Assistant Professor Wirichada Pan-ngum

Research Area: Bioinformatics & Stats (inc. Modelling and Computational Biology)
Technology Exchange: Computational biology and Medical statistics
Scientific Themes: Tropical Medicine & Global Health
Keywords: Mathematical modelling, Biostatistics and Epidemiology
Leptospirosis in Thailand

Leptospirosis in Thailand

Field work in the northeast of Thailand

Field work in the northeast of Thailand

Field survey on mixing contact pattern in migrant worker, Thailand

Field survey on mixing contact pattern in migrant worker, Thailand

Wirichada Pan-Ngum’s research mainly involves using a mixed approach including modelling and field surveys to gain better understanding of transmission routes of zoonotic diseases and the Human-Animal-Ecosystems interface. Her current work focuses on leptospirosis, one of many long-term health problems for agricultural workers in Thailand. Her model explores the importance of these environmental factors as well as the risk of disease exposure during traditional rice farming activities in relation to the incidence of human leptospirosis. Her other research interests include dengue, human contact patterns and population dynamics for infectious disease modelling.

In addition to her work at MORU, Wirichada is an Assistant Professor in the Department of Tropical Hygiene, Faculty of Tropical Medicine at Mahidol University. She teaches biostatistics and mathematical modelling. In addition, she serves as a project advisor for postgraduates on the Tropical Medicine and Biomedical and Health Informatics courses.

Name Department Institution Country
Deirdre Hollingsworth University of Warwick United Kingdom
Graham Medley London United Kingdom
Rukmanee N, Yimsamran S, Rukmanee P, Thanyavanich N, Maneeboonyang W, Puangsa-art S, Wuthisen P, Lawpoolsri S, Prommongkol S, Chaimoongkun W, Pan-ngum W. 2014. Knowledge, attitudes and practices (kap) regarding influenza A (H1N1) among a population living along Thai-Myanmar border, Ratchaburi Province, Thailand. Southeast Asian J. Trop. Med. Public Health, 45 (4), pp. 825-33. | Show Abstract

The 2009 influenza A (H1N1) outbreaks in Thailand was successfully controlled, partly through the use of electronic media to educate the public. People living along the Thai-Myanmar border may have less access to this electronic media or might have health beliefs that differ from the general Thai population with potential to impact an influenza outbreak. We conducted a survey to assess the knowledge, attitudes and practices regarding influenza among people living along the Thai-Myanmar boder in Ratchaburi Province, Thailand. Of 110 house- holds surveyed, 96% were Karen ethnicity. Greater than 50% were uneducated and most had a low family income. Knowledge about influenza was low. Attitudes regarding infection were mostly negative among the elderly in this area. Practices regarding influenza were moderately good. Education level was associated with knowledge and practice. Income level and wealth indicators were associated with knowledge and having a radio or TV was associated with good practices. Preventive behavior was associated with good knowledge but not with attitudes about influenza. Health education campaigns are needed in these communities to help people adopt desired changes in behavior to improve personal hygiene.

Pan-Ngum W, Kinyanjui T, Kiti M, Taylor S, Toussaint JF, Saralamba S, Van Effelterre T, Nokes DJ, White LJ. 2017. Predicting the relative impacts of maternal and neonatal respiratory syncytial virus (RSV) vaccine target product profiles: A consensus modelling approach. Vaccine, 35 (2), pp. 403-409. | Show Abstract

BACKGROUND: Respiratory syncytial virus (RSV) is the major viral cause of infant and childhood lower respiratory tract disease worldwide. Defining the optimal target product profile (TPP) is complicated due to a wide range of possible vaccine properties, modalities and an incomplete understanding of the mechanism of natural immunity. We report consensus population level impact projections based on two mathematical models applied to a low income setting. METHOD: Two structurally distinct age-specific deterministic compartmental models reflecting uncertainty associated with the natural history of infection and the mechanism by which immunity is acquired and lost were constructed. A wide range of vaccine TPPs were explored including dosing regime and uptake, and effects in the vaccinated individual on infectiousness, susceptibility, duration of protection, disease severity and interaction with maternal antibodies and natural induced immunity. These were combined with a range of vaccine implementation strategies, targeting the highest priority age group and calibrated using hospitalization data from Kilifi County Hospital, Kenya. FINDINGS: Both models were able to reproduce the data. The impact predicted by the two models was qualitatively similar across the range of TPPs, although one model consistently predicted higher impact than the other. For a proposed realistic range of scenarios of TPP combinations, the models predicted up to 70% reduction in hospitalizations in children under five years old. Vaccine designs which reduced the duration and infectiousness of infection were predicted to have higher impacts. The models were sensitive to the coverage and rate of loss of vaccine protection but not to the interaction between vaccine and maternal/naturally acquired immunity. CONCLUSION: The results suggest that vaccine properties leading to reduced virus circulation by lessening the duration and infectiousness of infection upon challenge are of major importance in population RSV disease control. These features should be a focus for vaccine development.

Sobhonslidsuk A, Poovorawan K, Soonthornworasiri N, Pan-Ngum W, Phaosawasdi K. 2016. The incidence, presentation, outcomes, risk of mortality and economic data of drug-induced liver injury from a national database in Thailand: a population-base study. BMC Gastroenterol, 16 (1), pp. 135. | Show Abstract

BACKGROUND: Toxic liver diseases are mainly caused by drug-induced liver injury (DILI). We assessed incidences and outcomes of DILI including associated factors for mortality. METHODS: We performed a population-based study of hospitalized patients with DILI. Information was retrieved from the Nationwide Hospital Admission Data using ICD-10 code of toxic liver diseases (K71) and additional codes (T36-T65). The associated factors were analyzed with log-rank test, univariate and multiple cox regression analysis. RESULTS: During 2009-2013, a total of 159,061 (average 21,165 per year) admissions were related to liver diseases. 6,516 admissions (1,303 per year) were due to toxic liver diseases. The most common type of toxic liver disease was acute hepatitis (33.5 %). In-hospital and 90-day mortality rates were 3.4 % and 17.2 %. DILI with cirrhosis yielded the highest in-hospital and 90-day mortality rates (15.8 % and 47.4 %). Acetaminophen, cirrhosis and age ≥ 60 years were seen in 0.5 %, 8.3 % and 50.1 % of patients who died versus 5 %, 2.3 % and 32.4 % of survivors. Factors associated with mortality were cirrhosis (HR 2.72, 95 % CI: 2.33-3.19), age ≥60 years (HR 2.16, 95 % CI: 1.96-2.38), human immunodeficiency viral infection (HR 2.11, 95 % CI: 1.88-2.36), chronic kidney disease (HR 1.59, 95 % CI: 1.33-1.90), chronic obstructive pulmonary disease and bronchiectasis (HR 1.55, 95 % CI: 1.17-2.04), malnutrition (HR 1.43, 95 % CI: 1.10-1.86) and male (HR 1.31, 95 % CI: 1.21-1.43). Acetaminophen DILI yielded lower risks of mortality (HR 0.24, 95 % CI: 0.13-0.42). The most common causes of DILI were acetaminophen (35.0 %) and anti-tuberculous drugs (34.7 %). CONCLUSIONS: DILI is an uncommon indication for hospitalization carrying lower risks of death except in patients with non-acetaminophen, cirrhosis, elderly or concomitant diseases.

