Predictive model for bacterial late-onset neonatal sepsis in a tertiary care hospital in Thailand.

BACKGROUND: Early diagnosis of neonatal sepsis is essential to prevent severe complications and avoid unnecessary use of antibiotics. The mortality of neonatal sepsis is over 18%in many countries. This study aimed to develop a predictive model for the diagnosis of bacterial late-onset neonatal sepsis. METHODS: A case-control study was conducted at Queen Sirikit National Institute of Child Health, Bangkok, Thailand. Data were derived from the medical records of 52 sepsis cases and 156 non-sepsis controls. Only proven bacterial neonatal sepsis cases were included in the sepsis group. The non-sepsis group consisted of neonates without any infection. Potential predictors consisted of risk factors, clinical conditions, laboratory data, and treatment modalities. The model was developed based on multiple logistic regression analysis. RESULTS: The incidence of late proven neonatal sepsis was 1.46%. The model had 6 significant variables: poor feeding, abnormal heart rate (outside the range 100-180 x/min), abnormal temperature (outside the range 36o-37.9 °C), abnormal oxygen saturation, abnormal leucocytes (according to Manroe's criteria by age), and abnormal pH (outside the range 7.27-7.45). The area below the Receiver Operating Characteristics (ROC) curve was 95.5%. The score had a sensitivity of 88.5% and specificity of 90.4%. CONCLUSION: A predictive model and a scoring system were developed for proven bacterial late-onset neonatal sepsis. This simpler tool is expected to somewhat replace microbiological culture, especially in resource-limited settings.

Immunogenicity and safety of inactivated chromatographically purified Vero cell-derived Japanese encephalitis vaccine in Thai children.

Inactivated mouse-brain-derived Japanese encephalitis vaccine has a worrisome safety profile and the live attenuated vaccine is unsuitable in immunodeficiency. This study aimed to evaluate the immunogenicity and safety of an inactivated chromatographically purified Vero-cell-derived JE vaccine (CVI-JE, Beijing P-3 strain) in children. 152 healthy Thai children, with an average (SD) age of 14.4 (3.8) months, received 3 doses of CVI-JE on days 0, 7-28, and one year. Homologous JE neutralizing antibody titers (NT) were measured. All subjects had seroprotection [geometric mean titer (GMT) 150] 28 days' post 2nd vaccination. The seroprotection rates at 1 year after primary series and and 1 month after the booster were 89.3% (GMT 49) and 100% (GMT 621), respectively. Local and systemic reactions-fever (17.6%), vomiting (8%), and poor appetite (5.3%)-were noted within 28 days' post-vaccination. All these symptoms were self-limited. CONCLUSIONS: CVI-JE is safe, immunogenic, and provided high NT.

Report on: "The 1st Workshop on National Immunization Programs and Vaccine Coverage in ASEAN Countries, April 30, 2015, Pattaya, Thailand".

The 1st Workshop on National Immunization Programs and Vaccine Coverage in Association of Southeast Asian Nations (ASEAN) Countries Group (WNIPVC-ASEAN) held a meeting on April 30, 2015, Pattaya, Thailand under the auspices of the Pediatric Infectious Diseases Society and the World Health Organization (WHO). Reports on the current status and initiatives of the national immunization program (NIP) in each ASEAN countries that attended were presented. These reports along with survey data collected from ministries of health in ASEAN countries NIPs demonstrate that good progress has been made toward the goal of the Global Vaccine Action Plan (GVAP). However, some ASEAN countries have fragile health care systems that still have insufficient vaccine coverage of some basic EPI antigens. Most ASEAN countries still do not have national coverage of some new and underused vaccines, and raising funds for the expansion of NIPs is challenging. Also, there is insufficient research into disease burden of vaccine preventable diseases and surveillance. Health care workers must advocate NIPs to government policy makers and other stakeholders as well as improve research and surveillance to achieve the goals of the GVAP.

DENGUE INFECTION IN PREGNANCY.

