Jonathan Yap

2009 Influenza A(H1N1) Seroconversion Rates and Risk Factors Among Distinct Adult Cohorts in Singapore

CONTEXT Singapore experienced a single epidemic wave of 2009 influenza A(H1N1) with epidemic activity starting in late June 2009 and peaking in early August before subsiding within a month. OBJECTIVE To compare the risk and factors associated with H1N1 seroconversion in different adult cohorts. DESIGN, SETTING, AND PARTICIPANTS A study with serial serological samples from 4 distinct cohorts: general population (n = 838), military personnel (n = 1213), staff from an acute care hospital (n = 558), and staff as well as residents from long-term care facilities (n = 300) from June 22, 2009, to October 15, 2009. Hemagglutination inhibition results of serum samples taken before, during, and after the epidemic and data from symptom questionnaires are presented. MAIN OUTCOME MEASURES A 4-fold or greater increase in titer between any of the 3 serological samples was defined as evidence of H1N1 seroconversion. RESULTS Baseline titers of 40 or more were observed in 22 members (2.6%; 95% confidence interval [CI], 1.7%-3.9%) of the community, 114 military personnel (9.4%; 95% CI, 7.9%-11.2%), 37 hospital staff (6.6%; 95% CI, 4.8%-9.0%), and 20 participants from long-term care facilities (6.7%; 95% CI, 4.4%-10.1%). In participants with 1 or more follow-up serum samples, 312 military personnel (29.4%; 95% CI, 26.8%-32.2%) seroconverted compared with 98 community members (13.5%; 95% CI, 11.2%-16.2%), 35 hospital staff (6.5%; 95% CI, 4.7%-8.9%), and only 3 long-term care participants (1.2%; 95% CI, 0.4%-3.5%). Increased frequency of seroconversion was observed for community participants from households in which 1 other member seroconverted (adjusted odds ratio [OR], 3.32; 95% CI, 1.50-7.33), whereas older age was associated with reduced odds of seroconversion (adjusted OR, 0.77 per 10 years; 95% CI, 0.64-0.93). Higher baseline titers were associated with decreased frequency of seroconversion in community (adjusted OR for every doubling of baseline titer, 0.48; 95% CI, 0.27-0.85), military (adjusted OR, 0.71; 95% CI, 0.61-0.81), and hospital staff cohorts (adjusted OR, 0.50; 95% CI, 0.26-0.93). CONCLUSION Following the June-September 2009 wave of 2009 influenza A(H1N1), 13% of the community participants seroconverted, and most of the adult population likely remained susceptible.

Oseltamivir ring prophylaxis for containment of 2009 H1N1 influenza outbreaks.

BACKGROUND From June 22 through June 25, 2009, four outbreaks of infection with the pandemic influenza A (H1N1) virus occurred in Singapore military camps. We report the efficacy of ring chemoprophylaxis (geographically targeted containment by means of prophylaxis) with oseltamivir to control outbreaks of 2009 H1N1 influenza in semiclosed environments. METHODS All personnel with suspected infection were tested and clinically isolated if infection was confirmed. In addition, we administered postexposure ring chemoprophylaxis with oseltamivir and segregated the affected military units to contain the spread of the virus. All personnel were screened three times weekly both for virologic infection, by means of nasopharyngeal swabs and reverse-transcriptase-polymerase-chain-reaction assay with sequencing, and for clinical symptoms, by means of questionnaires. RESULTS A total of 1175 personnel were at risk across the four sites, with 1100 receiving oseltamivir prophylaxis. A total of 75 personnel (6.4%) were infected before the intervention, and 7 (0.6%) after the intervention. There was a significant reduction in the overall reproductive number (the number of new cases attributable to the index case), from 1.91 (95% credible interval, 1.50 to 2.36) before the intervention to 0.11 (95% credible interval, 0.05 to 0.20) after the intervention. Three of the four outbreaks showed a significant reduction in the rate of infection after the intervention. Molecular analysis revealed that all four outbreaks were derived from the New York lineage of the 2009 H1N1 virus and that cases within each outbreak were due to transmission rather than unrelated episodes of infection. Of the 816 personnel treated with oseltamivir who were surveyed, 63 (7.7%) reported mild, nonrespiratory side effects of the drug, with no severe adverse events. CONCLUSIONS Oseltamivir ring chemoprophylaxis, together with prompt identification and isolation of infected personnel, was effective in reducing the impact of outbreaks of 2009 H1N1 influenza in semiclosed settings.

