Antigenic distance between primary and secondary dengue infections correlates with disease risk.

Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection even in previously exposed individuals. In addition, for some pathogens, such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease through a mechanism known as antibody-dependent enhancement. However, it remains unclear whether the antigenic distances between an individual's first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalizations across years. Here, we develop a framework that combines detailed antigenic and genetic characterization of viruses with details on hospitalized cases from 21 years of dengue surveillance in Bangkok, Thailand, to identify the role of the antigenic profile of circulating viruses in determining disease risk. We found that the risk of hospitalization depended on both the specific order of infecting serotypes and the antigenic distance between an individual's primary and secondary infections, with risk maximized at intermediate antigenic distances. These findings suggest that immune imprinting helps determine dengue disease risk and provide a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.

Antigenic diversity and dengue disease risk.

Many pathogens continuously change their protein structure in response to immune-driven selection, resulting in weakened protection. In addition, for some pathogens such as dengue virus, poorly targeted immunity is associated with increased risk of severe disease, through a mechanism known as antibody-dependent enhancement. However, it remains a mystery whether the antigenic distance between an individual's first infection and subsequent exposures dictate disease risk, explaining the observed large-scale differences in dengue hospitalisations across years. Here we develop an inferential framework that combines detailed antigenic and genetic characterisation of viruses, and hospitalised cases from 21 years of surveillance in Bangkok, Thailand to identify the role of the antigenic profile of circulating viruses in determining disease risk. We find that the risk of hospitalisation depends on both the specific order of infecting serotypes and the antigenic distance between an individual's primary and secondary infections, with risk maximised at intermediate antigenic distances. These findings suggest immune imprinting helps determine dengue disease risk, and provides a pathway to monitor the changing risk profile of populations and to quantifying risk profiles of candidate vaccines.

Outcomes among Thai children with risk conditions hospitalized for pneumococcal disease (invasive or non-bacteraemic pneumonia): A multi-centre, observational study.

Objective: To describe the risk condition status and clinical outcomes among Thai children hospitalized with pneumococcal disease. Methods: In this retrospective analysis, children with invasive pneumococcal disease (IPD) or x-ray-confirmed non-bacteraemic pneumococcal pneumonia (NBPP) were identified from nine hospitals in Thailand between 2010 and 2019. Data on risk factors and outcomes were extracted from medical records. Results: In total, 413 cases were identified: 319 IPD and 94 NBPP. Overall, 133 (32.2%) patients were admitted to intensive care units and 11/406 (2.7%) died. Twenty-seven percent of IPD cases had at-risk conditions and 15% had high-risk conditions. Most IPD cases (32.9%) occurred in children aged 2-4 years, and most NBPP cases (28.7%) occurred in infants aged 0-11 months. Of 51 Streptococcus pneumoniae isolates collected, 41 (80%) were pneumococcal 13-valent conjugate vaccine serotypes. Only 5.1% of children had received a pneumococcal vaccine. Conclusions: Most children with IPD and NBPP did not have high-risk or at-risk conditions, while 42% had at-risk or high-risk conditions for pneumococcal disease. Very few children in the cohort had received any type of pneumococcal vaccine. Increasing the availability of pneumococcal conjugate vaccines should be considered to reduce the burden of pneumococcal disease among children in Thailand.

Dose recommendations for intravenous colistin in pediatric patients from a prospective, multicenter, population pharmacokinetic study.

OBJECTIVES: The aim of this study was to describe the population pharmacokinetics of intravenous colistin use in children and to propose optimal dosage regimens. METHODS: A prospective, multicenter, population pharmacokinetic (PPK) study was conducted. Phoenix 64 version 8.3 was used for the PPK analysis. Simulations were performed to estimate the probability of target attainment for patients achieving target plasma colistin average steady-state concentrations (Css,avg). RESULTS: A total of 334 plasma colistin concentrations were obtained from 79 pediatric patients with a median age (interquartile range) of 2.6 years (0.8-6.8 years); 73 (92.4%) were admitted to intensive care units. Colistin pharmacokinetics were adequately described by a one-compartment model with first-order elimination along with serum creatinine (SCr) as a significant covariate in colistin clearance. The simulation demonstrated that the recommended dose of 5 mg of colistin base activity (CBA)/kg/day resulted in 18.2-63.0% probability of achieving a target Css,avg of 2 mg/l. With a lower targeted Css,avg of 1 mg/l, colistin dosing with 7.5 mg and 5 mg of CBA/kg/day were adequate for children with SCr levels of 0.1-0.3 mg/dl and >0.3 mg/dl, respectively. CONCLUSIONS: SCr is a significant covariate in colistin clearance in children. Colistin dosing should be selected according to the patient's SCr level and the desired target Css,avg.