While dengue infection is still on the increase in adults in Thailand, it also affects pregnant women, especially pregnant teenagers. This study was designed to investigate dengue infection during pregnancy. Seven cases of dengue infection in pregnant women were admitted to Ban Pong Hospital, Ratchaburi, Thailand, between 2008 and 2012. Dengue infection presented in all pregnancy trimesters. There were two severe cases: one was dengue hemorrhagic fever in the first trimester, and the second was at a critical stage of the infection during labor. There were three cases of abortion. These three cases included one complete, one incomplete, and one threatened abortion, with rising hematocrits of 22.8%, 17.1%, and 14.7%, respectively. Two out of the three teenage pregnancies experienced complete and threatened abortions, while the third abortion case was a threatened abortion pregnancy at the critical stage of infection during intrapartum. Leukopenia was identified in six out of seven women. Low baseline hematocrit and low maximum hematocrit were laboratory findings. Clinical management involved administration of intravenous fluids and antipyretics. Favorable outcomes can be obtained through early diagnosis and supportive treatment. The morbidity profile can be more serious in teenage pregnancies. Additional studies should be conducted to establish whether low baseline hematocrit, low percentages of rising hematocrit in pregnant women with dengue infection, and abortions (with a high degree of increasing hematocrit during the critical stage of the disease) are typical clinical signs.

Ethical considerations in malaria research proposal review: empirical evidence from 114 proposals submitted to an Ethics Committee in Thailand.

BACKGROUND: Malaria research is typically conducted in developing countries in areas of endemic disease. This raises specific ethical issues, including those related to local cultural concepts of health and disease, the educational background of study subjects, and principles of justice at the community and country level. Research Ethics Committees (RECs) are responsible for regulating the ethical conduct of research, but questions have been raised whether RECs facilitate or impede research, and about the quality of REC review itself. This study examines the review process for malaria research proposals submitted to the Ethics Committee of the Faculty of Tropical Medicine at Mahidol University, Thailand. METHODS: Proposals for all studies submitted for review from January 2010 to December 2014 were included. Individual REC members' reviewing forms were evaluated. Ethical issues (e.g., scientific merit, risk-benefit, sample size, or informed-consent) raised in the forms were counted and analysed according to characteristics, including study classification/design, use of specimens, study site, and study population. RESULTS: All 114 proposals submitted during the study period were analysed, comprising biomedical studies (17 %), drug trials (13 %), laboratory studies (24 %) and epidemiological studies (46 %). They included multi-site (13 %) and international studies (4 %), and those involving minority populations (28 %), children (17 %) and pregnant women (7 %). Drug trials had the highest proportion of questions raised for most ethical issues, while issues concerning privacy and confidentiality tended to be highest for laboratory and epidemiology studies. Clarifications on ethical issues were requested by the ethics committee more for proposals involving new specimen collection. Studies involving stored data and specimens tended to attract more issues around privacy and confidentiality. Proposals involving minority populations were more likely to raise issues than those that did not. Those involving vulnerable populations were more likely to attract concerns related to study rationale and design. CONCLUSIONS: This study stratified ethical issues raised in a broad spectrum of research proposals. The Faculty of Tropical Medicine at Mahidol University is a significant contributor to global malaria research output. The findings shed light on the ethical review process that may be useful for stakeholders, including researchers, RECs and sponsors, conducting malaria research in other endemic settings.

Neutralizing dengue antibody in pregnant Thai women and cord blood.