Poovorawan K, Pan-Ngum W, White LJ, Soonthornworasiri N, Wilairatana P, Wasitthankasem R, Tangkijvanich P, Poovorawan Y. 2016. Estimating the Impact of Expanding Treatment Coverage and Allocation Strategies for Chronic Hepatitis C in a Direct Antiviral Agent Era. PLoS ONE, 11 (9), pp. e0163095. | Show Abstract

Hepatitis C virus (HCV) infection is an important worldwide public health problem, and most of the global HCV burden is in low- to middle-income countries. This study aimed to estimate the future burden of chronic hepatitis C (CHC) and the impact of public health policies using novel antiviral agents in Thailand. A mathematical model of CHC transmission dynamics was constructed to examine the disease burden over the next 20 years using different treatment strategies. We compared and evaluated the current treatment (PEGylated interferon and ribavirin) with new treatments using novel direct-acting antiviral agents among various treatment policies. Thailand's CHC prevalence was estimated to decrease 1.09%-0.19% in 2015-2035. Expanding treatment coverage (i.e., a five-fold increment in treatment accessibility) was estimated to decrease cumulative deaths (33,007 deaths avoided, 25.5% reduction) from CHC-related decompensated cirrhosis and hepatocellular carcinoma (HCC). The yearly incidence of HCC-associated HCV was estimated to decrease from 2,305 to 1,877 cases yearly with expanding treatment coverage. A generalized treatment scenario (i.e., an equal proportional distribution of available treatment to individuals at all disease stages according to the number of cases at each stage) was predicted to further reduce death from HCC (9,170 deaths avoided, 11.3% reduction) and the annual incidence of HCC (i.e., a further decrease from 1,877 to 1,168 cases yearly, 37.7% reduction), but cumulative deaths were predicted to increase (by 3,626 deaths, 3.7% increase). Based on the extensive coverage scenario and the generalized treatment scenario, we estimated near-zero death from decompensated cirrhosis in 2031. In conclusion, CHC-related morbidity and mortality in Thailand are estimated to decrease dramatically over the next 20 years. Treatment coverage and allocation strategies are important factors that affect the future burden of CHC in resource-limited countries like Thailand.

Poovorawan K, Pan-Ngum W, Soonthornworasiri N, Kulrat C, Kittitrakul C, Wilairatana P, Treeprasertsuk S, Kitsahawong B, Phaosawasdi K. 2016. Burden of Liver Abscess and Survival Risk Score in Thailand: A Population-Based Study. Am. J. Trop. Med. Hyg., 95 (3), pp. 683-8. | Show Abstract

In Thailand, the burden of liver abscess, a life-threatening infectious disease, has not been thoroughly evaluated. We developed a predictive scoring system to estimate survival of patients with liver abscess using information from the 2008-2013 Nationwide Hospital Admission Data to evaluate the burden of liver abscess in Thailand. All patients with primary diagnosis of pyogenic liver abscess (PLA) and amoebic liver abscess (ALA) were included. Epidemiological data, baseline characteristics, hospital course, and survival were analyzed. Overall, 11,296 admissions comprising 8,423 patients from 844 hospitals across Thailand were eligible for analysis. The mean age was 52 ± 17 years and 66.1% of patients were male. ALA was significantly prevalent in southern and western border regions of Thailand, and PLA occurred nationwide. The highest incidence of liver abscess occurred in the rainy season (June-November, P < 0.01). The median length of hospital stay was 8 days (interquartile range = 4-13 days), and mean direct cost of hospitalization was 846 ± 1,574 USD. The overall inhospital mortality rate was 2.8%. Incidence of ALA decreased over the 5-year study period, whereas PLA incidence increased (P < 0.01). Using multivariable Cox regression methods with stepwise variable selection, we developed a final model with five highly significant baseline parameters associated with increased 60-day mortality: older age, PLA, underlying chronic kidney disease, cirrhosis, and human immunodeficiency virus infection. Range of estimated probability of 60-day survival was 95-16% at cumulative risk score 0-13. This simplified score is practical, and may help clinicians prioritize patients requiring more intensive care.

Lubell Y, Althaus T, Blacksell SD, Paris DH, Mayxay M, Pan-Ngum W, White LJ, Day NP, Newton PN. 2016. Modelling the Impact and Cost-Effectiveness of Biomarker Tests as Compared with Pathogen-Specific Diagnostics in the Management of Undifferentiated Fever in Remote Tropical Settings. PLoS ONE, 11 (3), pp. e0152420. | Show Abstract

BACKGROUND: Malaria accounts for a small fraction of febrile cases in increasingly large areas of the malaria endemic world. Point-of-care tests to improve the management of non-malarial fevers appropriate for primary care are few, consisting of either diagnostic tests for specific pathogens or testing for biomarkers of host response that indicate whether antibiotics might be required. The impact and cost-effectiveness of these approaches are relatively unexplored and methods to do so are not well-developed. METHODS: We model the ability of dengue and scrub typhus rapid tests to inform antibiotic treatment, as compared with testing for elevated C-Reactive Protein (CRP), a biomarker of host-inflammation. Using data on causes of fever in rural Laos, we estimate the proportion of outpatients that would be correctly classified as requiring an antibiotic and the likely cost-effectiveness of the approaches. RESULTS: Use of either pathogen-specific test slightly increased the proportion of patients correctly classified as requiring antibiotics. CRP testing was consistently superior to the pathogen-specific tests, despite heterogeneity in causes of fever. All testing strategies are likely to result in higher average costs, but only the scrub typhus and CRP tests are likely to be cost-effective when considering direct health benefits, with median cost per disability adjusted life year averted of approximately $48 USD and $94 USD, respectively. CONCLUSIONS: Testing for viral infections is unlikely to be cost-effective when considering only direct health benefits to patients. Testing for prevalent bacterial pathogens can be cost-effective, having the benefit of informing not only whether treatment is required, but also as to the most appropriate antibiotic; this advantage, however, varies widely in response to heterogeneity in causes of fever. Testing for biomarkers of host inflammation is likely to be consistently cost-effective despite high heterogeneity, and can also offer substantial reductions in over-use of antimicrobials in viral infections.

Vorasan N, Pan-Ngum W, Jittamala P, Maneeboonyang W, Rukmanee P, Lawpoolsri S. 2015. Long-term impact of childhood malaria infection on school performance among school children in a malaria endemic area along the Thai-Myanmar border. Malar. J., 14 pp. 401. | Show Abstract

BACKGROUND: Children represent a high-risk group for malaria worldwide. Among people in Thailand who have malaria during childhood, some may have multiple malaria attacks during their lifetime. Malaria may affect neurological cognition in children, resulting in short-term impairment of memory and language functions. However, little is known regarding the long-term effects of malaria infection on cognitive function. This study examines the long-term impact of malaria infection on school performance among school children living in a malaria-endemic area along the Thai-Myanmar border. METHODS: A retrospective cohort study was conducted among school children aged 6-17 years in a primary-secondary school of a sub-district of Ratchaburi Province, Thailand. History of childhood malaria infection was obtained from the medical records of the sole malaria clinic in the area. School performance was assessed by using scores for the subjects Thai Language and Mathematics in 2014. Other variables, such as demographic characteristics, perinatal history, nutritional status, and emotional intelligence, were also documented. RESULTS: A total of 457 students were included, 135 (30 %) of whom had a history of uncomplicated malaria infection. About half of the malaria-infected children had suffered infection before the age of four years. The mean scores for both Mathematics and Thai Language decreased in relation to the increasing number of malaria attacks. Most students had their last malaria episode more than two years previously. The mean scores were not associated with duration since the last malaria attack. The association between malaria infection and school performance was not significant after adjusting for potential confounders, including gender, school absenteeism over a semester term, and emotional intelligence. CONCLUSIONS: This study characterizes the long-term consequences of uncomplicated malaria disease during childhood. School performance was not associated with a history of malaria infection, considering that most students had their last malaria infection more than two years previously. These findings indicate that the impact of uncomplicated malaria infection on school performance may not be prolonged.

Maude RR, de Jong HK, Wijedoru L, Fukushima M, Ghose A, Samad R, Hossain MA, Karim MR, Faiz MA, Parry CM, CMCH Typhoid Study Group. 2015. The diagnostic accuracy of three rapid diagnostic tests for typhoid fever at Chittagong Medical College Hospital, Chittagong, Bangladesh. Trop. Med. Int. Health, 20 (10), pp. 1376-84. | Show Abstract

OBJECTIVE: To determine the diagnostic accuracy of three rapid diagnostic tests (RDTs) for typhoid fever in febrile hospitalised patients in Bangladesh. METHODS: Febrile adults and children admitted to Chittagong Medical College Hospital, Bangladesh, were investigated with Bact/Alert(®) blood cultures and real-time PCR to detect Salmonella enterica Typhi and Paratyphi A and assays for Rickettsia, leptospirosis and dengue fever. Acute serum samples were examined with the LifeAssay (LA) Test-it™ Typhoid IgM lateral flow assay detecting IgM antibodies against S. Typhi O antigen, CTKBiotech Onsite Typhoid IgG/IgM Combo Rapid-test cassette lateral flow assay detecting IgG and IgM antibodies against S. Typhi O and H antigens and SD Bioline line assay for IgG and IgM antibodies against S. Typhi proteins. RESULTS: In 300 malaria smear-negative febrile patients [median (IQR) age of 13.5 (5-31) years], 34 (11.3%) had confirmed typhoid fever: 19 positive by blood culture for S. Typhi (three blood PCR positive) and 15 blood culture negative but PCR positive for S. Typhi in blood. The respective sensitivity and specificity of the three RDTs in patients using a composite reference standard of blood culture and/or PCR-confirmed typhoid fever were 59% and 61% for LifeAssay, 59% and 74% for the CTK IgM and/or IgG, and 24% and 96% for the SD Bioline RDT IgM and/or IgG. The LifeAssay RDT had a sensitivity of 63% and a specificity of 91% when modified with a positive cut-off of ≥2+ and analysed using a Bayesian latent class model. CONCLUSIONS: These typhoid RDTs demonstrated moderate diagnostic accuracies, and better tests are needed.