Reconstructing unseen transmission events to infer dengue dynamics from viral sequences.

For most pathogens, transmission is driven by interactions between the behaviours of infectious individuals, the behaviours of the wider population, the local environment, and immunity. Phylogeographic approaches are currently unable to disentangle the relative effects of these competing factors. We develop a spatiotemporally structured phylogenetic framework that addresses these limitations by considering individual transmission events, reconstructed across spatial scales. We apply it to geocoded dengue virus sequences from Thailand (N = 726 over 18 years). We find infected individuals spend 96% of their time in their home community compared to 76% for the susceptible population (mainly children) and 42% for adults. Dynamic pockets of local immunity make transmission more likely in places with high heterotypic immunity and less likely where high homotypic immunity exists. Age-dependent mixing of individuals and vector distributions are not important in determining spread. This approach provides previously unknown insights into one of the most complex disease systems known and will be applicable to other pathogens.

Seroprotection rate in adults after 1-dose, 2-dose, and 3-dose series of a reduced-diphtheria-tetanus toxoid vaccine (Td) during a diphtheria outbreak in Thailand.

To evaluate seroprotection of different dosing strategies of reduced-diphtheria-tetanus-toxoid vaccine (Td) for adults during a diphtheria outbreak in Thailand, we enrolled 160 healthcare workers and 161 adults aged 20-60 years old and measured diphtheria antitoxin (DAT) level before administration of a Td vaccine. We scheduled a second Td at 4-8 weeks and a third Td at 6-12 months interval. DAT was measured 4 weeks after each dose. DAT levels of ≥0.1 and ≥1 IU/mL were considered as seroprotective and long-term seroprotective. Persons achieving long-term seroprotection were not given a further dose. The baseline seroprotection rate was 32.6%, which increased to 87.1% (95% confidence interval, 83.4-90.8%) after one dose. The seroprotection rate increased slightly with additional doses. The immune response was lowest among persons 30-49 years of age. We suggest 1-dose Td for adults during a diphtheria outbreak, and a 2-dose series being considered for those born before 1980.

Listening panel agreement and characteristics of lung sounds digitally recorded from children aged 1-59 months enrolled in the Pneumonia Etiology Research for Child Health (PERCH) case-control study.

INTRODUCTION: Paediatric lung sound recordings can be systematically assessed, but methodological feasibility and validity is unknown, especially from developing countries. We examined the performance of acoustically interpreting recorded paediatric lung sounds and compared sound characteristics between cases and controls. METHODS: Pneumonia Etiology Research for Child Health staff in six African and Asian sites recorded lung sounds with a digital stethoscope in cases and controls. Cases aged 1-59 months had WHO severe or very severe pneumonia; age-matched community controls did not. A listening panel assigned examination results of normal, crackle, wheeze, crackle and wheeze or uninterpretable, with adjudication of discordant interpretations. Classifications were recategorised into any crackle, any wheeze or abnormal (any crackle or wheeze) and primary listener agreement (first two listeners) was analysed among interpretable examinations using the prevalence-adjusted, bias-adjusted kappa (PABAK). We examined predictors of disagreement with logistic regression and compared case and control lung sounds with descriptive statistics. RESULTS: Primary listeners considered 89.5% of 792 case and 92.4% of 301 control recordings interpretable. Among interpretable recordings, listeners agreed on the presence or absence of any abnormality in 74.9% (PABAK 0.50) of cases and 69.8% (PABAK 0.40) of controls, presence/absence of crackles in 70.6% (PABAK 0.41) of cases and 82.4% (PABAK 0.65) of controls and presence/absence of wheeze in 72.6% (PABAK 0.45) of cases and 73.8% (PABAK 0.48) of controls. Controls, tachypnoea, >3 uninterpretable chest positions, crying, upper airway noises and study site predicted listener disagreement. Among all interpretable examinations, 38.0% of cases and 84.9% of controls were normal (p<0.0001); wheezing was the most common sound (49.9%) in cases. CONCLUSIONS: Listening panel and case-control data suggests our methodology is feasible, likely valid and that small airway inflammation is common in WHO pneumonia. Digital auscultation may be an important future pneumonia diagnostic in developing countries.