BACKGROUND: The WHO 'Global Strategy for Dengue Prevention and Control, 2012-2020' addresses the growing need for the treatment of dengue, and targets a 25% reduction in morbidity and 50% in mortality (using 2010 estimates as baseline). Achieving these goals requires future dengue prevention strategies that will employ both potential vaccines and sustainable vector-control measures. Maternally transferred dengue antibody is an important factor in determining the optimal age for dengue vaccination. OBJECTIVES: To estimate the seroprevalence of dengue antibodies among mothers living in an area of high endemicity--Ban Pong, Ratchaburi Province--and to assess maternal dengue antibodies transferred to cord blood. MATERIALS & METHODS: A cross-sectional study was conducted with 141 pregnant women who delivered at Ban Pong Hospital, Ratchaburi, Thailand. Maternal-cord paired sera were tested for dengue neutralizing (NT) antibody by PRNT50 assay. A ratio of ≥ 1:10 NT titer to dengue serotype was considered seropositive. RESULTS: Most mothers (137/141, 97.2%) had NT antibodies to at least one dengue serotype in their sera. At birth, the proportion of cord sera with NT antibodies to DEN-1, DEN-2, DEN-3, and DEN-4, were high and similar to the sera of their mothers, at 93.6%, 97.2%, 97.9%, and 92.2%, respectively. The dengue geometric mean titers (GMT) in cord blood were significantly higher than the maternal antibodies (p<0.001): highest in DEN-2, followed by DEN-3, and then DEN-1. The GMT of DEN-4 was the lowest among all four serotypes. CONCLUSIONS: Dengue infection is highly prevalent among pregnant women in this dengue-endemic area. Most of the cord blood had transferred dengue antibodies, which may have an impact on the disease burden in this population.

Congenital toxoplasmosis: an uncommon disease in Thailand.

BACKGROUND: The seroprevalence of toxoplasma antibodies in pregnant women and the prevalence of congenital infection differ widely between countries. A few cases of congenital toxoplasmosis diagnosed after the neonatal period, with long-term sequelae, have been reported in Thailand. No data on the prevalence of congenital toxoplasmosis have been documented and no screening for toxoplasmosis during pregnancy has been undertaken in Thailand. SUBJECTS AND METHODS: A questionnaire enquiring about cases of congenital toxoplasmosis during 1995-2013 was distributed to paediatricians in referral and university hospitals in Thailand and the responses were analysed. Specific toxoplasma IgM antibody and clinical features were used for diagnosis. RESULTS: There were 20 cases - 13 most likely and seven suspected cases of congenital toxoplasmosis. Most patients had systemic manifestations, but only 25% of diagnosed patients exhibited the classic triad of hydrocephalus, cerebral calcification and chorioretinitis. One of the five deceased patients lived beyond the age of 13 years and died of a pulmonary infection. All 15 surviving cases developed deafness, visual impairment or developmental delay. CONCLUSIONS: Twenty cases of congenital toxoplasmosis are reported. Delayed diagnosis and treatment resulted in a poor outcome. The prevention of toxoplasmosis in pregnant women and prompt diagnosis and appropriate treatment of congenital toxoplasmosis should be a priority in order to prevent a poor outcome in infected children.

Is your ethics committee efficient? Using "IRB Metrics" as a self-assessment tool for continuous improvement at the Faculty of Tropical Medicine, Mahidol University, Thailand.

Tensions between researchers and ethics committees have been reported in several institutions. Some reports suggest researchers lack confidence in the quality of institutional review board (IRB) reviews, and that emphasis on strict procedural compliance and ethical issues raised by the IRB might unintentionally lead to delays in correspondence between researchers and ethics committees, and/or even encourage prevarication/equivocation, if researchers perceive committee concerns and criticisms unjust. This study systematically analyzed the efficiency of different IRB functions, and the relationship between efficiency and perceived quality of the decision-making process. The major purposes of this study were thus (1) to use the IRB Metrics developed by the Faculty of Tropical Medicine, Mahidol University, Thailand (FTM-EC) to assess the operational efficiency and perceived effectiveness of its ethics committees, and (2) to determine ethical issues that may cause the duration of approval process to be above the target limit of 60 days. Based on a literature review of definitions and methods used and proposed for use, in assessing aspects of IRB quality, an "IRB Metrics" was developed to assess IRB processes using a structure-process-outcome measurement model. To observe trends in the indicators evaluated, data related to all protocols submitted to the two panels of the FTM-EC (clinical and non-clinical), between January 2010-September 2013, were extracted and analyzed. Quantitative information based on IRB Metrics structure-process-outcome illuminates different areas for internal-process improvement. Ethical issues raised with researchers by the IRB, which were associated with the duration of the approval process in protocol review, could be considered root causes of tensions between the parties. The assessment of IRB structure-process-outcome thus provides a valuable opportunity to strengthen relationships and reduce conflicts between IRBs and researchers, with positive outcomes for all parties involved in the conduct of human-subject research.