White LJ, Flegg JA, Phyo AP, Wiladpai-ngern JH, Bethell D, Plowe C, Anderson T, Nkhoma S, Nair S, Tripura R et al. 2015. Defining the in vivo phenotype of artemisinin-resistant falciparum malaria: a modelling approach. PLoS Med., 12 (4), pp. e1001823. | Show Abstract

BACKGROUND: Artemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker 'Kelch 13' and in vitro sensitivity tests. However, current cut-off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment ('day-3'), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions. METHODS AND FINDINGS: Data from 1,518 patients on the Thai-Myanmar and Thai-Cambodian borders with parasite half-life assessments after artesunate treatment were analysed. Half-lives followed a bimodal distribution. A statistical approach was developed to infer the characteristics of the component distributions and their relative contribution to the composite mixture. A model representing two parasite subpopulations with geometric mean (IQR) parasite half-lives of 3.0 (2.4-3.9) hours and 6.50 (5.7-7.4) hours was consistent with the data. For individual patients, the parasite half-life provided a predicted likelihood of an artemisinin-resistant infection which depends on the population prevalence of resistance in that area. Consequently, a half-life where the probability is 0.5 varied between 3.5 and 5.5 hours. Using this model, the current 'day-3' cut-off value of 10% predicts the potential presence of artemisinin-resistant infections in most but not all scenarios. These findings are relevant to the low-transmission setting of Southeast Asia. Generalisation to a high transmission setting as in regions of Sub-Saharan Africa will need additional evaluation. CONCLUSIONS: Characterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearance and artemisinin resistance, as well as the predictive value of the 10% cut-off in 'day-3' parasitaemia. The findings are important for the interpretation of in vitro sensitivity tests and molecular markers for artemisinin resistance and for contextualising the 'day 3' threshold to account for initial parasitaemia and sample size.

Cooper BS, Boni MF, Pan-ngum W, Day NP, Horby PW, Olliaro P, Lang T, White NJ, White LJ, Whitehead J. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med., 12 (4), pp. e1001815. | Show Abstract

BACKGROUND: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. METHODS AND FINDINGS: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. CONCLUSIONS: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Suwanpakdee S, Kaewkungwal J, White LJ, Asensio N, Ratanakorn P, Singhasivanon P, Day NP, Pan-Ngum W. 2015. Spatio-temporal patterns of leptospirosis in Thailand: is flooding a risk factor? Epidemiol. Infect., 143 (10), pp. 2106-15. | Show Abstract

We studied the temporal and spatial patterns of leptospirosis, its association with flooding and animal census data in Thailand. Flood data from 2010 to 2012 were extracted from spatial information taken from satellite images. The incidence rate ratio (IRR) was used to determine the relationship between spatio-temporal flooding patterns and the number of human leptospirosis cases. In addition, the area of flood coverage, duration of waterlogging, time lags between flood events, and a number of potential animal reservoirs were considered in a sub-analysis. There was no significant temporal trend of leptospirosis over the study period. Statistical analysis showed an inconsistent relationship between IRR and flooding across years and regions. Spatially, leptospirosis occurred repeatedly and predominantly in northeastern Thailand. Our findings suggest that flooding is less influential in leptospirosis transmission than previously assumed. High incidence of the disease in the northeastern region is explained by the fact that agriculture and animal farming are important economic activities in this area. The periodic rise and fall of reported leptospirosis cases over time might be explained by seasonal exposure from rice farming activities performed during the rainy season when flood events often occur. We conclude that leptospirosis remains an occupational disease in Thailand.

Monyarit S, Pan-ngum W, Lawpoolsri S, Yimsamran S, Pongnumkul S, Kaewkungwal J, Singhasivanon P. 2014. Advantages of using voiced questionnaire and image capture application for data collection from a minority group in rural areas along the Thailand-Myanmar border. Inform Prim Care, 21 (4), pp. 179-88. | Show Abstract

AIMS: To compare the quality of data collection via electronic data capture (EDC) with voiced questionnaire (QNN) and data image capture features using a tablet versus standard paper-based QNN, to assess the user's perception of using the EDC tool, and to compare user satisfaction with the two methods. STUDY DESIGN: Randomised cross-over study. Study sites: This study was conducted in two villages along the Thailand-Myanmar border. METHODOLOGY: This study included 30 community health volunteers (CHVs) and 120 Karen hill tribe villagers. Employing a cross-over study design, the CHVs were allocated randomly to two groups, in which they performed interviews in different sequences using EDC and QNN. RESULTS: Data discrepancies were found between the two data-collection methods, when data from the paper-based and image-capture methods were compared, and when conducting skip pattern questions. More than 90% of the CHVs perceived the EDC to be useful and easy to use. Both interviewers and interviewees were more satisfied with the EDC compared with QNN in terms of format, ease of use, and system speed. CONCLUSION: The EDC can effectively be used as an alternative method to paper-based QNNs for data collection. It produces more accurate data that can be considered evidence-based.

Punyadee N, Mairiang D, Thiemmeca S, Komoltri C, Pan-Ngum W, Chomanee N, Charngkaew K, Tangthawornchaikul N, Limpitikul W, Vasanawathana S et al. 2015. Microparticles provide a novel biomarker to predict severe clinical outcomes of dengue virus infection. J. Virol., 89 (3), pp. 1587-607. | Show Abstract

UNLABELLED: Shedding of microparticles (MPs) is a consequence of apoptotic cell death and cellular activation. Low levels of circulating MPs in blood help maintain homeostasis, whereas increased MP generation is linked to many pathological conditions. Herein, we investigated the role of MPs in dengue virus (DENV) infection. Infection of various susceptible cells by DENV led to apoptotic death and MP release. These MPs harbored a viral envelope protein and a nonstructural protein 1 (NS1) on their surfaces. Ex vivo analysis of clinical specimens from patients with infections of different degrees of severity at multiple time points revealed that MPs generated from erythrocytes and platelets are two major MP populations in the circulation of DENV-infected patients. Elevated levels of red blood cell-derived MPs (RMPs) directly correlated with DENV disease severity, whereas a significant decrease in platelet-derived MPs was associated with a bleeding tendency. Removal by mononuclear cells of complement-opsonized NS1-anti-NS1 immune complexes bound to erythrocytes via complement receptor type 1 triggered MP shedding in vitro, a process that could explain the increased levels of RMPs in severe dengue. These findings point to the multiple roles of MPs in dengue pathogenesis. They offer a potential novel biomarker candidate capable of differentiating dengue fever from the more serious dengue hemorrhagic fever. IMPORTANCE: Dengue is the most important mosquito-transmitted viral disease in the world. No vaccines or specific treatments are available. Rapid diagnosis and immediate treatment are the keys to achieve a positive outcome. Dengue virus (DENV) infection, like some other medical conditions, changes the level and composition of microparticles (MPs), tiny bag-like structures which are normally present at low levels in the blood of healthy individuals. This study investigated how MPs in culture and patients' blood are changed in response to DENV infection. Infection of cells led to programmed cell death and MP release. In patients' blood, the majority of MPs originated from red blood cells and platelets. Decreased platelet-derived MPs were associated with a bleeding tendency, while increased levels of red blood cell-derived MPs (RMPs) correlated with more severe disease. Importantly, the level of RMPs during the early acute phase could serve as a biomarker to identify patients with potentially severe disease who require immediate care.