The Happy Teen programme: a holistic outpatient clinic-based approach to prepare HIV-infected youth for the transition from paediatric to adult medical care services in Thailand.

INTRODUCTION: We developed an 18-month Happy Teen 2 (HT2) programme comprised of a one-day workshop, two half-day sessions, and three individual sessions to prepare HIV-infected youth for the transition from paediatric to adult HIV care services. We describe the programme and evaluate the change in youth's knowledge scores. METHODS: We implemented the HT2 programme among HIV-infected Thai youth aged 14-22 years who were aware of their HIV status and receiving care at two hospitals in Bangkok (Siriraj Hospital, Queen Sirikit National Institute of Child Health [QSNICH]). Staff interviewed youth using a standardized questionnaire to assess HIV and health-related knowledge at baseline and at 12 and 18 months while they participated in the programme. We examined factors associated with a composite knowledge score ≥95% at month 18 using logistic regression. RESULTS: During March 2014-July 2016, 192 of 245 (78%) eligible youth were interviewed at baseline. Of these, 161 (84%) returned for interviews at 12 and 18 months. Among the 161 youth, the median age was 17 years, 74 (46%) were female, and 99% were receiving antiretroviral treatment. The median composite score was 45% at baseline and increased to 82% at 12 months and 95% at 18 months (P < 0.001). The range of median knowledge scores for antiretroviral management, HIV monitoring, HIV services, and family planning significantly increased from baseline (range 0-75%) to (range 67-100%) at 12 months and to 100% at 18 months (P < 0.001). Almost all youth were able to describe education and career goals at 12 and 18 months compared to 75% at baseline. In multivariable analysis, a composite knowledge score at 18 months >95% was associated with education level >high school (aOR: 2.15, 95%CI, 1.03-4.48) and receipt care at QSNICH (aOR: 2.43, 95%CI, 1.18-4.98). Youth whose mother and father had died were less likely to have score ≥95% (aOR: 0.22, 95%CI, 0.07-0.67) than those with living parents. CONCLUSIONS: Knowledge useful for a successful transition from paediatric to adult HIV care increased among youth participating in the HT2 programme. Youth follow-up will continue to assess the impact of improved knowledge on outcomes following the transition to adult care services.

Treatment Outcomes of the Uncomplicated Upper Respiratory Tract Infection and Acute Diarrhea in Preschool Children Comparing Those with and without Antibiotic Prescription.

BACKGROUND: Upper respiratory tract infection (URI) and acute diarrhea are the two most common reasons for ambulatory visits among young children. Unnecessary use of antibiotics to treat such conditions pose significant financial burden and can result in untoward side effects as well as risk of antimicrobial resistance. On the other hand, inadequate antibiotic treatment in certain cases may increase the risk of suppurative complications and/or invasive infection in this population. OBJECTIVE: To compare the treatment outcomes between those with and without antibiotic treatment for the uncomplicated upper respiratory tract infection and acute diarrhea in young children. MATERIAL AND METHOD: A prospective observational study was conducted in two groups of previously healthy children presenting with acute uncomplicated URI (aged 2 to 5 years) or acute diarrhea (aged 6 months to 5 years). On initial enrolment date, patients were treated by a pediatrician who was not a member of the study investigators. The decision for antibiotic prescription was based entirely on attending physicians' discretion. Data regarding clinical presentations, diagnosis, treatment options, and reasons for antibiotic prescription (if any) were collected. Follow-up phone interviews were conducted on day 3 of enrolment to evaluate treatment outcomes. RESULTS: Two hundred nine cases with symptoms compatible with acute URI, and/or 199 cases with acute diarrhea were enrolled between August and November 2013. Antibiotic prescription rates for URI and diarrhea groups were 30.2% and 13.6%, respectively. Among children presenting with URI symptoms, 80.4% (n = 168) were classified as having upper respiratory tract infection e.g., common cold, acute sinusitis, pharyngitis whereas the other 19.6% were diagnosed with other conditions e.g., lower respiratory tract infection, pneumonia, viral exanthema after evaluation by a pediatrician. Overall improvement rates on day 3 were 92.3% and 86.9%for uncomplicated URIand diarrhea group, respectively. Among URI group, parental satisfaction rates were 100% and 96.6% in those received and did not receive antibiotic, respectively (p = 0.188), whereas in the diarrhea group, there were 100% and 92.7, (p = 0.35), respectively. Univariate analyses indicated that the crude odds ratios (OR) and 95% confidence intervals (CI) of treatment failure comparing those with and without antibiotics were 0.5 (0.2, 1.7) and 1.5 (0.6, 3.7) for URI and diarrhea, respectively. Logistic regression analyses indicated that antibiotic treatment was not significantly associated with better treatment outcomes for both URI and diarrhea cases i.e., adjusted ORs and 95% CI of antibiotic for requirement of additional treatment were 1.06 (0.14, 8.15) for URI cases. Further adjusted OR and 95% CI of antibiotic for treatment failure was 0.8 (0.2, 2.9) for acute diarrhea cases. CONCLUSION: Antibiotic did not appear to provide clinical benefit in the management of uncomplicated URI and/or acute diarrhea among previously healthy young children.