Ethical issues in research involving minority populations: the process and outcomes of protocol review by the Ethics Committee of the Faculty of Tropical Medicine, Mahidol University, Thailand.

BACKGROUND: Recruiting minorities into research studies requires special attention, particularly when studies involve "extra-vulnerable" participants with multiple vulnerabilities, e.g., pregnant women, the fetuses/neonates of ethnic minorities, children in refugee camps, or cross-border migrants. This study retrospectively analyzed submissions to the Ethics Committee of the Faculty of Tropical Medicine (FTM-EC) in Thailand. Issues related to the process and outcomes of proposal review, and the main issues for which clarification/revision were requested on studies, are discussed extensively. METHODS: The study data were extracted from proposals and amendments submitted to the FTM-EC during the period October 2009 - September 2012, and then analyzed qualitatively and quantitatively. The main issues for clarification/revision were analyzed by thematic content analysis. RESULTS: 373 proposals were submitted; 44 studies involved minority groups with 21 extra-vulnerable minorities. All clinical and 2/3 of non-clinical studies submitted for initial review underwent full-board review. For combined clinical and non-clinical study submissions, 92.1% were referred back to the investigators and approved after clarification/revision, while 2.7% were deferred due to major/critical changes, and 2.1% not approved due to substantial violations of ethical principles. The main issues needing clarification/revision differed between all studies and those involving minorities: participant information sheet (62.2% vs. 86.4%), informed consent/assent form (51.2% vs. 86.4%), and research methodology (80.7% vs. 84.1%), respectively. The main ethical issues arising during the meetings, regarding studies involving minorities, included ensuring no exploitation, coercion, or pressure on the minority to participate; methodology not affecting their legal status; considering ethnicity and cultural structure; and providing appropriate compensation. CONCLUSION: Delays in the approval or non-approval of studies involving minorities were mainly due to major or minor deviations from acceptable ethical standards and/or unclear research methodology. The FTM-EC has employed several mechanisms in its operations, including transparency in the review process, building good relationships via open communication with investigators, requesting investigators to consider closely the necessity to enroll minority groups and the risk-benefits for individuals and their communities, and the inclusion of minority-community engagement when developing the proposal. Other effective activities include annual study-site inspections, and offering refresher courses to raise awareness of minority and vulnerability issues among researchers.

Protective efficacy of the recombinant, live-attenuated, CYD tetravalent dengue vaccine in Thai schoolchildren: a randomised, controlled phase 2b trial.

BACKGROUND: Roughly half the world's population live in dengue-endemic countries, but no vaccine is licensed. We investigated the efficacy of a recombinant, live, attenuated tetravalent dengue vaccine. METHODS: In this observer-masked, randomised, controlled, monocentre, phase 2b, proof-of-concept trial, healthy Thai schoolchildren aged 4-11 years were randomly assigned (2:1) to receive three injections of dengue vaccine or control (rabies vaccine or placebo) at months 0, 6, and 12. Randomisation was by computer-generated permuted blocks of six and participants were assigned with an interactive response system. Participants were actively followed up until month 25. All acute febrile illnesses were investigated. Dengue viraemia was confirmed by serotype-specific RT-PCR and non-structural protein 1 ELISA. The primary objective was to assess protective efficacy against virologically confirmed, symptomatic dengue, irrespective of severity or serotype, occurring 1 month or longer after the third injection (per-protocol analysis). This trial is registered at ClinicalTrials.gov, NCT00842530. FINDINGS: 4002 participants were assigned to vaccine (n=2669) or control (n=1333). 3673 were included in the primary analysis (2452 vaccine, 1221 control). 134 cases of virologically confirmed dengue occurred during the study. Efficacy was 30·2% (95% CI -13·4 to 56·6), and differed by serotype. Dengue vaccine was well tolerated, with no safety signals after 2 years of follow-up after the first dose. INTERPRETATION: These data show for the first time that a safe vaccine against dengue is possible. Ongoing large-scale phase 3 studies in various epidemiological settings will provide pivotal data for the CYD dengue vaccine candidate. FUNDING: Sanofi Pasteur.

