Cost of Acute and Sequelae Care for Japanese Encephalitis Patients, Bangladesh, 2011-2021.

Japanese encephalitis (JE) is associated with an immense social and economic burden. Published cost-of-illness data come primarily from decades-old studies. To determine the cost of care for patients with acute JE and initial and long-term sequelae from the societal perspective, we recruited patients with laboratory-confirmed JE from the past 10 years of JE surveillance in Bangladesh and categorized them as acute care, initial sequalae, and long-term sequelae patients. Among 157 patients, we categorized 55 as acute, 65 as initial sequelae (53 as both categories), and 90 as long-term sequelae. The average (median) societal cost of an acute JE episode was US $929 ($909), of initial sequelae US $75 ($33), and of long-term sequelae US $47 ($14). Most families perceived the effect of JE on their well-being to be extreme and had sustained debt for JE expenses. Our data about the high cost of JE can be used by decision makers in Bangladesh.

Japanese Encephalitis Virus as Cause of Acute Encephalitis, Bhutan.

In 2011, Bhutan's Royal Centre for Disease Control began Japanese encephalitis (JE) surveillance at 5 sentinel hospitals throughout Bhutan. During 2011-2018, a total of 20 JE cases were detected, indicating JE virus causes encephalitis in Bhutan. Maintaining JE surveillance will help improve understanding of JE epidemiology in this country.

Utility of Population Attributable Fraction Assessment in Guiding Interventions to Reduce Low Birthweight in the High-Altitude State of Colorado.

Objectives We evaluated the ability of population attributable fraction (PAF) assessments to alter significant modifiable risks for low birthweight (LBW) and the impact of high altitude as a risk for LBW in Colorado. Methods Logistic regression analysis of birth certificate parameters in 1995-1997 identified risk factors for PAF assessment. PAF for birth at high altitude, multiple births, and LBW in singleton births were determined. Subsequent analysis of singleton LBW risks, using number needed to treat (NNT) analysis, estimated how elimination of major modifiable risk factors could reduce LBW in the study population. Public health interventions were initiated and PAF analysis conducted 12 years afterward to determine the effect of interventions. Results PAF in singleton births revealed low maternal weight gain in pregnancy and maternal smoking as the greatest modifiable attributable risk factors for LBW (12.7/12.5 %, respectively, in 1995-1997 and 12.9/7.1 % in 2007-2009). Significant interaction between these variables resulted in PAF of 34.4 % when the two occurred together in 1995-1997, decreasing to 19.4 % in 2007-2009. NNT analysis of singleton births in 1995-1997 revealed that eliminating low maternal weight gain, smoking, late prenatal care in all women and interpregnancy intervals <1 year in multiparous women reduced LBW by 46.5 %. The respective proportional reductions in PAF of 40.3 and 46.3 % for maternal smoking and weight gain/smoking interaction were associated with a 1.4 % LBW reduction in singleton births between the two study periods. Conclusions for Practice PAF and NNT analyses are valuable tools to predict intervention targets to lower LBW.

Impact of time to treatment of oseltamivir on influenza hospitalization cost among Korean children.

BACKGROUND: Although oseltamivir is a common influenza treatment, there is a lack of data on the economic benefits of timely oseltamivir treatment. METHODS: From February 2004 through June 2007, 116 hospitalized children ≤ 15 years of age with laboratory-confirmed influenza who received oseltamivir were identified via retrospective medical chart review. Demographic, clinical, and cost data were abstracted and multivariate linear regression was used to assess the association between oseltamivir time to treatment and treatment-related costs among hospitalized children with laboratory-confirmed influenza. RESULTS: Overall, 28% (n = 33) of patients were treated with oseltamivir ≥ day 3 of admission. Rapid influenza diagnostic test was used in a significantly lower proportion of patients treated with oseltamivir ≥ day 3 of admission compared with those who received oseltamivir earlier. On multivariate linear regression, initiation of oseltamivir ≥ day 3 of admission was associated with a 60.84% increase (95%CI: 32.59-95.11) in treatment-related hospital costs, compared with initiation on admission. CONCLUSION: Delayed initiation of oseltamivir was found to be associated with increased treatment-related hospital costs among children hospitalized with laboratory-confirmed influenza.