Clinical outcomes of children with carbapenem-resistant Acinetobacter baumannii bacteremia.

BACKGROUND: A relentless increase in the rate of carbapenem-resistant among Acinetobacter baumannii has substantially reduced the access to effective antimicrobial regimens. Currently limited information is available regarding the prognosis or outcomes of children with blood stream infection caused by carbapenem resistant A. baumanii. OBJECTIVE: To determine the clinical outcomes and predictors for fatality among children with carbapenem-resistant A. baumannii (CRAB) bloodstream infection (BSI). MATERIAL AND METHOD: A retrospective descriptive study was conducted among children hospitalized at the Queen Sirikit National Institute of Child Health (Children's Hospital), Bangkok, Thailand. Those who had CRAB isolated from blood cultures during theperiod between October 2005 and September 2010 were included in the study. RESULTS: A total of 89 cases of BSI caused by CRAB were identified. The incidence was 1.2 cases per 1,000 hospitalized patients. The median age at onset of bacteremia was 62 days and 88% had at least one underlying comorbidity. The 2-week and 30-day case fatality rates were 39% and 42%, respectively. A large proportion of deaths (63%) occurred before blood culture results became available. Extended spectrum resistance, defined as resistance to all other first line antibiotics at the hospital, i.e., all cephalosporins, aminoglycoside, quinolone and carbapenems, was significantly associated with a higher 2-week case fatality rate (CFR) (48% compared with 23% among their counterpart, p = 0.028) and death at an earlier stage of the bacteremia (Kaplan-Meierp = 0.016). In univariate analysis, factors associated with 2-week case fatality include malignancy-associated febrile neutropenia, fever ≥2 days before the initiation of appropriate antibiotic, presence of septic shock, organ dysfunction, and being infected by extended spectrum resistant strains. Correspondingly, CFR of cases who received ≥1 appropriate empiric antibiotics within 24 hours of clinical suspicion appears to be lower albeit not reaching statistical significance, than their counterpart, i.e., the CFRs between the two groups were 10% vs. 23%, respectively (p = 0.675). Colistin susceptibility based on disc diffusion test remained high (100%) in this sample. Nevertheless, those who received colistin treatment had a 2-week CFR of 20%. On the other hand, none of the cases infected with sulbactam susceptible strain, who received sulbactam containing regimen (n = 15), died. No significant renal toxicity was observed among children receiving colistin treatment in our sample. CONCLUSION: Carbapenem resistant A. baumannii bacteremia exhibited a high fatality rate, which mainly occurred before the pathogen was known to the clinicians. Extended spectrum resistance was associated with high fatality rate. Early administration of effective empirical antibiotics such as colistin and sulbactam in this sample was associated with lower fatality rate among children affected by this condition.

Risk factors and outcomes of influenza infection among children presenting with influenza-like illness.

OBJECTIVE: Limited data were available to guide management, counseling, and/or diagnostic investigation among children presenting with influenza-like illness (ILI). During a recent period of high influenza activity, we wished to determine the frequency, outcomes, and factors associated with influenza infection among children presenting with ILI. MATERIAL AND METHOD: During September and October 2010, children presenting with ILI were enrolled. Nasal swabs were sent for polymerase chain reaction (PCR) to determine the frequency and types of influenza. Information of demographic characteristics, potential risk factors, and short-term outcomes of study participants were collected. RESULTS: Among 300 enrolled subjects, influenza infections were identified in 170 (56.7%) cases; 45.7% (n = 137) were influenza A and 11% (n = 33) were influenza B. Most cases recovered uneventfully with a 3.7% (n = 11) hospitalization rate. Risks for hospitalization did not differ by infection status (2.4% vs. 5.4% between those with and without influenza infection, respectively) or types of influenza infection. Logistic regression analysis indicated that older age, having a household member with acute respiratory illness (ARI) during the previous 7 days, having an underlying co-morbidity, and a history of premature birth were associated with influenza, with adjusted odds ratios and 95% confidence intervals of 1.19 (1.087, 1.30), 3.21 (1.096, 9.424), 2.15 (1.244, 3.728), and 0.08 (0.007, 0.876), respectively. CONCLUSION: The outcomes of influenza-associated ILI were generally favourable, with no fatalities and 2.4% risk for hospitalization. Among children presenting with ILI, age, household contact with ARI, and co morbidities increased the likelihood of influenza, whereas history of premature birth was negatively associated with influenza.