Dengue infection in children in Ratchaburi, Thailand: a cohort study. I. Epidemiology of symptomatic acute dengue infection in children, 2006-2009.

BACKGROUND: There is an urgent need to field test dengue vaccines to determine their role in the control of the disease. Our aims were to study dengue epidemiology and prepare the site for a dengue vaccine efficacy trial. METHODS AND FINDINGS: We performed a prospective cohort study of children in primary schools in central Thailand from 2006 through 2009. We assessed the epidemiology of dengue by active fever surveillance for acute febrile illness as detected by school absenteeism and telephone contact of parents, and dengue diagnostic testing. Dengue accounted for 394 (6.74%) of the 5,842 febrile cases identified in 2882, 3104, 2717 and 2312 student person-years over the four years, respectively. Dengue incidence was 1.77% in 2006, 3.58% in 2007, 5.74% in 2008 and 3.29% in 2009. Mean dengue incidence over the 4 years was 3.6%. Dengue virus (DENV) types were determined in 333 (84.5%) of positive specimens; DENV serotype 1 (DENV-1) was the most common (43%), followed by DENV-2 (29%), DENV-3 (20%) and DENV-4 (8%). Disease severity ranged from dengue hemorrhagic fever (DHF) in 42 (10.5%) cases, dengue fever (DF) in 142 (35.5%) cases and undifferentiated fever (UF) in 210 (52.5%) cases. All four DENV serotypes were involved in all disease severity. A majority of cases had secondary DENV infection, 95% in DHF, 88.7% in DF and 81.9% in UF. Two DHF (0.5%) cases had primary DENV-3 infection. CONCLUSION: The results illustrate the high incidence of dengue with all four DENV serotypes in primary school children, with approximately 50% of disease manifesting as mild clinical symptoms of UF, not meeting the 1997 WHO criteria for dengue. Severe disease (DHF) occurred in one tenth of cases. Data of this type are required for clinical trials to evaluate the efficacy of dengue vaccines in large scale clinical trials.

Dengue infection in children in Ratchaburi, Thailand: a cohort study. II. Clinical manifestations.

BACKGROUND: Dengue infection is one of the most important mosquito-borne diseases. More data regarding the disease burden and the prevalence of each clinical spectrum among symptomatic infections and the clinical manifestations are needed. This study aims to describe the incidence and clinical manifestations of symptomatic dengue infection in Thai children during 2006 through 2008. STUDY DESIGN: This study is a school-based prospective open cohort study with a 9,448 person-year follow-up in children aged 3-14 years. Active surveillance for febrile illnesses was done in the studied subjects. Subjects who had febrile illness were asked to visit the study hospital for clinical and laboratory evaluation, treatment, and serological tests for dengue infection. The clinical data from medical records, diary cards, and data collection forms were collected and analyzed. RESULTS: Dengue infections were the causes of 12.1% of febrile illnesses attending the hospital, including undifferentiated fever (UF) (49.8%), dengue fever (DF) (39.3%) and dengue hemorrhagic fever (DHF) (10.9%). Headache, anorexia, nausea/vomiting and myalgia were common symptoms occurring in more than half of the patients. The more severe dengue spectrum (i.e., DHF) had higher temperature, higher prevalence of nausea/vomiting, abdominal pain, rash, diarrhea, petechiae, hepatomegaly and lower platelet count. DHF cases also had significantly higher prevalence of anorexia, nausea/vomiting and abdominal pain during day 3-6 and diarrhea during day 4-6 of illness. The absence of nausea/vomiting, abdominal pain, diarrhea, petechiae, hepatomegaly and positive tourniquet test may predict non-DHF. CONCLUSION: Among symptomatic dengue infection, UF is most common followed by DF and DHF. Some clinical manifestations may be useful to predict the more severe disease (i.e., DHF). This study presents additional information in the clinical spectra of symptomatic dengue infection.

