up calls twice a week. For those identified, influenza and respiratory syncytical virus (RSV) were tested by point-of-care test kits. We calculated overall and stratified (by trimester or age group) incidence rates (IR) and used Cox proportional hazard regression for risk factor analyses. Among 1260 unvaccinated pregnant women enrolled, overall IRs for ILI, sARI and influenza A were 11.8 (95% confidence interval (C.I):11.2-12.4), 0.1 (95%C.I:0.0-0.4), and 1.7 (95%C.I:1.5-1.9) per 1,000person-days, respectively. One sARI case was influenza A positive. IRs and adjusted hazard ratios (Adj.HR) for ILI and influenza A were lowest in the third trimester. Those with co-morbidity were 1.4 times more likely to develop ILI [Adj.HR:1.4 (95%C.I:1.1-1.9)]. Among 1304 infants enrolled, overall ILI and sARI IRs were 15.2 (95%C.I:14.5-15.8) and 20.5 (95%C.I:19.7-21.3) per 1,000person-days, respectively. From the tested ILI (77.6%) and sARI (30.6%) cases, the overall positivity rates were 6.3% (influenza A), 1.1% (influenza B) and 9.3% (RSV). Positivity rates of influenza A and RSV tend to increase with age. sARI cases were 1.4 times more likely to be male [Adj.HR:1.4 (95%C.I:1.1-1.8)]. Among all influenza A and RSV positive infants, 11.8% and 68.0% were respectively identified among sARI hospitalized cases. CONCLUSION: We observed low overall influenza A burden in both groups, though underestimation was likely due to point-of-care tests used. For infants, RSV burden was more significant than influenza A. These findings would be useful for establishing control strategies for both viruses in Mongolia.