Clinical characteristics and cost of chickenpox hospitalization in Thai children.

BACKGROUND: Although primary Varicella-Zoster-Virus (VZV) infection generally causes uncomplicated illness confined to skin and mucous membrane among healthy children, it infrequently causes life-threatening infection especially among immuno-suppressed hosts or young infants. Limited information is available regarding the clinical features, outcomes, and the financial burden incurred by severe primary varicella infection in Thai children who required hospitalization. OBJECTIVE: To determine clinical characteristics particularly the disease severity, prevalence of complication, case fatality rate, and use of healthcare resources in terms of length of stay as well as direct medical cost of varicella-associated hospitalization in children. MATERIAL AND METHOD: A retrospective descriptive study was conducted among children aged one month to 18 years who were hospitalized with chickenpox between 2007 and 2011 at the Queen Sirikit National Institute of Child Health, Bangkok, Thailand. Information on clinical manifestations, complications, and outcomes were obtained by medical record abstraction, and data on hospital charges were obtained from the hospital financial database. RESULTS: A total of 101 cases of chickenpox were identified, with a median (interquartile range IQR) age of 4 (0.8, 7.25) years. Underlying predisposing conditions for severe varicella infection were identified in 35 cases (34.7%). Seventy four of 101 (73.3%) patients developed complications, with skin and soft tissue infections being the most common (50.5%), followed by pneumonia (12.7%) and neurological complications (6.4%). There were no fatal cases. Median (IQR) duration of hospitalization and hospital charges were 6 (3, 9) days and US$ 330.2 ($139.3, $1,013.5), respectively. Children with predisposing conditions for severe varicella were significantly older, incurring 6-fold higher hospital charges and 2-fold longer hospitalization compared to their counterparts. CONCLUSION: The high rate of complicated varicella and financial burden reported in this study suggested that the severity of varicella complications in children might have been previously underestimated. This study provides relevant information regarding the burden of hospitalized varicella infection among both otherwise healthy children as well as children with predisposing immuno-suppression.

Establishing of National Birth Defects Registry in Thailand.

BACKGROUND: Deaths attributed to birth defects are a major cause of infant and under-five mortality as well as lifetime disabilities among those who survive. In Thailand, birth defects contribute to 21% of neonatal deaths. There is currently no systematic registry for congenital anomalies in Thailand. Queen Sirikit National Institute of Child Health has initiated a Thailand Birth Defects Registry to capture birth defects among newborn infants. OBJECTIVE: To establish the national birth defects registry in order to determine the burden of birth defects in Thailand. MATERIAL AND METHOD: The birth defects data come from four main sources: National Birth Registry Database; National Health Security Office's reimbursement database; Online Birth Defect Registry Database designed to capture new cases that were detected later; and birth defects data from 20 participated hospitals. All data are linked by unique 13-digit national identification number and International Classification of Diseases (ICD)-10 codes. This registry includes 19 common structural birth defects conditions and pilots in 20 hospitals. The registry is hospital-based, hybrid reporting system, including only live births whose information was collected up to 1 year of age. RESULTS: 3,696 infants out of 67,813 live births (8.28% of total live births in Thailand) were diagnosed with congenital anomalies. The prevalence rate of major anomalies was 26.12 per 1,000 live births. The five most common birth defects were congenital heart defects, limb anomalies, cleft lip/cleft palate, Down syndrome, and congenital hydrocephalus respectively. CONCLUSION: The present study established the Birth Defects Registry by collecting data from four databases in Thailand. Information obtained from this registry and surveillance is essential in the planning for effective intervention programs for birth defects. The authors suggest that this program should be integrated in the existing public health system to ensure sustainability.