Influenza excess mortality from 1950–2000 in tropical Singapore

Introduction Tropical regions have been shown to exhibit different influenza seasonal patterns compared to their temperate counterparts. However, there is little information about the burden of annual tropical influenza epidemics across time, and the relationship between tropical influenza epidemics compared with other regions. Methods Data on monthly national mortality and population was obtained from 1947 to 2003 in Singapore. To determine excess mortality for each month, we used a moving average analysis for each month from 1950 to 2000. From 1972, influenza viral surveillance data was available. Before 1972, information was obtained from serial annual government reports, peer-reviewed journal articles and press articles. Results The influenza pandemics of 1957 and 1968 resulted in substantial mortality. In addition, there were 20 other time points with significant excess mortality. Of the 12 periods with significant excess mortality post-1972, only one point (1988) did not correspond to a recorded influenza activity. For the 8 periods with significant excess mortality periods before 1972 excluding the pandemic years, 2 years (1951 and 1953) had newspaper reports of increased pneumonia deaths. Excess mortality could be observed in almost all periods with recorded influenza outbreaks but did not always exceed the 95% confidence limits of the baseline mortality rate. Conclusion Influenza epidemics were the likely cause of most excess mortality periods in post-war tropical Singapore, although not every epidemic resulted in high mortality. It is therefore important to have good influenza surveillance systems in place to detect influenza activity.

Inactivated trivalent seasonal influenza vaccine induces limited cross-reactive neutralizing antibody responses against 2009 pandemic and 1934 PR8 H1N1 strains

BACKGROUND In June 2009, we conducted a prospective study in Singapore on 51 individuals to determine their serologic responses before and following receipt of the 2009 Southern Hemisphere seasonal influenza vaccine. MATERIALS AND METHODS Paired serum samples were obtained before and 3-4 weeks after vaccination. Virus microneutralization assays were performed to quantify antibodies against A/Brisbane/59/2007 vaccine, pandemic H1N1-2009 and A/Puerto Rico/08/34 H1N1 strains. RESULTS Post-vaccination, 43%, 12% and 24% of subjects displayed a 4-fold or greater rise in neutralizing antibody titers against the three strains, respectively. There was a positive correlation among individuals who showed increased titers to both pandemic H1N1-2009 and A/Puerto Rico/08/34 (p<0.001). However, this correlation was not observed for A/Brisbane/59/2007 with either strain. The relative conservation and accessibility of predicted B-cell epitopes may explain the limited cross-reactivity of the antibodies directed against common H1N1 epitopes. CONCLUSIONS These results suggest that seasonal influenza vaccination confers a certain degree of cross-protection to other H1N1 strains. The correlation in cross-reactive antibody titers to A/Puerto Rico/08/34 and pandemic H1N1-2009 implies that previous exposure to pre-1957 H1N1 strains may confer some protection against the 2009 pandemic strain.

Serological Response in RT-PCR Confirmed H1N1-2009 Influenza A by Hemagglutination Inhibition and Virus Neutralization Assays: An Observational Study

Background We describe the serological response following H1N1-2009 influenza A infections confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). Methodology and Principal Findings The study included patients admitted to hospital, subjects of a seroepidemiologic cohort study, and participants identified from outbreak studies in Singapore. Baseline (first available blood sample) and follow-up blood samples were analyzed for antibody titers to H1N1-2009 and recently circulating seasonal influenza A virus strains by hemagglutination inhibition (HI) and virus micro-neutralization (VM) assays. 267 samples from 118 cases of H1N1-2009 were analyzed. Geometric mean titers by HI peaked at 123 (95% confidence interval, CI 43-356) between days 30 to 39. The chance of observing seroconversion (four-fold or greater increase of antibodies) was maximized when restricting analysis to 45 participants with baseline sera collected within 5 days of onset and follow-up sera collected 15 or more days after onset; for these participants, 82% and 89% seroconverted to A/California/7/2009 H1N1 by HI and VM respectively. A four-fold or greater increase in cross-reactive antibody titers to seasonal A/Brisbane/59/2007 H1N1, A/Brisbane/10/2007 H3N2 and A/Wisconsin/15/2009 H3N2 occurred in 20%, 18% and 16% of participants respectively. Conclusions and Significance Appropriately timed paired serology detects 80–90% RT-PCR confirmed H1N1-2009; Antibodies from infection with H1N1-2009 cross-reacted with seasonal influenza viruses.