Moore CE, Pan-Ngum W, Wijedoru LP, Sona S, Nga TV, Duy PT, Vinh PV, Chheng K, Kumar V, Emary K et al. 2014. Evaluation of the diagnostic accuracy of a typhoid IgM flow assay for the diagnosis of typhoid fever in Cambodian children using a Bayesian latent class model assuming an imperfect gold standard. Am. J. Trop. Med. Hyg., 90 (1), pp. 114-20. | Show Abstract

Rapid diagnostic tests are needed for typhoid fever (TF) diagnosis in febrile children in endemic areas. Five hundred children admitted to the hospital in Cambodia between 2009 and 2010 with documented fever (≥ 38°C) were investigated using blood cultures (BCs), Salmonella Typhi/Paratyphi A real-time polymerase chain reactions (PCRs), and a Typhoid immunoglobulin M flow assay (IgMFA). Test performance was determined by conventional methods and Bayesian latent class modeling. There were 32 cases of TF (10 BC- and PCR-positive cases, 14 BC-positive and PCR-negative cases, and 8 BC-negative and PCR-positive cases). IgMFA sensitivity was 59.4% (95% confidence interval = 41-76), and specificity was 97.8% (95% confidence interval = 96-99). The model estimate sensitivity for BC was 81.0% (95% credible interval = 54-99). The model estimate sensitivity for PCR was 37.8% (95% credible interval = 26-55), with a specificity of 98.2% (95% credible interval = 97-99). The model estimate sensitivity for IgMFA (≥ 2+) was 77.9% (95% credible interval = 58-90), with a specificity of 97.5% (95% credible interval = 95-100). The model estimates of IgMFA sensitivity and specificity were comparable with BCs and better than estimates using conventional analysis.

Pan-ngum W, Blacksell SD, Lubell Y, Pukrittayakamee S, Bailey MS, de Silva HJ, Lalloo DG, Day NP, White LJ, Limmathurotsakul D. 2013. Estimating the true accuracy of diagnostic tests for dengue infection using bayesian latent class models. PLoS ONE, 8 (1), pp. e50765. | Show Abstract

BACKGROUND: Accuracy of rapid diagnostic tests for dengue infection has been repeatedly estimated by comparing those tests with reference assays. We hypothesized that those estimates might be inaccurate if the accuracy of the reference assays is not perfect. Here, we investigated this using statistical modeling. METHODS/PRINCIPAL FINDINGS: Data from a cohort study of 549 patients suspected of dengue infection presenting at Colombo North Teaching Hospital, Ragama, Sri Lanka, that described the application of our reference assay (a combination of Dengue IgM antibody capture ELISA and IgG antibody capture ELISA) and of three rapid diagnostic tests (Panbio NS1 antigen, IgM antibody and IgG antibody rapid immunochromatographic cassette tests) were re-evaluated using bayesian latent class models (LCMs). The estimated sensitivity and specificity of the reference assay were 62.0% and 99.6%, respectively. Prevalence of dengue infection (24.3%), and sensitivities and specificities of the Panbio NS1 (45.9% and 97.9%), IgM (54.5% and 95.5%) and IgG (62.1% and 84.5%) estimated by bayesian LCMs were significantly different from those estimated by assuming that the reference assay was perfect. Sensitivity, specificity, PPV and NPV for a combination of NS1, IgM and IgG cassette tests on admission samples were 87.0%, 82.8%, 62.0% and 95.2%, respectively. CONCLUSIONS: Our reference assay is an imperfect gold standard. In our setting, the combination of NS1, IgM and IgG rapid diagnostic tests could be used on admission to rule out dengue infection with a high level of accuracy (NPV 95.2%). Further evaluation of rapid diagnostic tests for dengue infection should include the use of appropriate statistical models.

White LJ, Newton PN, Maude RJ, Pan-ngum W, Fried JR, Mayxay M, Maude RR, Day NP. 2012. Defining disease heterogeneity to guide the empirical treatment of febrile illness in resource poor settings. PLoS ONE, 7 (9), pp. e44545. | Show Abstract

BACKGROUND: Malaria incidence is in decline in many parts of SE Asia leading to a decreasing proportion of febrile illness that is attributable to malaria. However in the absence of rapid, affordable and accurate diagnostic tests, the non-malaria causes of these illnesses cannot be reliably identified. Studies on the aetiology of febrile illness have indicated that the causes are likely to vary by geographical location within countries (i.e. be spatially heterogeneous) and that national empirical treatment policies based on the aetiology measured in a single location could lead to inappropriate treatment. METHODS: Using data from Vientiane as a reference for the incidence of major febrile illnesses in the Lao People's Democratic Republic (Laos) and estimated incidences, plausible incidence in other Lao provinces were generated using a mathematical model for a range of national and local scale variations. For a range of treatment protocols, the mean number of appropriate treatments was predicted and the potential impact of a spatially explicit national empirical treatment protocol assessed. FINDINGS: The model predicted a negative correlation between number of appropriate treatments and the level of spatial heterogeneity. A spatially explicit national treatment protocol was predicted to increase the number of appropriate treatments by 50% for intermediate levels of spatial heterogeneity. CONCLUSIONS: The results suggest that given even only moderate spatial variation, a spatially explicit treatment algorithm will result in a significant improvement in the outcome of undifferentiated fevers in Laos and other similar resource poor settings.

Hendriksen IC, Mwanga-Amumpaire J, von Seidlein L, Mtove G, White LJ, Olaosebikan R, Lee SJ, Tshefu AK, Woodrow C, Amos B et al. 2012. Diagnosing severe falciparum malaria in parasitaemic African children: a prospective evaluation of plasma PfHRP2 measurement. PLoS Med., 9 (8), pp. e1001297. | Show Abstract

BACKGROUND: In African children, distinguishing severe falciparum malaria from other severe febrile illnesses with coincidental Plasmodium falciparum parasitaemia is a major challenge. P. falciparum histidine-rich protein 2 (PfHRP2) is released by mature sequestered parasites and can be used to estimate the total parasite burden. We investigated the prognostic significance of plasma PfHRP2 and used it to estimate the malaria-attributable fraction in African children diagnosed with severe malaria. METHODS AND FINDINGS: Admission plasma PfHRP2 was measured prospectively in African children (from Mozambique, The Gambia, Kenya, Tanzania, Uganda, Rwanda, and the Democratic Republic of the Congo) aged 1 month to 15 years with severe febrile illness and a positive P. falciparum lactate dehydrogenase (pLDH)-based rapid test in a clinical trial comparing parenteral artesunate versus quinine (the AQUAMAT trial, ISRCTN 50258054). In 3,826 severely ill children, Plasmadium falciparum PfHRP2 was higher in patients with coma (p = 0.0209), acidosis (p<0.0001), and severe anaemia (p<0.0001). Admission geometric mean (95%CI) plasma PfHRP2 was 1,611 (1,350-1,922) ng/mL in fatal cases (n = 381) versus 1,046 (991-1,104) ng/mL in survivors (n = 3,445, p<0.0001), without differences in parasitaemia as assessed by microscopy. There was a U-shaped association between log(10) plasma PfHRP2 and risk of death. Mortality increased 20% per log(10) increase in PfHRP2 above 174 ng/mL (adjusted odds ratio [AOR] 1.21, 95%CI 1.05-1.39, p = 0.009). A mechanistic model assuming a PfHRP2-independent risk of death in non-malaria illness closely fitted the observed data and showed malaria-attributable mortality less than 50% with plasma PfHRP2≤174 ng/mL. The odds ratio (OR) for death in artesunate versus quinine-treated patients was 0.61 (95%CI 0.44-0.83, p = 0.0018) in the highest PfHRP2 tertile, whereas there was no difference in the lowest tertile (OR 1.05; 95%CI 0.69-1.61; p = 0.82). A limitation of the study is that some conclusions are drawn from a mechanistic model, which is inherently dependent on certain assumptions. However, a sensitivity analysis of the model indicated that the results were robust to a plausible range of parameter estimates. Further studies are needed to validate our findings. CONCLUSIONS: Plasma PfHRP2 has prognostic significance in African children with severe falciparum malaria and provides a tool to stratify the risk of "true" severe malaria-attributable disease as opposed to other severe illnesses in parasitaemic African children.

