Vernon J Lee

Publications of Vernon J Lee

• Diabetes with hypertension as risk factors for adult dengue hemorrhagic Fever in a predominantly dengue serotype 2 epidemic: a case control study.

  Authors: Junxiong Pang, Agus Salim, Vernon J Lee, Martin L Hibberd, Kee Seng Chia, Yee Sin Leo, David C Lye

  PLoS neglected tropical diseases. 05/2012; 6(5):e1641.

  Dengue hemorrhagic fever (DHF) is a severe form of dengue, characterized by bleeding and plasma leakage. A number of DHF risk factors had been suggested. However, these risk factors may not beDengue hemorrhagic fever (DHF) is a severe form of dengue, characterized by bleeding and plasma leakage. A number of DHF risk factors had been suggested. However, these risk factors may not be generalized to all populations and epidemics for screening and clinical management of patients at risk of developing DHF. This study explored demographic and comorbidity risk factors for DHF in adult dengue epidemics in Singapore in year 2006 (predominantly serotype 1) and in year 2007-2008 (predominantly serotype 2). A retrospective case-control study was conducted with 149 DHF and 326 dengue fever (DF) patients from year 2006, and 669 DHF and 1,141 DF patients from year 2007-2008. Demographic and reported comorbidity data were collected from patients previously. We performed multivariate logistic regression to assess the association between DHF and demographic and co-morbidities for year 2006 and year 2007-2008, respectively. Only Chinese (adjusted odds ratio [AOR] = 1.90; 95% confidence interval [CI]: 1.01-3.56) was independently associated with DHF in year 2006. In contrast, age groups of 30-39 years (AOR = 1.41; 95% CI:1.09-1.81), 40-49 years (AOR = 1.34; 95% CI:1.09-1.81), female (AOR = 1.57; 95% CI:1.28-1.94), Chinese (AOR = 1.67; 95% CI:1.24-2.24), diabetes (AOR = 1.78; 95% CI:1.06-2.97), and diabetes with hypertension (AOR = 2.16; 95%CI:1.18-3.96) were independently associated with DHF in year 2007-2008. Hypertension was proposed to have effect modification on the risk of DHF outcome in dengue patients with diabetes. Chinese who had diabetes with hypertension had 2.1 (95% CI:1.07-4.12) times higher risk of DHF compared with Chinese who had no diabetes and no hypertension. Adult dengue patients in Singapore who were 30-49 years, Chinese, female, had diabetes or diabetes with hypertension were at greater risk of developing DHF during epidemic of predominantly serotype 2. These risk factors can be used to guide triaging of patients who require closer clinical monitoring and early hospitalization in Singapore, when confirmed in more studies.

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

  Authors: Jonathan Yap, Chi Hsien Tan, Alex R Cook, Jin Phang Loh, Paul A Tambyah, Boon Huan Tan, Vernon J Lee

  BMC infectious diseases. 01/2012; 12(1):12.

  ABSTRACT: Influenza infections may result in different clinical presentations. This study aims to determine the clinical differences between circulating influenza strains in a young healthy adultABSTRACT: Influenza 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. A 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. There 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. Influenza 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.

• Economic impact of dengue illness and the cost-effectiveness of future vaccination programs in Singapore.

  Authors: Luis R Carrasco, Linda K Lee, Vernon J Lee, Eng Eong Ooi, Donald S Shepard, Tun L Thein, Victor Gan, Alex R Cook, David Lye, Lee Ching Ng, Yee Sin Leo

  PLoS neglected tropical diseases. 12/2011; 5(12):e1426.

