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.

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.

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.

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.

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.

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.

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.

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.

Short report: immune response and occurrence of dengue infection in thai children three to eight years after vaccination with live attenuated tetravalent dengue vaccine.

From 1992 to 1997, 140 Thai children 4-15 years of age received an investigational live attenuated tetravalent dengue vaccine (LATDV). These children were contacted 3-8 years later in 2001 to assess humoral immunity and investigate whether they were subsequently at higher risk of developing severe dengue. One hundred thirteen were successfully contacted and participated in this retrospective cohort study with two age- and address-matched controls per vaccinee. The number of vaccinated subjects with neutralizing antibodies increased compared with 3-8 years earlier, which was probably due to subsequent wild-type dengue infections. There were no excess hospitalizations for clinically suspected dengue fever (DF) or dengue hemorrhagic fever (DHF) in vaccinees (one with DF and three with DHF) compared with controls (14 with DHF). Results suggest that preexisting dengue antibodies induced by LATDV do not enhance dengue illness, and the use of the vaccine in a dengue-endemic area is safe.

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.

Life-saving rectal artesunate for complicated malaria in children.

We report the effectiveness of two regimens of rectal artesunate formulation in treating 13 Thai children with cerebral/complicated falciparum malaria. The drug was given at an initial dose of 40 mg/kg bodyweight, in 3 or 4 divided doses in the first 24 hours, followed by 10 mg/kg bodyweight once daily for three consecutive days. Mefloquine, at a dose of 15 mg/kg bodyweight was given orally at 72 hours after the initial dose of artesunate, followed by 10 mg/kg bodyweight 6 hours later. Three cases with cerebral malaria gained consciousness within 20 hours of artesunate administration. The median time required for reduction of parasitemia by 90% of the initial value (P90) in 13 children was 11.2 hours. No recrudescence was observed in any of the patients during the 28-day follow-up period. Plasma concentrations of artesunate and dihydroartemisinin (active plasma metabolite of artesunate) measured in two patients who received the high initial dose regimen (20 mg/ kg bodyweight) suggested rapid absorption and adequate plasma concentrations of both compounds following the administration of artesunate via the rectal route. Further studies for the optimized regimen of rectal artesunate in the treatment of cerebral/complicated childhood falciparum malaria in areas of multidrug resistance are warranted.

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.

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.

Safety and immunogenicity of a three dose regimen of two tetravalent live-attenuated dengue vaccines in five- to twelve-year-old Thai children.

OBJECTIVE: The safety and immunogenicity of tetravalent live-attenuated dengue vaccines after a three dose vaccination series were evaluated in Thai children. METHOD: One hundred three healthy flavivirus-seronegative schoolchildren ages 5 to 12 years were randomized to receive either dengue vaccine containing 3, 2, 1 and 2 log10 of the 50% cell culture infective dose, respectively, of the live-attenuated dengue vaccine serotypes 1, 2, 3 and 4 per dose (F3212; n = 40) or 3, 3, 1 and 3 log10 of the 50% cell culture infective dose (F3313; n = 42) or purified Vero cell rabies vaccine (control group; n = 21) given in a two dose schedule (3 to 5 months apart). A third dose was administered 8 to 12 months after the second dose to 90 subjects. Safety and immunogenicity were evaluated within 28 days after each injection. RESULTS: No serious adverse event related to the vaccines occurred. Most children experienced mild to moderate fever, rash, headache and myalgia occurring within 12 days after Dose 1 and generally lasting 3 days or less. One subject in Group F3212 had a 1-week dengue-like fever. Reactogenicity was minimal after Doses 2 and 3. Transient mild variations in liver enzymes and hematologic indices were noted mainly after Dose 1. After the third dose 89% of the subjects in Group F3212 seroconverted (neutralizing antibody response, > or =10) to all four serotypes, and all children in Group F3313 seroconverted. CONCLUSION: This study demonstrates a moderate although improvable reactogenicity and high seroconversion rates against the four serotypes of dengue after a three dose schedule of tetravalent live-attenuated dengue vaccine in children.

Safety and immunogenicity of tetravalent live-attenuated dengue vaccines in Thai adult volunteers: role of serotype concentration, ratio, and multiple doses.

Dengue fever, caused by four serotypes of a mosquito-borne virus, is a growing problem in tropical countries. Currently, there is no treatment or vaccine. We evaluated safety and immunogenicity of two doses, given six months apart, of seven formulations of dengue tetravalent live-attenuated vaccine (containing different concentrations of the component viruses) versus placebo in 59 flavivirus-seronegative Thai adults. The first dose was the more reactogenic. Most volunteers experienced clinically moderate fever, headache, myalgia, eye pain or rash 7-11 days after injection, generally lasting three days or less. Modest decreases in platelets and neutrophils were observed. After one dose, 58% of dengue recipients seroconverted (neutralizing antibody level > or = 1:10) against > or = 3 serotypes; 35% seroconverted against all four. After the second dose, seroconversion was 76% and 71%, respectively. All subjects seroconverted to serotype 3 after one dose. Serotype 4 elicited the lowest primary response but the highest increase in seroconversion after the second dose.

Prevalence of intestinal parasitic infection among Thai people with mental handicaps.

The prevalence of intestinal parasitic infection was studied by stool examination in institutionalized and non-institutionalized Thai people with mental handicaps. It was found that the prevalence of infection was much higher in institutionalized (57.6%) than in non-institutionalized people (7.5%). The common parasites found in institutionalized people were Trichuris trichiura (29.7%), Entamoeba coli (23.1%), Giardia intestinalis (8.0%), Hymenolepis nana (7.8%), and Entamoeba histolytica/dispar (7.1%). Institutionalized mentally handicapped people should be considered as a high risk group for intestinal parasitic infection and a parasitic control measure should be emphasized.

Single-dose therapy for giardiasis in school-age children.

A randomized controlled trial was carried out to study the efficacy of combined albendazole and praziquantel in the treatment of giardiasis in school-age children. Eighty-four children were randomly allocated to 3 groups: group 1 (n = 31) albendazole 400 mg combined with praziquantel 20 mg/kg; group 2 (n = 26) albendazole 800 mg as a single dose; group 3 (n = 27) tinidazole 50 mg/kg as a single dose. The treatment was considered curative when Giardia was not found in two consecutive stool samples. The parasitological cure rate was 74.2% for combined single-dose albendazole-praziquantel, 50% and 92.6% in the albendazole and tinidazole groups respectively (p = 0.0023). There was no statistically significant difference between the cure rates of the combined regimen and tinidazole (p > 0.05). This combined regimen was considered safe, with only minor side-effects being observed. Of the single-dose regimens, tinidazole still achieves the highest parasitological cure rate for giardiasis. The albendazole-praziquantel combined regimen may be an alternative single-dose therapy for giardiasis in children, especially as this combination will eradicate common intestinal protozoa and co-existing helminths. Whether the dosage of this combination treatment should be adjusted for G. intestinalis remains to be established by further study.