Estimating the cost of illness of acute Japanese encephalitis and sequelae care in Vietnam and Laos: A cross-sectional study.

BACKGROUND: Japanese encephalitis (JE) is a leading cause of acute encephalitis syndrome and resulting neurological disability in Asia and the Western Pacific. This study aims to estimate the cost of acute care, initial rehabilitation and sequelae care, in Vietnam and Laos. METHODOLOGY: We conducted a cross-sectional retrospective study using a micro-costing approach from the health system and household perspectives. Out-of-pocket direct medical and non-medical costs, indirect costs, and family impact were reported by patients and/or caregivers. Hospitalization costs were extracted from hospital charts. Acute costs covered expenditures from pre-hospital to follow-up visits while sequelae care costs were estimated from expenditures in the last 90 days. All costs are in 2021 US dollars. PRINCIPAL FINDINGS: 242 patients in two major sentinel sites in the North and South of Vietnam and 65 patients in a central hospital in Vientiane, Laos, with laboratory-confirmed JE were recruited regardless of age, sex, and ethnicity. In Vietnam, the mean total cost was $3,371 per acute JE episode (median $2,071, standard error [SE] $464) while annual costs were $404 for initial sequelae care (median $0, SE $220) and $320 for long-term sequelae care (median $0, SE $108). In Laos, the mean hospitalization costs in acute stage were $2,005 (median $1,698, SE $279) and the mean annual costs were $2,317 (median $0, SE $2,233) for initial sequelae care and $89 (median $0, SE $57) for long-term sequelae care. In both countries, most patients did not seek care for their sequelae. Families perceived extreme impact from JE and 20% to 30% of households still had sustained debts years after acute JE. CONCLUSIONS: JE patients and families in Vietnam and Laos suffer extreme medical, economic, and social hardship. This has policy implications for improving JE prevention in these two JE-endemic countries.

Expanding japanese encephalitis vaccination to selected endemic indonesia provinces: A cost-effectiveness analysis.

Introduction: A Markov model was used to evaluate the potential health and economic impact of introducing JE vaccine nationally and in selected endemic areas of Indonesia compared to no vaccination from government and societal perspectives over a child's lifetime horizon. Methods: Costs were obtained from hospitalized JE suspected patient billing data from 2014 to 2019 in seven provinces. Local data burden data were derived from the literature. Analysis considered several scenarios, including national and sub-regional introduction in seven provinces via a one-time vaccination campaign in all children 1-15 years old followed by routine immunization among infants (RI), or RI alone without vaccination campaign. Results and discussions: Across scenarios, JE vaccination was projected to range from cost-saving to cost-effective compared to no vaccination at a willingness-to-pay threshold of 0.5x gross domestic product per capita. Including a one-time campaign would avert nearly three times as many JE cases and deaths compared to RI alone while still providing good value for money.

Antibody persistence and immune memory response following primary vaccination and boosting with live attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) in Bangladesh: A phase 4 open-label clinical trial.