Pukrittayakamee S, Jittamala P, Stepniewska K, Lindegardh N, Chueasuwanchai S, Leowattana W, Phakdeeraj A, Permpunpanich S, Hanpithakpong W, Pan-Ngum W et al. 2011. An open-label crossover study to evaluate potential pharmacokinetic interactions between oral oseltamivir and intravenous zanamivir in healthy Thai adults. Antimicrob. Agents Chemother., 55 (9), pp. 4050-7. | Show Abstract

There is no parenteral formulation of the neuraminidase inhibitor oseltamivir, the most widely used anti-influenza virus drug. Oseltamivir resistance is an increasing problem. Zanamivir is effective against the most prevalent oseltamivir-resistant influenza viruses. A parenteral formulation of zanamivir is in development for the treatment of severe influenza. It is not known if there is any pharmacokinetic interaction between the two drugs. Sixteen healthy Thai adult volunteers were studied in an open-label, four-period, randomized two-sequence crossover pharmacokinetic study in which zanamivir was given by constant-rate infusion or slow intravenous injection either alone or together with oral oseltamivir. Plasma concentration profiles of oseltamivir, the active metabolite oseltamivir carboxylate, and zanamivir were measured by liquid chromatography-mass spectrometry-mass spectrometry. Both drugs were well tolerated alone and in combination. The maximum plasma concentrations and the areas under the plasma concentration-time curves (AUC) of oseltamivir and oseltamivir carboxylate were not significantly different when oseltamivir was given separately or together with zanamivir. Maximum plasma concentrations of zanamivir were 10% (95% confidence interval, 7 to 12%) higher when zanamivir was infused concurrently with oral oseltamivir than with infusions before or after oral oseltamivir. The plasma zanamivir total AUC was positively correlated with the total oseltamivir carboxylate AUC (Pearson's correlation coefficient [r(P)] = 0.720, P = 0.002, n = 16) but not with the oseltamivir AUC (r(p) = 0.121, n = 16). There is no clinically significant pharmacokinetic interaction between oseltamivir and zanamivir.

Saralamba S, Pan-Ngum W, Maude RJ, Lee SJ, Tarning J, Lindegårdh N, Chotivanich K, Nosten F, Day NP, Socheat D et al. 2011. Intrahost modeling of artemisinin resistance in Plasmodium falciparum. Proc. Natl. Acad. Sci. U.S.A., 108 (1), pp. 397-402. | Show Abstract

Artemisinin-resistant Plasmodium falciparum malaria has emerged in western Cambodia. Resistance is characterized by prolonged in vivo parasite clearance times (PCTs) following artesunate treatment. The biological basis is unclear. The hypothesis that delayed parasite clearance results from a stage-specific reduction in artemisinin sensitivity of the circulating young asexual parasite ring stages was examined. A mathematical model was developed, describing the intrahost parasite stage-specific pharmacokinetic-pharmacodynamic relationships. Model parameters were estimated using detailed pharmacokinetic and parasite clearance data from 39 patients with uncomplicated falciparum malaria treated with artesunate from Pailin (western Cambodia) where artemisinin resistance was evident and 40 patients from Wang Pha (northwestern Thailand) where efficacy was preserved. The mathematical model reproduced the observed parasite clearance for each patient with an accurate goodness of fit (rmsd: 0.03-0.67 in log(10) scale). The parameter sets that provided the best fits with the observed in vivo data consist of a highly conserved concentration-effect relationship for the trophozoite and schizont parasite stages, but a variable relationship for the ring stages. The model-derived assessment suggests that the efficacy of artesunate on ring stage parasites is reduced significantly in Pailin. This result supports the hypothesis that artemisinin resistance mainly reflects reduced ring-stage susceptibility and predicts that doubling the frequency of dosing will accelerate clearance of artemisinin-resistant parasites.

Dondorp AM, Fanello CI, Hendriksen IC, Gomes E, Seni A, Chhaganlal KD, Bojang K, Olaosebikan R, Anunobi N, Maitland K et al. 2010. Artesunate versus quinine in the treatment of severe falciparum malaria in African children (AQUAMAT): an open-label, randomised trial. Lancet, 376 (9753), pp. 1647-57. | Show Abstract

BACKGROUND: Severe malaria is a major cause of childhood death and often the main reason for paediatric hospital admission in sub-Saharan Africa. Quinine is still the established treatment of choice, although evidence from Asia suggests that artesunate is associated with a lower mortality. We compared parenteral treatment with either artesunate or quinine in African children with severe malaria. METHODS: This open-label, randomised trial was undertaken in 11 centres in nine African countries. Children (<15 years) with severe falciparum malaria were randomly assigned to parenteral artesunate or parenteral quinine. Randomisation was in blocks of 20, with study numbers corresponding to treatment allocations kept inside opaque sealed paper envelopes. The trial was open label at each site, and none of the investigators or trialists, apart from for the trial statistician, had access to the summaries of treatment allocations. The primary outcome measure was in-hospital mortality, analysed by intention to treat. This trial is registered, number ISRCTN50258054. FINDINGS: 5425 children were enrolled; 2712 were assigned to artesunate and 2713 to quinine. All patients were analysed for the primary outcome. 230 (8·5%) patients assigned to artesunate treatment died compared with 297 (10·9%) assigned to quinine treatment (odds ratio [OR] stratified for study site 0·75, 95% CI 0·63-0·90; relative reduction 22·5%, 95% CI 8·1-36·9; p=0·0022). Incidence of neurological sequelae did not differ significantly between groups, but the development of coma (65/1832 [3·5%] with artesunate vs 91/1768 [5·1%] with quinine; OR 0·69 95% CI 0·49-0·95; p=0·0231), convulsions (224/2712 [8·3%] vs 273/2713 [10·1%]; OR 0·80, 0·66-0·97; p=0·0199), and deterioration of the coma score (166/2712 [6·1%] vs 208/2713 [7·7%]; OR 0·78, 0·64-0·97; p=0·0245) were all significantly less frequent in artesunate recipients than in quinine recipients. Post-treatment hypoglycaemia was also less frequent in patients assigned to artesunate than in those assigned to quinine (48/2712 [1·8%] vs 75/2713 [2·8%]; OR 0·63, 0·43-0·91; p=0·0134). Artesunate was well tolerated, with no serious drug-related adverse effects. INTERPRETATION: Artesunate substantially reduces mortality in African children with severe malaria. These data, together with a meta-analysis of all trials comparing artesunate and quinine, strongly suggest that parenteral artesunate should replace quinine as the treatment of choice for severe falciparum malaria worldwide. FUNDING: The Wellcome Trust.

von Seidlein L, Olaosebikan R, Hendriksen IC, Lee SJ, Adedoyin OT, Agbenyega T, Nguah SB, Bojang K, Deen JL, Evans J et al. 2012. Predicting the clinical outcome of severe falciparum malaria in african children: findings from a large randomized trial. Clin. Infect. Dis., 54 (8), pp. 1080-90. | Show Abstract

BACKGROUND: Data from the largest randomized, controlled trial for the treatment of children hospitalized with severe malaria were used to identify such predictors of a poor outcome from severe malaria. METHODS: African children (<15 years) with severe malaria participated in a randomized comparison of parenteral artesunate and parenteral quinine in 9 African countries. Detailed clinical assessment was performed on admission. Parasite densities were assessed in a reference laboratory. Predictors of death were examined using a multivariate logistic regression model. RESULTS: Twenty indicators of disease severity were assessed, out of which 5 (base deficit, impaired consciousness, convulsions, elevated blood urea, and underlying chronic illness) were associated independently with death. Tachypnea, respiratory distress, deep breathing, shock, prostration, low pH, hyperparasitemia, severe anemia, and jaundice were statistically significant indicators of death in the univariate analysis but not in the multivariate model. Age, glucose levels, axillary temperature, parasite density, heart rate, blood pressure, and blackwater fever were not related to death in univariate models. CONCLUSIONS: Acidosis, cerebral involvement, renal impairment, and chronic illness are key independent predictors for a poor outcome in African children with severe malaria. Mortality is markedly increased in cerebral malaria combined with acidosis. Clinical Trial Registration. ISRCTN50258054.