  Dengue illness causes 50-100 million infections worldwide and threatens 2.5 billion people in the tropical and subtropical regions. Little is known about the disease burden and economic impact ofDengue illness causes 50-100 million infections worldwide and threatens 2.5 billion people in the tropical and subtropical regions. Little is known about the disease burden and economic impact of dengue in higher resourced countries or the cost-effectiveness of potential dengue vaccines in such settings. We estimate the direct and indirect costs of dengue from hospitalized and ambulatory cases in Singapore. We consider inter alia the impacts of dengue on the economy using the human-capital and the friction cost methods. Disease burden was estimated using disability-adjusted life years (DALYs) and the cost-effectiveness of a potential vaccine program was evaluated. The average economic impact of dengue illness in Singapore from 2000 to 2009 in constant 2010 US$ ranged between $0.85 billion and $1.15 billion, of which control costs constitute 42%-59%. Using empirically derived disability weights, we estimated an annual average disease burden of 9-14 DALYs per 100 000 habitants, making it comparable to diseases such as hepatitis B or syphilis. The proportion of symptomatic dengue cases detected by the national surveillance system was estimated to be low, and to decrease with age. Under population projections by the United Nations, the price per dose threshold for which vaccines stop being more cost-effective than the current vector control program ranged from $50 for mass vaccination requiring 3 doses and only conferring 10 years of immunity to $300 for vaccination requiring 2 doses and conferring lifetime immunity. The thresholds for these vaccine programs to not be cost-effective for Singapore were $100 and $500 per dose respectively. Dengue illness presents a serious economic and disease burden in Singapore. Dengue vaccines are expected to be cost-effective if reasonably low prices are adopted and will help to reduce the economic and disease burden of dengue in Singapore substantially.

• Validation of probability equation and decision tree in predicting subsequent dengue hemorrhagic fever in adult dengue inpatients in Singapore.

  Authors: Tun L Thein, Yee-Sin Leo, Vernon J Lee, Yan Sun, David C Lye

  The American journal of tropical medicine and hygiene. 11/2011; 85(5):942-5.

  We developed a probability equation and a decision tree from 1,973 predominantly dengue serotype 1 hospitalized adult dengue patients in 2004 to predict progression to dengue hemorrhagic fever (DHF),We developed a probability equation and a decision tree from 1,973 predominantly dengue serotype 1 hospitalized adult dengue patients in 2004 to predict progression to dengue hemorrhagic fever (DHF), applied in our clinic since March 2007. The parameters predicting DHF were clinical bleeding, high serum urea, low serum protein, and low lymphocyte proportion. This study validated these in a predominantly dengue serotype 2 cohort in 2007. The 1,017 adult dengue patients admitted to Tan Tock Seng Hospital, Singapore had a median age of 35 years. Of 933 patients without DHF on admission, 131 progressed to DHF. The probability equation predicted DHF with a sensitivity (Sn) of 94%, specificity (Sp) 17%, positive predictive value (PPV) 16%, and negative predictive value (NPV) 94%. The decision tree predicted DHF with a Sn of 99%, Sp 12%, PPV 16%, and NPV 99%. Both tools performed well despite a switch in predominant dengue serotypes.

• Comparability of different methods for estimating influenza infection rates over a single epidemic wave.

  Authors: Vernon J Lee, Mark I Chen, Jonathan Yap, Jocelyn Ong, Wei-Yen Lim, Raymond T P Lin, Ian Barr, Jimmy B S Ong, Tze Minn Mak, Lee Gan Goh, Yee Sin Leo, Paul M Kelly, Alex R Cook

  American journal of epidemiology. 06/2011; 174(4):468-78.

  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 fromEstimation 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.

• Cost-effectiveness of different human papillomavirus vaccines in Singapore.

  Authors: Vernon J Lee, Sun Kuie Tay, Yee Leong Teoh, Mei Yin Tok

  BMC public health. 03/2011; 11:203.

  Human papillomavirus (HPV) vaccines are widely available and there have been studies exploring their potential clinical impact and cost-effectiveness. However, few studies have compared theHuman papillomavirus (HPV) vaccines are widely available and there have been studies exploring their potential clinical impact and cost-effectiveness. However, few studies have compared the cost-effectiveness among the 2 main vaccines available - a bivalent vaccine against HPV 16/18, and a quadrivalent vaccine against 6/11/16/18. We explore the cost-effectiveness of these two HPV vaccines in tropical Singapore. We developed a Markov state-transition model to represent the natural history of cervical cancer to predict HPV infection, cancer incidence, mortality, and costs. Cytologic screening and treatment of different outcomes of HPV infection were incorporated. Vaccination was provided to a cohort of 12-year old females in Singapore, followed up until death. Based on available vaccines on the market, the bivalent vaccine had increased effectiveness against a wider range of HPV types, while the quadrivalent vaccine had effectiveness against genital warts. Incremental cost-effectiveness ratios (ICER) compared vaccination to no-vaccination, and between the two vaccines. Sensitivity analyses explored differences in vaccine effectiveness and uptake, and other key input parameters. For the no vaccination scenario, 229 cervical cancer cases occurred over the cohort's lifetime. The total discounted cost per individual due to HPV infection was SGD$275 with 28.54 discounted life-years. With 100% vaccine coverage, the quadrivalent vaccine reduced cancers by 176, and had an ICER of SGD$12,866 per life-year saved. For the bivalent vaccine, 197 cancers were prevented with an ICER of $12,827 per life-year saved. Comparing the bivalent to the quadrivalent vaccine, the ICER was $12,488 per life-year saved. However, the cost per QALY saved for the quadrivalent vaccine compared to no vaccine was $9,071, while it was $10,392 for the bivalent vaccine, with the quadrivalent vaccine dominating the bivalent vaccine due to the additional QALY effect from reduction in genital warts. The overall outcomes were most sensitive to vaccine cost and coverage. HPV vaccination is a cost-effective strategy, and should be considered a possible strategy to reduce the impact of HPV infection.