Comparability of Different Methods for Estimating Influenza Infection Rates Over a Single Epidemic Wave

Estimation of influenza infection rates is important for determination of the extent of epidemic spread and for calculation of severity indicators. The authors compared estimated infection rates from paired and cross-sectional serologic surveys, rates of influenza like illness (ILI) obtained from sentinel general practitioners (GPs), and ILI samples that tested positive for influenza using data from similar periods collected during the 2009 H1N1 epidemic in Singapore. The authors performed sensitivity analyses to assess the robustness of estimates to input parameter uncertainties, and they determined sample sizes required for differing levels of precision. Estimates from paired seroconversion were 17% (95% Bayesian credible interval (BCI): 14, 20), higher than those from cross-sectional serology (12%, 95% BCI: 9, 17). Adjusted ILI estimates were 15% (95% BCI: 10, 25), and estimates computed from ILI and laboratory data were 12% (95% BCI: 8, 18). Serologic estimates were least sensitive to the risk of input parameter misspecification. ILI-based estimates were more sensitive to parameter misspecification, though this was lessened by incorporation of laboratory data. Obtaining a 5-percentage-point spread for the 95% confidence interval in infection rates would require more than 1,000 participants per serologic study, a sentinel network of 90 GPs, or 50 GPs when combined with laboratory samples. The various types of estimates will provide comparable findings if accurate input parameters can be obtained.

Knowledge, attitudes and practices towards pandemic influenza among cases, close contacts, and healthcare workers in tropical Singapore: a cross-sectional survey

BackgroundEffective influenza pandemic management requires understanding of the factors influencing behavioral changes. We aim to determine the differences in knowledge, attitudes and practices in various different cohorts and explore the pertinent factors that influenced behavior in tropical Singapore.MethodsWe performed a cross-sectional knowledge, attitudes and practices survey in the Singapore military from mid-August to early-October 2009, among 3054 personnel in four exposure groups - laboratory-confirmed H1N1-2009 cases, close contacts of cases, healthcare workers, and general personnel.Results1063 (34.8%) participants responded. The mean age was 21.4 (SE 0.2) years old. Close contacts had the highest knowledge score (71.7%, p = 0.004) while cases had the highest practice scores (58.8%, p < 0.001). There was a strong correlation between knowledge and practice scores (r = 0.27, p < 0.01) and knowledge and attitudes scores (r = 0.21, p < 0.01). The significant predictors of higher practice scores were higher knowledge scores (p < 0.001), Malay ethnicity (p < 0.001), exposure group (p < 0.05) and lower education level (p < 0.05). The significant predictors for higher attitudes scores were Malay ethnicity (p = 0.014) and higher knowledge scores (p < 0.001). The significant predictor for higher knowledge score was being a contact (p = 0.007).ConclusionKnowledge is a significant influence on attitudes and practices in a pandemic, and personal experience influences practice behaviors. Efforts should be targeted at educating the general population to improve practices in the current pandemic, as well as for future epidemics.

Seroconversion and asymptomatic infections during oseltamivir prophylaxis against Influenza A H1N1 2009.

BackgroundAnti-viral prophylaxis is used to prevent the transmission of influenza. We studied serological confirmation of 2009 Influenza A (H1N1) infections during oseltamivir prophylaxis and after cessation of prophylaxis.MethodsBetween 22 Jun and 16 Jul 09, we performed a cohort study in 3 outbreaks in the Singapore military where post-exposure oseltamivir ring chemoprophylaxis (75 mg daily for 10 days) was administered. The entire cohort was screened by RT-PCR (with HA gene primers) using nasopharyngeal swabs three times a week. Three blood samples were taken for haemagglutination inhibition testing - at the start of outbreak, 2 weeks after completion of 10 day oseltamivir prophylaxis, and 3 weeks after the pandemics peak in Singapore. Questionnaires were also administered to collect clinical symptoms.Results237 personnel were included for analysis. The overall infection rate of 2009 Influenza A (H1N1) during the three outbreaks was 11.4% (27/237). This included 11 index cases and 16 personnel (7.1%) who developed four-fold or higher rise in antibody titres during oseltamivir prophylaxis. Of these 16 personnel, 8 (3.5%) were symptomatic while the remaining 8 personnel (3.5%) were asymptomatic and tested negative on PCR. Post-cessation of prophylaxis, an additional 23 (12.1%) seroconverted. There was no significant difference in mean fold-rise in GMT between those who seroconverted during and post-prophylaxis (11.3 vs 11.7, p = 0.888). No allergic, neuropsychiatric or other severe side-effects were noted.ConclusionsPost-exposure oseltamivir prophylaxis reduced the rate of infection during outbreaks, and did not substantially increase subsequent infection rates upon cessation. Asymptomatic infections occur during prophylaxis, which may confer protection against future infection. Post-exposure prophylaxis is effective as a measure in mitigating pandemic influenza outbreaks.