INTRODUCTION: Japanese encephalitis (JE) virus is one of the leading causes of viral encephalitis across temperate and tropical zones of Asia. The live attenuated SA 14-14-2 JE vaccine (CD-JEV) is one of three vaccines prequalified by the World Health Organization (WHO) to prevent JE. WHO currently recommends a single CD-JEV dose for infants in endemic settings. However, in the absence of long-term immunogenicity data, WHO has indicated a need for long-term immunogenicity studies to inform optimal dosing schedules and determine the need for booster doses. METHODS: This Phase 4, open-label clinical study measured neutralizing antibody (NAb) titers in Bangladeshi children three and four years after primary CD-JEV vaccination and 7 and 28 days after a booster CD-JEV vaccination given four years after primary vaccination. The study also assessed the tolerability and safety of the booster dose. A NAb titer of ≥1:10 was considered seroprotective. RESULTS: Of 560 children vaccinated between 10 and 12 months of age with CD-JEV three years earlier and enrolled in this study from 30 July 2015 through 03 January 2016, 52 (9.3%; 95% CI: 7.2-12.0) had a seroprotective titer at enrollment. One year later, of 533 children, 66 (12.4%; 95% CI: 9.9-15.5) had a seroprotective titer before receiving a booster dose. Of 524 children who received a booster CD-JEV dose, 479 (91.4%; 95% CI: 88.7-93.5) and 514 (98.1%; 95% CI: 96.5-99.0) were seroprotected 7 and 28 days later, respectively. The geometric mean titer (GMT) was 6 (95% CI: 6-6) at baseline, 105 (95% CI: 93-119) 7 days post-booster, and 167 (95% CI: 152-183) 28 days post-booster. No vaccine-associated neurologic adverse events or other serious adverse events were noted following the booster dose. CONCLUSIONS: Although most children did not have measurable antibody titers three and four years after a single primary CD-JEV dose, more than 90% of seronegative children had a strong anamnestic response within one week of a booster dose. This suggests that these children were immune despite the absence of measurable NAb prior to their booster.ClinicalTrials.gov Identifier: NCT02514746.

Dengue virus infection in Africa.

Reported incidence of dengue has increased worldwide in recent decades, but little is known about its incidence in Africa. During 1960-2010, a total of 22 countries in Africa reported sporadic cases or outbreaks of dengue; 12 other countries in Africa reported dengue only in travelers. The presence of disease and high prevalence of antibody to dengue virus in limited serologic surveys suggest endemic dengue virus infection in all or many parts of Africa. Dengue is likely underrecognized and underreported in Africa because of low awareness by health care providers, other prevalent febrile illnesses, and lack of diagnostic testing and systematic surveillance. Other hypotheses to explain low reported numbers of cases include cross-protection from other endemic flavivirus infections, genetic host factors protecting against infection or disease, and low vector competence and transmission efficiency. Population-based studies of febrile illness are needed to determine the epidemiology and true incidence of dengue in Africa.

New dengue virus type 1 genotype in Colombo, Sri Lanka.

The number of cases and severity of disease associated with dengue infection in Sri Lanka has been increasing since 1989, when the first epidemic of dengue hemorrhagic fever was recorded. We identified a new dengue virus 1 strain circulating in Sri Lanka that coincided with the 2009 dengue epidemic.

Dengue vaccine trial guidelines and role of large-scale, post proof-of-concept demonstration projects in bringing a dengue vaccine to use in dengue endemic areas.

In this review, we consider the issues impacting conduct and design of dengue vaccine trials with reference to the recently published World Health Organization "Guidelines for Conduct of Clinical Trials of Dengue Vaccines in Endemic Areas." We discuss logistic, scientific and ethical challenges concerning evaluation and introduction of dengue vaccines; these range from randomized trials that establish "proof of concept" of vaccine efficacy, to post-"proof of concept" trials, particularly demonstration projects likely to be required for licensure or for the introduction of an already licensed vaccine into public use. We clarify and define the meaning of "proof of concept" in the clinical trial context and the meaning of terms "phase 2b", "phase 3b" and "demonstration project", which are commonly used but have not been defined well in the clinical literature.

Immunogenicity and safety of concurrent or sequential administration of live, attenuated SA 14-14-2 Japanese encephalitis vaccine (CD-JEV) and measles-mumps-rubella vaccine in infants 9-12 months of age in the Philippines: A non-inferiority Phase 4 randomized clinical trial.