• Investigation of causes of oseltamivir chemoprophylaxis failures during influenza A (H1N1-2009) outbreaks.

  Authors: Vernon J Lee, Jonathan Yap, Sebastian Maurer-Stroh, Raphael T C Lee, Frank Eisenhaber, Joshua K Tay, Pei Jun Ting, Jin Phang Loh, Christopher W Wong, Boon Huan Tan, Evelyn S C Koay, Paul M Kelly, Martin L Hibberd

  Journal of clinical virology : the official publication of the Pan American Society for Clinical Virology. 02/2011; 50(2):104-8.

  Antiviral post-exposure prophylaxis with oseltamivir has been used as a strategy in mitigating the Influenza A (H1N1-2009) pandemic. There have been few reports of well-documented prophylaxisAntiviral post-exposure prophylaxis with oseltamivir has been used as a strategy in mitigating the Influenza A (H1N1-2009) pandemic. There have been few reports of well-documented prophylaxis failures and the reasons for failure. We report herein a series of 10 cases of prophylaxis failures and explore the reasons behind their prophylaxis failure. In the early pandemic phase, the military employed oseltamivir post-exposure ring-prophylaxis of affected units. From June 22 to July 30, 2009, cases of laboratory-confirmed prophylaxis failures were identified. Nasopharyngeal swabs were collected and tested by PCR. Samples with sufficient RNA material were sent for whole genome sequencing, and screened for mutations that confer oseltamivir resistance, especially the H275Y mutation. Ten cases of laboratory-confirmed prophylaxis failure were identified, with a mean age of 22.3 years. One case was asymptomatic; the remaining 9 had fever or cough but without severe complications. The mean duration of exposure before starting oseltamivir was 1.9 days (SD 0.9), while the mean duration of oseltamivir consumption before symptom onset was 1.9 days (SD 1.4). None of the samples had the H275Y mutation or other known mutations that confer resistance. From the whole genome sequencing, several mutations at the HA (T220S, E275V, T333A, D239G); PB2 (K660R, L607V, V292I); NS1 (F103S), and NP (W104G) gene segments were detected, but none of them were likely to result in anti-viral resistance. Primary prophylaxis failures exhibited mild symptoms without complications; all did not have the H275Y mutation and were unlikely to result from other mutations.

• Strategies for antiviral stockpiling for future influenza pandemics: a global epidemic-economic perspective.

  Authors: Luis R Carrasco, Vernon J Lee, Mark I Chen, David B Matchar, James P Thompson, Alex R Cook

  Journal of the Royal Society, Interface / the Royal Society. 02/2011; 8(62):1307-13.

  Influenza pandemics present a global threat owing to their potential mortality and substantial economic impacts. Stockpiling antiviral drugs to manage a pandemic is an effective strategy to offsetInfluenza pandemics present a global threat owing to their potential mortality and substantial economic impacts. Stockpiling antiviral drugs to manage a pandemic is an effective strategy to offset their negative impacts; however, little is known about the long-term optimal size of the stockpile under uncertainty and the characteristics of different countries. Using an epidemic-economic model we studied the effect on total mortality and costs of antiviral stockpile sizes for Brazil, China, Guatemala, India, Indonesia, New Zealand, Singapore, the UK, the USA and Zimbabwe. In the model, antivirals stockpiling considerably reduced mortality. There was greater potential avoidance of expected costs in the higher resourced countries (e.g. from $55 billion to $27 billion over a 30 year time horizon for the USA) and large avoidance of fatalities in those less resourced (e.g. from 11.4 to 2.3 million in Indonesia). Under perfect allocation, higher resourced countries should aim to store antiviral stockpiles able to cover at least 15 per cent of their population, rising to 25 per cent with 30 per cent misallocation, to minimize fatalities and economic costs. Stockpiling is estimated not to be cost-effective for two-thirds of the world's population under current antivirals pricing. Lower prices and international cooperation are necessary to make the life-saving potential of antivirals cost-effective in resource-limited countries.