Lubell Y, Riewpaiboon A, Dondorp AM, von Seidlein L, Mokuolu OA, Nansumba M, Gesase S, Kent A, Mtove G, Olaosebikan R et al. 2011. Cost-effectiveness of parenteral artesunate for treating children with severe malaria in sub-Saharan Africa. Bull. World Health Organ., 89 (7), pp. 504-12. | Show Abstract

OBJECTIVE: To explore the cost-effectiveness of parenteral artesunate for the treatment of severe malaria in children and its potential impact on hospital budgets. METHODS: The costs of inpatient care of children with severe malaria were assessed in four of the 11 sites included in the African Quinine Artesunate Malaria Treatment trial, conducted with over 5400 children. The drugs, laboratory tests and intravenous fluids provided to 2300 patients from admission to discharge were recorded, as was the length of inpatient stay, to calculate the cost of inpatient care. The data were matched with pooled clinical outcomes and entered into a decision model to calculate the cost per disability-adjusted life year (DALY) averted and the cost per death averted. FINDINGS: The mean cost of treating severe malaria patients was similar in the two study groups: 63.5 United States dollars (US$) (95% confidence interval, CI: 61.7-65.2) in the quinine arm and US$ 66.5 (95% CI: 63.7-69.2) in the artesunate arm. Children treated with artesunate had 22.5% lower mortality than those treated with quinine and the same rate of neurological sequelae: (artesunate arm: 2.3 DALYs per patient; quinine arm: 3.0 DALYs per patient). Compared with quinine as a baseline, artesunate showed an incremental cost per DALY averted and an incremental cost per death averted of US$ 3.8 and US$ 123, respectively. CONCLUSION: Artesunate is a highly cost-effective and affordable alternative to quinine for treating children with severe malaria. The budgetary implications of adopting artesunate for routine use in hospital-based care are negligible.

Rukmanee N, Yimsamran S, Rukmanee P, Thanyavanich N, Maneeboonyang W, Puangsa-art S, Wuthisen P, Lawpoolsri S, Prommongkol S, Chaimoongkun W, Pan-ngum W. 2014. Knowledge, attitudes and practices (kap) regarding influenza A (H1N1) among a population living along Thai-Myanmar border, Ratchaburi Province, Thailand. Southeast Asian J. Trop. Med. Public Health, 45 (4), pp. 825-33. | Show Abstract

The 2009 influenza A (H1N1) outbreaks in Thailand was successfully controlled, partly through the use of electronic media to educate the public. People living along the Thai-Myanmar border may have less access to this electronic media or might have health beliefs that differ from the general Thai population with potential to impact an influenza outbreak. We conducted a survey to assess the knowledge, attitudes and practices regarding influenza among people living along the Thai-Myanmar boder in Ratchaburi Province, Thailand. Of 110 house- holds surveyed, 96% were Karen ethnicity. Greater than 50% were uneducated and most had a low family income. Knowledge about influenza was low. Attitudes regarding infection were mostly negative among the elderly in this area. Practices regarding influenza were moderately good. Education level was associated with knowledge and practice. Income level and wealth indicators were associated with knowledge and having a radio or TV was associated with good practices. Preventive behavior was associated with good knowledge but not with attitudes about influenza. Health education campaigns are needed in these communities to help people adopt desired changes in behavior to improve personal hygiene.

Pan-Ngum W, Kinyanjui T, Kiti M, Taylor S, Toussaint JF, Saralamba S, Van Effelterre T, Nokes DJ, White LJ. 2017. Predicting the relative impacts of maternal and neonatal respiratory syncytial virus (RSV) vaccine target product profiles: A consensus modelling approach. Vaccine, 35 (2), pp. 403-409. | Show Abstract

BACKGROUND: Respiratory syncytial virus (RSV) is the major viral cause of infant and childhood lower respiratory tract disease worldwide. Defining the optimal target product profile (TPP) is complicated due to a wide range of possible vaccine properties, modalities and an incomplete understanding of the mechanism of natural immunity. We report consensus population level impact projections based on two mathematical models applied to a low income setting. METHOD: Two structurally distinct age-specific deterministic compartmental models reflecting uncertainty associated with the natural history of infection and the mechanism by which immunity is acquired and lost were constructed. A wide range of vaccine TPPs were explored including dosing regime and uptake, and effects in the vaccinated individual on infectiousness, susceptibility, duration of protection, disease severity and interaction with maternal antibodies and natural induced immunity. These were combined with a range of vaccine implementation strategies, targeting the highest priority age group and calibrated using hospitalization data from Kilifi County Hospital, Kenya. FINDINGS: Both models were able to reproduce the data. The impact predicted by the two models was qualitatively similar across the range of TPPs, although one model consistently predicted higher impact than the other. For a proposed realistic range of scenarios of TPP combinations, the models predicted up to 70% reduction in hospitalizations in children under five years old. Vaccine designs which reduced the duration and infectiousness of infection were predicted to have higher impacts. The models were sensitive to the coverage and rate of loss of vaccine protection but not to the interaction between vaccine and maternal/naturally acquired immunity. CONCLUSION: The results suggest that vaccine properties leading to reduced virus circulation by lessening the duration and infectiousness of infection upon challenge are of major importance in population RSV disease control. These features should be a focus for vaccine development.

Sobhonslidsuk A, Poovorawan K, Soonthornworasiri N, Pan-Ngum W, Phaosawasdi K. 2016. The incidence, presentation, outcomes, risk of mortality and economic data of drug-induced liver injury from a national database in Thailand: a population-base study. BMC Gastroenterol, 16 (1), pp. 135. | Show Abstract

BACKGROUND: Toxic liver diseases are mainly caused by drug-induced liver injury (DILI). We assessed incidences and outcomes of DILI including associated factors for mortality. METHODS: We performed a population-based study of hospitalized patients with DILI. Information was retrieved from the Nationwide Hospital Admission Data using ICD-10 code of toxic liver diseases (K71) and additional codes (T36-T65). The associated factors were analyzed with log-rank test, univariate and multiple cox regression analysis. RESULTS: During 2009-2013, a total of 159,061 (average 21,165 per year) admissions were related to liver diseases. 6,516 admissions (1,303 per year) were due to toxic liver diseases. The most common type of toxic liver disease was acute hepatitis (33.5 %). In-hospital and 90-day mortality rates were 3.4 % and 17.2 %. DILI with cirrhosis yielded the highest in-hospital and 90-day mortality rates (15.8 % and 47.4 %). Acetaminophen, cirrhosis and age ≥ 60 years were seen in 0.5 %, 8.3 % and 50.1 % of patients who died versus 5 %, 2.3 % and 32.4 % of survivors. Factors associated with mortality were cirrhosis (HR 2.72, 95 % CI: 2.33-3.19), age ≥60 years (HR 2.16, 95 % CI: 1.96-2.38), human immunodeficiency viral infection (HR 2.11, 95 % CI: 1.88-2.36), chronic kidney disease (HR 1.59, 95 % CI: 1.33-1.90), chronic obstructive pulmonary disease and bronchiectasis (HR 1.55, 95 % CI: 1.17-2.04), malnutrition (HR 1.43, 95 % CI: 1.10-1.86) and male (HR 1.31, 95 % CI: 1.21-1.43). Acetaminophen DILI yielded lower risks of mortality (HR 0.24, 95 % CI: 0.13-0.42). The most common causes of DILI were acetaminophen (35.0 %) and anti-tuberculous drugs (34.7 %). CONCLUSIONS: DILI is an uncommon indication for hospitalization carrying lower risks of death except in patients with non-acetaminophen, cirrhosis, elderly or concomitant diseases.