Percutaneous mitral valve repair with the MitraClip: early results from the MitraClip Asia-Pacific Registry (MARS).

AIMS Percutaneous MitraClip therapy has been shown to be safe and efficacious in mitral regurgitation (MR). Our aim was to describe early outcomes in patients from the Asia- Pacific region. METHODS AND RESULTS The MitraClip Asia-Pacific Registry (MARS) includes data from eight different centres in five countries in the Asia-Pacific region. The primary efficacy outcome was reduction in MR to ≤2+ at 30 days. The safety outcome was 30-day freedom from major adverse events (MAE), defined as the composite of death, myocardial infarction, non-elective cardiac surgery, renal failure, transfusion of ≥2 units of blood, ventilation for >48 hours, septicaemia, and new onset atrial fibrillation. A total of 142 patients underwent the MitraClip procedure from February 2011 to October 2013. Fifty-three point five percent (76) of patients had functional MR, 45.8% (65) had degenerative MR and 0.7% (1) had mixed MR. The acute procedural success rate was 93.7% (133). Thirty-one point seven percent of the patients were in NYHA Class I-II at baseline, compared to 82.1% at 30 days (p<0.001). Zero percent (0) of the patients had ≤2+ MR at baseline compared to 76.8% (109) at 30 days (p<0.001). CONCLUSIONS Results from the Asia-Pacific region show that the MitraClip procedure is effective in reducing mitral regurgitation and has favourable short-term safety outcomes.

Differing clinical characteristics between influenza strains among young healthy adults in the tropics.

BackgroundInfluenza infections may result in different clinical presentations. This study aims to determine the clinical differences between circulating influenza strains in a young healthy adult population in the tropics.MethodsA febrile respiratory illness (FRI) (fever ≥ 37.5°C with cough and/or sore throat) surveillance program was started in 4 large military camps in Singapore on May 2009. Personnel with FRI who visited the camp clinics from 11 May 2009 to 25 June 2010 were recruited. Nasal washes and interviewer-administered questionnaires on demographic information and clinical features were obtained from consenting participants. All personnel who tested positive for influenza were included in the study. Overall symptom load was quantified by counting the symptoms or signs, and differences between strains evaluated using linear models.ResultsThere were 434 (52.9%) pandemic H1N1-2009, 58 (7.1%) seasonal H3N2, 269 (32.8%) influenza B, and 10 (1.2%) seasonal H1N1 cases. Few seasonal influenza A (H1N1) infections were detected and were therefore excluded from analyses, together with undetermined influenza subtypes (44 (1.5%)), or more than 1 co-infecting subtype (6 (0.2%)). Pandemic H1N1-2009 cases had significantly fewer symptoms or signs (mean 7.2, 95%CI 6.9-7.4, difference 1.6, 95%CI 1.2-2.0, p < 0.001) than the other two subtypes (mean 8.7, 95%CI 8.5-9.0). There were no statistical differences between H3N2 and influenza B (p = 0.58). Those with nasal congestion, rash, eye symptoms, injected pharynx or fever were more likely to have H3N2; and those with sore throat, fever, injected pharynx or rhinorrhoea were more likely to have influenza B than H1N1-2009.ConclusionsInfluenza cases have different clinical presentations in the young adult population. Pandemic H1N1 influenza cases had fewer and milder clinical symptoms than seasonal influenza. As we only included febrile cases and had no information on the proportion of afebrile infections, further research is needed to confirm whether the relatively milder presentation of pandemic versus seasonal influenza infections applies to all infections or only febrile illnesses.