• Effectiveness of pandemic H1N1-2009 vaccination in reducing laboratory confirmed influenza infections among military recruits in tropical Singapore.

  Authors: Vernon J Lee, Chi Hsien Tan, Jonathan Yap, Alex R Cook, Pei-Jun Ting, Jin-Phang Loh, Qiuhan Gao, Mark I Chen, Wee Lee Kang, Boon Huan Tan, Paul A Tambyah

  PloS one. 01/2011; 6(10):e26572.

  Limited information is available about pandemic H1N1-2009 influenza vaccine effectiveness in tropical communities. We studied the effectiveness of a pandemic H1N1 vaccination program in reducingLimited information is available about pandemic H1N1-2009 influenza vaccine effectiveness in tropical communities. We studied the effectiveness of a pandemic H1N1 vaccination program in reducing influenza cases in Singapore. A surveillance study was conducted among military personnel presenting with febrile respiratory illness from mid-2009 to mid-2010. Consenting individuals underwent nasal washes, which were tested with RT-PCR and subtyped. A vaccination program (inactivated monovalent Panvax H1N1-2009 vaccine) was carried out among recruits. A Bayesian hierarchical model was used to quantify relative risks in the pre- and post-vaccination periods. An autoregressive generalised linear model (GLM) was developed to minimise confounding. Of 2858 participants, 437 (15.3%), 60 (2.1%), and 273 (9.6%) had pandemic H1N1, H3N2, and influenza B. The ratio of relative risks for pandemic H1N1 infection before and after vaccination for the recruit camp relative to other camps was 0.14 (0.016,0.49); for H3N2, 0.44 (0.035,1.8); and for influenza B, 18 (0.77,89). Using the GLM for the recruit camp, post-vaccination weekly cases decreased by 54% (37%,67%, p<0.001) from that expected without vaccination; influenza B increased by 66 times (9-479 times, p<0.001); with no statistical difference for H3N2 (p = 0.54). Pandemic vaccination reduced H1N1-2009 disease burden among military recruits. Routine seasonal influenza vaccination should be considered.

• Confirmed adult dengue deaths in Singapore: 5-year multi-center retrospective study.

  Authors: Yee-Sin Leo, Tun L Thein, Dale A Fisher, Jenny G Low, Helen M Oh, Rajmohan L Narayanan, Victor C Gan, Vernon J Lee, David C Lye

  BMC infectious diseases. 01/2011; 11:123.

  Dengue re-emerges in Singapore despite decades of effective vector control; the infection predominantly afflicts adults. Severe dengue not fulfilling dengue hemorrhagic fever (DHF) criteria accordingDengue re-emerges in Singapore despite decades of effective vector control; the infection predominantly afflicts adults. Severe dengue not fulfilling dengue hemorrhagic fever (DHF) criteria according to World Health Organization (WHO) 1997 guideline was increasingly reported. A new WHO 2009 guideline emphasized warning signs and a wider range of severe dengue manifestations. We aim to evaluate the utility of these two guidelines in confirmed adult dengue fatalities. We conducted a multi-center retrospective chart review of all confirmed adult dengue deaths in Singapore from 1 January 2004 to 31 December 2008. Of 28 adult dengue deaths, median age was 59 years. Male gender comprised 67.9% and co-morbidities existed in 75%. From illness onset, patients presented for admission at a median of 4 days and death occurred at a median of 12 days. Intensive care admission was required in 71.4%. Probable dengue was diagnosed in 32.1% by WHO 1997 criteria and 78.6% by WHO 2009. The earliest warning sign was persistent vomiting at a median of 1.5 days. Hematocrit change ≥20% concurrent with platelet count <20 × 10^9/L was associated with the shortest interval to death at a median of 3 days. Only 35.7% of death cases fulfilled DHF criteria by WHO 1997 versus severe dengue in 100.0% by WHO 2009 criteria. Deaths were due to shock and organ failure. Acute renal impairment occurred in 71.4%, impaired consciousness 57.1% and severe hepatitis 53.6%. In our adult fatal dengue cohort, WHO 2009 criteria had higher sensitivity in diagnosing probable dengue and severe dengue compared with WHO 1997. As warning signs, persistent vomiting occurred early and hematocrit change ≥20% concurrent with platelet count <20 × 10^9/L preceded death most closely.