Poovorawan K, Pan-Ngum W, White LJ, Soonthornworasiri N, Wilairatana P, Wasitthankasem R, Tangkijvanich P, Poovorawan Y. 2016. Estimating the Impact of Expanding Treatment Coverage and Allocation Strategies for Chronic Hepatitis C in a Direct Antiviral Agent Era. PLoS ONE, 11 (9), pp. e0163095. | Show Abstract

Hepatitis C virus (HCV) infection is an important worldwide public health problem, and most of the global HCV burden is in low- to middle-income countries. This study aimed to estimate the future burden of chronic hepatitis C (CHC) and the impact of public health policies using novel antiviral agents in Thailand. A mathematical model of CHC transmission dynamics was constructed to examine the disease burden over the next 20 years using different treatment strategies. We compared and evaluated the current treatment (PEGylated interferon and ribavirin) with new treatments using novel direct-acting antiviral agents among various treatment policies. Thailand's CHC prevalence was estimated to decrease 1.09%-0.19% in 2015-2035. Expanding treatment coverage (i.e., a five-fold increment in treatment accessibility) was estimated to decrease cumulative deaths (33,007 deaths avoided, 25.5% reduction) from CHC-related decompensated cirrhosis and hepatocellular carcinoma (HCC). The yearly incidence of HCC-associated HCV was estimated to decrease from 2,305 to 1,877 cases yearly with expanding treatment coverage. A generalized treatment scenario (i.e., an equal proportional distribution of available treatment to individuals at all disease stages according to the number of cases at each stage) was predicted to further reduce death from HCC (9,170 deaths avoided, 11.3% reduction) and the annual incidence of HCC (i.e., a further decrease from 1,877 to 1,168 cases yearly, 37.7% reduction), but cumulative deaths were predicted to increase (by 3,626 deaths, 3.7% increase). Based on the extensive coverage scenario and the generalized treatment scenario, we estimated near-zero death from decompensated cirrhosis in 2031. In conclusion, CHC-related morbidity and mortality in Thailand are estimated to decrease dramatically over the next 20 years. Treatment coverage and allocation strategies are important factors that affect the future burden of CHC in resource-limited countries like Thailand.

Poovorawan K, Pan-Ngum W, Soonthornworasiri N, Kulrat C, Kittitrakul C, Wilairatana P, Treeprasertsuk S, Kitsahawong B, Phaosawasdi K. 2016. Burden of Liver Abscess and Survival Risk Score in Thailand: A Population-Based Study. Am. J. Trop. Med. Hyg., 95 (3), pp. 683-8. | Show Abstract

In Thailand, the burden of liver abscess, a life-threatening infectious disease, has not been thoroughly evaluated. We developed a predictive scoring system to estimate survival of patients with liver abscess using information from the 2008-2013 Nationwide Hospital Admission Data to evaluate the burden of liver abscess in Thailand. All patients with primary diagnosis of pyogenic liver abscess (PLA) and amoebic liver abscess (ALA) were included. Epidemiological data, baseline characteristics, hospital course, and survival were analyzed. Overall, 11,296 admissions comprising 8,423 patients from 844 hospitals across Thailand were eligible for analysis. The mean age was 52 ± 17 years and 66.1% of patients were male. ALA was significantly prevalent in southern and western border regions of Thailand, and PLA occurred nationwide. The highest incidence of liver abscess occurred in the rainy season (June-November, P < 0.01). The median length of hospital stay was 8 days (interquartile range = 4-13 days), and mean direct cost of hospitalization was 846 ± 1,574 USD. The overall inhospital mortality rate was 2.8%. Incidence of ALA decreased over the 5-year study period, whereas PLA incidence increased (P < 0.01). Using multivariable Cox regression methods with stepwise variable selection, we developed a final model with five highly significant baseline parameters associated with increased 60-day mortality: older age, PLA, underlying chronic kidney disease, cirrhosis, and human immunodeficiency virus infection. Range of estimated probability of 60-day survival was 95-16% at cumulative risk score 0-13. This simplified score is practical, and may help clinicians prioritize patients requiring more intensive care.

Lubell Y, Althaus T, Blacksell SD, Paris DH, Mayxay M, Pan-Ngum W, White LJ, Day NP, Newton PN. 2016. Modelling the Impact and Cost-Effectiveness of Biomarker Tests as Compared with Pathogen-Specific Diagnostics in the Management of Undifferentiated Fever in Remote Tropical Settings. PLoS ONE, 11 (3), pp. e0152420. | Show Abstract

BACKGROUND: Malaria accounts for a small fraction of febrile cases in increasingly large areas of the malaria endemic world. Point-of-care tests to improve the management of non-malarial fevers appropriate for primary care are few, consisting of either diagnostic tests for specific pathogens or testing for biomarkers of host response that indicate whether antibiotics might be required. The impact and cost-effectiveness of these approaches are relatively unexplored and methods to do so are not well-developed. METHODS: We model the ability of dengue and scrub typhus rapid tests to inform antibiotic treatment, as compared with testing for elevated C-Reactive Protein (CRP), a biomarker of host-inflammation. Using data on causes of fever in rural Laos, we estimate the proportion of outpatients that would be correctly classified as requiring an antibiotic and the likely cost-effectiveness of the approaches. RESULTS: Use of either pathogen-specific test slightly increased the proportion of patients correctly classified as requiring antibiotics. CRP testing was consistently superior to the pathogen-specific tests, despite heterogeneity in causes of fever. All testing strategies are likely to result in higher average costs, but only the scrub typhus and CRP tests are likely to be cost-effective when considering direct health benefits, with median cost per disability adjusted life year averted of approximately $48 USD and $94 USD, respectively. CONCLUSIONS: Testing for viral infections is unlikely to be cost-effective when considering only direct health benefits to patients. Testing for prevalent bacterial pathogens can be cost-effective, having the benefit of informing not only whether treatment is required, but also as to the most appropriate antibiotic; this advantage, however, varies widely in response to heterogeneity in causes of fever. Testing for biomarkers of host inflammation is likely to be consistently cost-effective despite high heterogeneity, and can also offer substantial reductions in over-use of antimicrobials in viral infections.

Vorasan N, Pan-Ngum W, Jittamala P, Maneeboonyang W, Rukmanee P, Lawpoolsri S. 2015. Long-term impact of childhood malaria infection on school performance among school children in a malaria endemic area along the Thai-Myanmar border. Malar. J., 14 pp. 401. | Show Abstract

BACKGROUND: Children represent a high-risk group for malaria worldwide. Among people in Thailand who have malaria during childhood, some may have multiple malaria attacks during their lifetime. Malaria may affect neurological cognition in children, resulting in short-term impairment of memory and language functions. However, little is known regarding the long-term effects of malaria infection on cognitive function. This study examines the long-term impact of malaria infection on school performance among school children living in a malaria-endemic area along the Thai-Myanmar border. METHODS: A retrospective cohort study was conducted among school children aged 6-17 years in a primary-secondary school of a sub-district of Ratchaburi Province, Thailand. History of childhood malaria infection was obtained from the medical records of the sole malaria clinic in the area. School performance was assessed by using scores for the subjects Thai Language and Mathematics in 2014. Other variables, such as demographic characteristics, perinatal history, nutritional status, and emotional intelligence, were also documented. RESULTS: A total of 457 students were included, 135 (30 %) of whom had a history of uncomplicated malaria infection. About half of the malaria-infected children had suffered infection before the age of four years. The mean scores for both Mathematics and Thai Language decreased in relation to the increasing number of malaria attacks. Most students had their last malaria episode more than two years previously. The mean scores were not associated with duration since the last malaria attack. The association between malaria infection and school performance was not significant after adjusting for potential confounders, including gender, school absenteeism over a semester term, and emotional intelligence. CONCLUSIONS: This study characterizes the long-term consequences of uncomplicated malaria disease during childhood. School performance was not associated with a history of malaria infection, considering that most students had their last malaria infection more than two years previously. These findings indicate that the impact of uncomplicated malaria infection on school performance may not be prolonged.

Maude RR, de Jong HK, Wijedoru L, Fukushima M, Ghose A, Samad R, Hossain MA, Karim MR, Faiz MA, Parry CM, CMCH Typhoid Study Group. 2015. The diagnostic accuracy of three rapid diagnostic tests for typhoid fever at Chittagong Medical College Hospital, Chittagong, Bangladesh. Trop. Med. Int. Health, 20 (10), pp. 1376-84. | Show Abstract

OBJECTIVE: To determine the diagnostic accuracy of three rapid diagnostic tests (RDTs) for typhoid fever in febrile hospitalised patients in Bangladesh. METHODS: Febrile adults and children admitted to Chittagong Medical College Hospital, Bangladesh, were investigated with Bact/Alert(®) blood cultures and real-time PCR to detect Salmonella enterica Typhi and Paratyphi A and assays for Rickettsia, leptospirosis and dengue fever. Acute serum samples were examined with the LifeAssay (LA) Test-it™ Typhoid IgM lateral flow assay detecting IgM antibodies against S. Typhi O antigen, CTKBiotech Onsite Typhoid IgG/IgM Combo Rapid-test cassette lateral flow assay detecting IgG and IgM antibodies against S. Typhi O and H antigens and SD Bioline line assay for IgG and IgM antibodies against S. Typhi proteins. RESULTS: In 300 malaria smear-negative febrile patients [median (IQR) age of 13.5 (5-31) years], 34 (11.3%) had confirmed typhoid fever: 19 positive by blood culture for S. Typhi (three blood PCR positive) and 15 blood culture negative but PCR positive for S. Typhi in blood. The respective sensitivity and specificity of the three RDTs in patients using a composite reference standard of blood culture and/or PCR-confirmed typhoid fever were 59% and 61% for LifeAssay, 59% and 74% for the CTK IgM and/or IgG, and 24% and 96% for the SD Bioline RDT IgM and/or IgG. The LifeAssay RDT had a sensitivity of 63% and a specificity of 91% when modified with a positive cut-off of ≥2+ and analysed using a Bayesian latent class model. CONCLUSIONS: These typhoid RDTs demonstrated moderate diagnostic accuracies, and better tests are needed.