Decay and persistence of maternal dengue antibodies among infants in Bangkok.

Abstract. Maternal dengue antibodies are important in determining the optimal age of dengue vaccination, but no study has quantified the heterogeneity of antibody decay and persistence in infants. We used longitudinal regression methods and survival analysis to measure decay and persistence times of serotype-specific neutralizing antibodies in 139 infants in Bangkok. A biphasic decay pattern was found with half-life times of 24-29 days between birth and 3 months and 44-150 days after 3 months. Atypical decay rates were found in 17% of infants for dengue virus-1 and -4. Median persistence times of plaque reduction neutralization tests > 10 ranged from 6 to 9 months. Persistence times for individuals could not be predicted based on antibody values at birth. Vaccination against dengue before 12 months of age would be ineffective if maternal antibodies at plaque reduction neutralization test levels below 80 interfere with vaccine uptake. Projections of average antibody persistence based on values at birth should be avoided in studies on dengue pathogenesis in infants.

Dengue antibody in Thai children from maternally transferred antibody to acquired infection.

This prospective cohort study examined serotype-specific neutralizing serum antibodies to dengue in 55 maternal-newborn pairs, at 3, 6, 9, 12, 18, and 24 months, and again at 4 to 8 years of age. In all, 95% of the mothers had neutralizing antibody to at least one dengue serotype, and 92.7% of the maternally transferred antibody had disappeared in 12-month-old infants. In all, 31 infants had serologically confirmed dengue infection; 5 symptomatic and 29 inapparent infections were reported. The increasing trend of inapparent infections among the older age group warrants further study of the need for effective dengue vaccination beyond 2 years of age.

Pneumococcal infections in high-risk and immunocompromised hosts.

Streptococcus pneumoniae is an important cause of morbidity and mortality worldwide, it is responsible for invasive pneumococcal disease (IPD) (e.g. meningitis, bacteremic pneumonia and bacteremia) and non-IPD (e.g. pneumonia, acute otitis media, and sinusitis). IPD is preceded by nasopharyngeal colonization with high incidence of disease among young children, the elderly, persons with underlying medical conditions and immunocompromised hosts. The term "immunocompromised host" is generally applied to a variety of patients with various immune defects. The factors that contribute to the development of IPD include host immunity (specific and innate), genetic and environment. Specific defects in host responses to pneumococcal infections may due to very young age, deficiencies in levels of antibodies and complement factors, and splenic dysfunction. The combinations of these defects contribute to the increased rates of IPD. The immunocompromising and other conditions that predispose to pneumococcal disease were described.

A three-year clinical study on immunogenicity, safety, and booster response of purified chick embryo cell rabies vaccine administered intramuscularly or intradermally to 12- to 18-month-old Thai children, concomitantly with Japanese encephalitis vaccine.

After concomitant administration of purified chick embryo cell rabies vaccine and Japanese encephalitis vaccine to toddlers, adequate rabies and Japanese encephalitis virus neutralizing antibodies concentrations were demonstrated by day 49, 7 days after a booster at 1 year, and in the majorly at 3 years postvaccination. The inclusion of rabies vaccine in the expanded program on immunization should be considered in rabies endemic countries.

Age-specific prevalence of dengue antibodies in Bangkok infants and children.

Seroprevalence of dengue antibodies were determined in healthy children in Bangkok. At 9, 12, and 18 months of age 23%, 9%, and 17% of children respectively had neutralizing antibodies against one or more serotypes. DEN1 was the most prevalent, followed by DEN3, DEN2, and DEN4. Twelve children had serologic evidence of dengue infection. The nadir of dengue antibodies in children was at 12 months of age. In highly endemic areas, dengue vaccination could be needed at an early age.

Chronic diarrhea and abnormal serum immunoglobulin levels: a case report.

A 15-year-old Thai boy with multiple episodes of chronic diarrhea caused by giardiasis with hypogammaglobulin M and IgG4 subclass deficiency (but normal antibody response to rabies vaccine) is reported. Immune status follow-up is necessary for a definite diagnosis and proper management.