• Early outbreak of 2009 influenza A (H1N1) in Mexico prior to identification of pH1N1 virus.

  Authors: Ying-Hen Hsieh, Stefan Ma, Jorge X Velasco Hernandez, Vernon J Lee, Wei Yen Lim

  PloS one. 01/2011; 6(8):e23853.

  BACKGROUND: In the aftermath of the global spread of 2009 influenza A (pH1N1) virus, still very little is known of the early stages of the outbreak in Mexico during the early months of the year,BACKGROUND: In the aftermath of the global spread of 2009 influenza A (pH1N1) virus, still very little is known of the early stages of the outbreak in Mexico during the early months of the year, before the virus was identified. METHODOLOGY/MAIN FINDINGS: We fit a simple mathematical model, the Richards model, to the number of excess laboratory-confirmed influenza cases in Mexico and Mexico City during the first 15 weeks in 2009 over the average influenza case number of the previous five baseline years of 2004-2008 during the same period to ascertain the turning point (or the peak incidence) of a wave of early influenza infections, and to estimate the transmissibility of the virus during these early months in terms of its basic reproduction number. The results indicate that there may have been an early epidemic in Mexico City as well as in all of Mexico during February/March. Based on excess influenza cases, the estimated basic reproduction number R₀ for the early outbreak was 1.59 (0.55 to 2.62) for Mexico City during weeks 5-9, and 1.25 (0.76, 1.74) for all of Mexico during weeks 5-14. CONCLUSIONS: We established the existence of an early epidemic in Mexico City and in all of Mexico during February/March utilizing the routine influenza surveillance data, although the location of seeding is unknown. Moreover, estimates of R₀ as well as the time of peak incidence (the turning point) for Mexico City and all of Mexico indicate that the early epidemic in Mexico City in February/March had been more transmissible (larger R₀) and peaked earlier than the rest of the country. Our conclusion lends support to the possibility that the virus could have already spread to other continents prior to the identification of the virus and the reporting of lab-confirmed pH1N1 cases in North America in April.

• A clinical diagnostic model for predicting influenza among young adult military personnel with febrile respiratory illness in Singapore.

  Authors: Vernon J Lee, Jonathan Yap, Alex R Cook, Chi Hsien Tan, Jin-Phang Loh, Wee-Hong Koh, Elizabeth A S Lim, Jasper C W Liaw, Janet S W Chew, Iqbal Hossain, Ka Wei Chan, Pei-Jun Ting, Sock-Hoon Ng, Qiuhan Gao, Paul M Kelly, Mark I Chen, Paul A Tambyah, Boon Huan Tan

  PloS one. 01/2011; 6(3):e17468.

  Influenza infections present with wide-ranging clinical features. We aim to compare the differences in presentation between influenza and non-influenza cases among those with febrile respiratoryInfluenza infections present with wide-ranging clinical features. We aim to compare the differences in presentation between influenza and non-influenza cases among those with febrile respiratory illness (FRI) to determine predictors of influenza infection. Personnel with FRI (defined as fever ≥ 37.5 °C, with cough or sore throat) were recruited from the sentinel surveillance system in the Singapore military. Nasal washes were collected, and tested using the Resplex II and additional PCR assays for etiological determination. Interviewer-administered questionnaires collected information on patient demographics and clinical features. Univariate comparison of the various parameters was conducted, with statistically significant parameters entered into a multivariate logistic regression model. The final multivariate model for influenza versus non-influenza cases was used to build a predictive probability clinical diagnostic model. 821 out of 2858 subjects recruited from 11 May 2009 to 25 Jun 2010 had influenza, of which 434 (52.9%) had 2009 influenza A (H1N1), 58 (7.1%) seasonal influenza A (H3N2) and 269 (32.8%) influenza B. Influenza-positive cases were significantly more likely to present with running nose, chills and rigors, ocular symptoms and higher temperature, and less likely with sore throat, photophobia, injected pharynx, and nausea/vomiting. Our clinical diagnostic model had a sensitivity of 65% (95% CI: 58%, 72%), specificity of 69% (95% CI: 62%, 75%), and overall accuracy of 68% (95% CI: 64%, 71%), performing significantly better than conventional influenza-like illness (ILI) criteria. Use of a clinical diagnostic model may help predict influenza better than the conventional ILI definition among young adults with FRI.