White LJ, Flegg JA, Phyo AP, Wiladpai-ngern JH, Bethell D, Plowe C, Anderson T, Nkhoma S, Nair S, Tripura R et al. 2015. Defining the in vivo phenotype of artemisinin-resistant falciparum malaria: a modelling approach. PLoS Med., 12 (4), pp. e1001823. | Show Abstract

BACKGROUND: Artemisinin-resistant falciparum malaria has emerged in Southeast Asia, posing a major threat to malaria control. It is characterised by delayed asexual-stage parasite clearance, which is the reference comparator for the molecular marker 'Kelch 13' and in vitro sensitivity tests. However, current cut-off values denoting slow clearance based on the proportion of individuals remaining parasitaemic on the third day of treatment ('day-3'), or on peripheral blood parasite half-life, are not well supported. We here explore the parasite clearance distributions in an area of artemisinin resistance with the aim refining the in vivo phenotypic definitions. METHODS AND FINDINGS: Data from 1,518 patients on the Thai-Myanmar and Thai-Cambodian borders with parasite half-life assessments after artesunate treatment were analysed. Half-lives followed a bimodal distribution. A statistical approach was developed to infer the characteristics of the component distributions and their relative contribution to the composite mixture. A model representing two parasite subpopulations with geometric mean (IQR) parasite half-lives of 3.0 (2.4-3.9) hours and 6.50 (5.7-7.4) hours was consistent with the data. For individual patients, the parasite half-life provided a predicted likelihood of an artemisinin-resistant infection which depends on the population prevalence of resistance in that area. Consequently, a half-life where the probability is 0.5 varied between 3.5 and 5.5 hours. Using this model, the current 'day-3' cut-off value of 10% predicts the potential presence of artemisinin-resistant infections in most but not all scenarios. These findings are relevant to the low-transmission setting of Southeast Asia. Generalisation to a high transmission setting as in regions of Sub-Saharan Africa will need additional evaluation. CONCLUSIONS: Characterisation of overlapping distributions of parasite half-lives provides quantitative insight into the relationship between parasite clearance and artemisinin resistance, as well as the predictive value of the 10% cut-off in 'day-3' parasitaemia. The findings are important for the interpretation of in vitro sensitivity tests and molecular markers for artemisinin resistance and for contextualising the 'day 3' threshold to account for initial parasitaemia and sample size.

Cooper BS, Boni MF, Pan-ngum W, Day NP, Horby PW, Olliaro P, Lang T, White NJ, White LJ, Whitehead J. 2015. Evaluating clinical trial designs for investigational treatments of Ebola virus disease. PLoS Med., 12 (4), pp. e1001815. | Show Abstract

BACKGROUND: Experimental treatments for Ebola virus disease (EVD) might reduce EVD mortality. There is uncertainty about the ability of different clinical trial designs to identify effective treatments, and about the feasibility of implementing individually randomised controlled trials during an Ebola epidemic. METHODS AND FINDINGS: A treatment evaluation programme for use in EVD was devised using a multi-stage approach (MSA) with two or three stages, including both non-randomised and randomised elements. The probabilities of rightly or wrongly recommending the experimental treatment, the required sample size, and the consequences for epidemic outcomes over 100 d under two epidemic scenarios were compared for the MSA, a sequential randomised controlled trial (SRCT) with up to 20 interim analyses, and, as a reference case, a conventional randomised controlled trial (RCT) without interim analyses. Assuming 50% 14-d survival in the population treated with the current standard of supportive care, all designs had similar probabilities of identifying effective treatments correctly, while the MSA was less likely to recommend treatments that were ineffective. The MSA led to a smaller number of cases receiving ineffective treatments and faster roll-out of highly effective treatments. For less effective treatments, the MSA had a high probability of including an RCT component, leading to a somewhat longer time to roll-out or rejection. Assuming 100 new EVD cases per day, the MSA led to between 6% and 15% greater reductions in epidemic mortality over the first 100 d for highly effective treatments compared to the SRCT. Both the MSA and SRCT led to substantially fewer deaths than a conventional RCT if the tested interventions were either highly effective or harmful. In the proposed MSA, the major threat to the validity of the results of the non-randomised components is that referral patterns, standard of care, or the virus itself may change during the study period in ways that affect mortality. Adverse events are also harder to quantify without a concurrent control group. CONCLUSIONS: The MSA discards ineffective treatments quickly, while reliably providing evidence concerning effective treatments. The MSA is appropriate for the clinical evaluation of EVD treatments.

Suwanpakdee S, Kaewkungwal J, White LJ, Asensio N, Ratanakorn P, Singhasivanon P, Day NP, Pan-Ngum W. 2015. Spatio-temporal patterns of leptospirosis in Thailand: is flooding a risk factor? Epidemiol. Infect., 143 (10), pp. 2106-15. | Show Abstract

We studied the temporal and spatial patterns of leptospirosis, its association with flooding and animal census data in Thailand. Flood data from 2010 to 2012 were extracted from spatial information taken from satellite images. The incidence rate ratio (IRR) was used to determine the relationship between spatio-temporal flooding patterns and the number of human leptospirosis cases. In addition, the area of flood coverage, duration of waterlogging, time lags between flood events, and a number of potential animal reservoirs were considered in a sub-analysis. There was no significant temporal trend of leptospirosis over the study period. Statistical analysis showed an inconsistent relationship between IRR and flooding across years and regions. Spatially, leptospirosis occurred repeatedly and predominantly in northeastern Thailand. Our findings suggest that flooding is less influential in leptospirosis transmission than previously assumed. High incidence of the disease in the northeastern region is explained by the fact that agriculture and animal farming are important economic activities in this area. The periodic rise and fall of reported leptospirosis cases over time might be explained by seasonal exposure from rice farming activities performed during the rainy season when flood events often occur. We conclude that leptospirosis remains an occupational disease in Thailand.

Monyarit S, Pan-ngum W, Lawpoolsri S, Yimsamran S, Pongnumkul S, Kaewkungwal J, Singhasivanon P. 2014. Advantages of using voiced questionnaire and image capture application for data collection from a minority group in rural areas along the Thailand-Myanmar border. Inform Prim Care, 21 (4), pp. 179-88. | Show Abstract

AIMS: To compare the quality of data collection via electronic data capture (EDC) with voiced questionnaire (QNN) and data image capture features using a tablet versus standard paper-based QNN, to assess the user's perception of using the EDC tool, and to compare user satisfaction with the two methods. STUDY DESIGN: Randomised cross-over study. Study sites: This study was conducted in two villages along the Thailand-Myanmar border. METHODOLOGY: This study included 30 community health volunteers (CHVs) and 120 Karen hill tribe villagers. Employing a cross-over study design, the CHVs were allocated randomly to two groups, in which they performed interviews in different sequences using EDC and QNN. RESULTS: Data discrepancies were found between the two data-collection methods, when data from the paper-based and image-capture methods were compared, and when conducting skip pattern questions. More than 90% of the CHVs perceived the EDC to be useful and easy to use. Both interviewers and interviewees were more satisfied with the EDC compared with QNN in terms of format, ease of use, and system speed. CONCLUSION: The EDC can effectively be used as an alternative method to paper-based QNNs for data collection. It produces more accurate data that can be considered evidence-based.

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