• Effectiveness of public health measures in mitigating pandemic influenza spread: a prospective sero-epidemiological cohort study.

  Authors: Vernon J Lee, Jonathan Yap, Alex R Cook, Mark I Chen, Joshua K Tay, Ian Barr, Anne Kelso, Boon Huan Tan, Jin Phang Loh, Raymond Lin, Lin Cui, Paul M Kelly, Yee Sin Leo, Kee Seng Chia, Wee Lee Kang, Paul A Tambyah, Benjamin Seet

  The Journal of infectious diseases. 11/2010; 202(9):1319-26.

  Few studies have validated the effectiveness of public health interventions in reducing influenza spread in real‐life settings. We aim to validate these measures used during the 2009 pandemic. FromFew studies have validated the effectiveness of public health interventions in reducing influenza spread in real‐life settings. We aim to validate these measures used during the 2009 pandemic. From 22 June to 9 October 2009, we performed a prospective observational cohort study using paired serum samples and symptom review among 3 groups of Singapore military personnel. "Normal" units were subjected to prevailing pandemic response policies. "Essential" units and health care workers had additional public health interventions (eg, enhanced surveillance with isolation, segregation, personal protective equipment). Samples were tested by hemagglutination inhibition; the principal outcome was seroconversion to 2009 influenza A(H1N1). In total, 1015 individuals in 14 units completed the study, with 29% overall seroconversion. Seroconversion among essential units (17%) and health care workers (11%) was significantly lower than that in normal units (44%) (P = .001). Symptomatic illness attributable to influenza was also lower in essential units (5%) and health care workers (2%) than in normal units (12%) (P = .06). Adjusted for confounders, unit type was the only significant variable influencing overall seroconversion ( P < .05). From multivariate analysis within each unit, age (P < .001) and baseline antibody titer (P = .012 ) were inversely related to seroconversion risk. Public health measures are effective in limiting influenza transmission in closed environments.

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

  Authors: Vernon J Lee, Joshua K Tay, Mark I C Chen, M C Phoon, M L Xie, Y Wu, Cynthia X X Lee, Jonathan Yap, K R Sakharkar, M K Sakharkar, Raymond T Lin, Lin Cui, Paul M Kelly, Yee Sin Leo, Yee Joo Tan, Vincent T K Chow

  Vaccine. 10/2010; 28(42):6852-7.

  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 influenzaIn 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. 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. 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. 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.

• Oseltamivir ring prophylaxis for containment of 2009 H1N1 influenza outbreaks.

  Authors: Vernon J Lee, Jonathan Yap, Alex R Cook, Mark I Chen, Joshua K Tay, Boon Huan Tan, Jin Phang Loh, Seok Wei Chew, Wee Hong Koh, Raymond Lin, Lin Cui, Charlie W H Lee, Wing-Kin Sung, Christopher W Wong, Martin L Hibberd, Wee Lee Kang, Benjamin Seet, Paul A Tambyah

  The New England journal of medicine. 06/2010; 362(23):2166-74.

  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 chemoprophylaxisFrom 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. 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. 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. 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.

• Elimination of malaria risk through integrated combination strategies in a tropical military training island.

  Authors: Vernon J Lee, Samuel Ow, Harold Heah, Meng Yaw Tan, Patrick Lam, Lee-Ching Ng, Sai Gek Lam-Phua, Abdul Qadir Imran, Benjamin Seet

  The American journal of tropical medicine and hygiene. 06/2010; 82(6):1024-9.

  On the military training facility of Tekong Island, Singapore, a comprehensive vector-borne disease control program was started in end-2006 to reduce mosquito populations and negate the need forOn the military training facility of Tekong Island, Singapore, a comprehensive vector-borne disease control program was started in end-2006 to reduce mosquito populations and negate the need for anti-malaria chemoprophylaxis. The program was based on 1) preventing importation of malaria through screening of visitors, 2) preventing human-to-mosquito transmission through early case detection and mosquito control, 3) preventing mosquito-to-human transmission through personal protection, and 4) contingency plans. Systematic environmental works were performed to reduce breeding sites, and insecticide use targeted both adult mosquitoes and larvae. Mosquito populations declined from 103 mosquitoes per sampling site in January 2007 to 6 per site by March 2007 (P < 0.001). The proportion of positive ovitraps declined from 93% in January 2007-2% in March 2007 (P < 0.001). There were no malaria cases on the island despite chemoprophylaxis termination, showing that comprehensive combination vector-control strategies were effective in reducing the risk of malaria.

• Treatment of exertional heat injuries with portable body cooling unit in a mass endurance event.

  Authors: Pang Hee-Nee, Mong Rupeng, Vernon J Lee, Wei-Chong Chua, Benjamin Seet

  The American journal of emergency medicine. 02/2010; 28(2):246-8.

• Serological response in RT-PCR confirmed H1N1-2009 influenza a by hemagglutination inhibition and virus neutralization assays: an observational study.

  Authors: Mark I Chen, Ian G Barr, Gerald C H Koh, Vernon J Lee, Caroline P S Lee, Robert Shaw, Cui Lin, Jonathan Yap, Alex R Cook, Boon Huan Tan, Jin Phang Loh, Timothy Barkham, Vincent T K Chow, Raymond T P Lin, Yee-Sin Leo

  PloS one. 01/2010; 5(8):e12474.

  We describe the serological response following H1N1-2009 influenza A infections confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). The study included patients admitted toWe describe the serological response following H1N1-2009 influenza A infections confirmed by reverse-transcriptase polymerase chain reaction (RT-PCR). 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. Appropriately timed paired serology detects 80-90% RT-PCR confirmed H1N1-2009; Antibodies from infection with H1N1-2009 cross-reacted with seasonal influenza viruses.

• Real-time epidemic monitoring and forecasting of H1N1-2009 using influenza-like illness from general practice and family doctor clinics in Singapore.

  Authors: Jimmy Boon Som Ong, Mark I-Cheng Chen, Alex R Cook, Huey Chyi Lee, Vernon J Lee, Raymond Tzer Pin Lin, Paul Ananth Tambyah, Lee Gan Goh

  PloS one. 01/2010; 5(4):e10036.

  Reporting of influenza-like illness (ILI) from general practice/family doctor (GPFD) clinics is an accurate indicator of real-time epidemic activity and requires little effort to set up, making itReporting of influenza-like illness (ILI) from general practice/family doctor (GPFD) clinics is an accurate indicator of real-time epidemic activity and requires little effort to set up, making it suitable for developing countries currently experiencing the influenza A (H1N1-2009) pandemic or preparing for subsequent epidemic waves. We established a network of GPFDs in Singapore. Participating GPFDs submitted returns via facsimile or e-mail on their work days using a simple, standard data collection format, capturing: gender; year of birth; "ethnicity"; residential status; body temperature (degrees C); and treatment (antiviral or not); for all cases with a clinical diagnosis of an acute respiratory illness (ARI). The operational definition of ILI in this study was an ARI with fever of 37.8 degrees C or more. The data were processed daily by the study co-ordinator and fed into a stochastic model of disease dynamics, which was refitted daily using particle filtering, with data and forecasts uploaded to a website which could be publicly accessed. Twenty-three GPFD clinics agreed to participate. Data collection started on 2009-06-26 and lasted for the duration of the epidemic. The epidemic appeared to have peaked around 2009-08-03 and the ILI rates had returned to baseline levels by the time of writing. This real-time surveillance system is able to show the progress of an epidemic and indicates when the peak is reached. The resulting information can be used to form forecasts, including how soon the epidemic wave will end and when a second wave will appear if at all.

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

  Authors: Vernon J Lee, Jonathan Yap, Joshua K Tay, Ian Barr, Qiuhan Gao, Hanley J Ho, Boon Huan Tan, Paul M Kelly, Paul A Tambyah, Anne Kelso, Mark I Chen

  BMC infectious diseases. 01/2010; 10:164.

  Anti-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 cessationAnti-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. Between 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 pandemic's peak in Singapore. Questionnaires were also administered to collect clinical symptoms. 237 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. Post-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.