INTRODUCTION: Japanese encephalitis (JE) virus is the leading cause of viral encephalitis across temperate and tropical zones of Asia. The live attenuated SA 14-14-2 JE vaccine (CD-JEV) is one of three vaccines prequalified by the World Health Organization (WHO) to prevent JE. When incorporating a new vaccine into a country's Expanded Program on Immunization (EPI), it is important to show that the new vaccine can be administered concurrently with other routine pediatric vaccines without impairing the immune responses or changing the safety profiles of the co-administered vaccines. This Phase 4 open-label study evaluated the safety and immunogenicity of measles-mumps-rubella (MMR) vaccine co-administered with CD-JEV. METHODS: The study randomized 628 healthy Filipino children aged between 9 and 10 months to receive MMR and CD-JEV concurrently or separately. MMR immunogenicity was measured 56 days after MMR vaccination using a measles plaque reduction neutralization test (PRNT), anti-mumps immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA), and anti-rubella IgG ELISA, respectively. Neutralizing antibody against JE virus was measured 28 days after CD-JEV vaccination using PRNT. Safety was assessed through solicitation of immediate reactions, adverse events (AEs) within 14 days of vaccination, unsolicited AEs occurring within 28 days, and serious adverse events (SAEs) during participation in the study. RESULTS/CONCLUSIONS: During the study, no post-vaccinal encephalitis cases or related SAEs were reported in either group. Concurrent immunization with CD-JEV and MMR vaccines was not associated with any unusual safety signals when compared with sequential immunization. No significant differences between the regimens were seen in seropositivity or serology titer/concentration results for any of the antigens. Co-administration of CD-JEV and MMR was non-inferior to single administration of either vaccine.

Persistence of IgM Antibodies after Vaccination with Live Attenuated Japanese Encephalitis Vaccine.

Japanese encephalitis (JE) is a vaccine-preventable, mosquito-borne disease. Substantial progress with JE control in Asia has been made during the past decade, with most endemic countries now having JE vaccination programs, commonly using live attenuated SA14-14-2 JE vaccine (trade name CD-JEV). If a child develops encephalitis during the weeks to months following CD-JEV vaccination and anti-JE virus IgM (JE IgM) antibody is detected in serum, the question arises if this is JE virus infection indicating vaccine failure, or persistent JE IgM antibody postvaccination. To better understand JE IgM seropositivity following vaccination, sera from 268 children from a previous CD-JEV study were tested by two different JE IgM assays to determine JE IgM antibody frequency on days 28, 180, and 365 postvaccination. With the CDC JE IgM antibody capture ELISA (MAC-ELISA), 110 children (41%) had JE IgM positive or equivocal results on their day 28 sample, and eight (3%) and two (1%) had positive or equivocal results on day 180 and day 365 samples, respectively. With the InBios JE Detect™ MAC-ELISA (Seattle, WA), 118 (44%) children had positive or equivocal results on day 28 sample, and three (1%) and one (0.4%) had positive or equivocal results on day 180 and day 365 samples, respectively. Our results indicate that more than 40% children vaccinated with CD-JEV can have JE IgM antibodies in their serum at 1 month postvaccination but JE IgM antibody is rare by 6 months. These data will help healthcare workers assess the likelihood that JE IgM antibodies in the serum of a child with encephalitis after vaccination are vaccine related.

Lessons learned from the Advancing Maternal Immunization collaboration: identifying evidence gaps for informed respiratory syncytial virus maternal immunization decision-making.

In an increasingly crowded vaccine landscape, global and country decision-makers will require evidence-based and disease-specific information when prioritizing new public health interventions. The Advancing Maternal Immunization collaboration (AMI) was designed to develop a cross-program strategy to advance respiratory syncytial virus (RSV) maternal immunization (MI) availability and accessibility in low- and middle-income countries by completing a comprehensive RSV MI gap analysis and developing an actionable roadmap report. By engaging and coordinating key stakeholders using a web-based communication platform and developing standardized tools, AMI was able to facilitate interaction and consensus between members. This paper describes the methodology used to create and manage AMI's work. We share lessons learned from our approach to inform other groups conducting similar work requiring cross-sectoral engagement. This approach could be adapted to efficiently conduct gap analyses for other health interventions that require input and coordination across a variety of topic areas, disciplines, geographies, and stakeholders.

Congenital hypothyroidism and the second newborn metabolic screening in Colorado, USA.

OBJECTIVE: To evaluate the effectiveness of a second newborn screening for congenital hypothyroidism (CH). METHODS: All infants born in Colorado, USA, from July 1996 through June 2004 had a total thyroxine measured with secondary thyroid stimulating hormone determination. RESULTS: The number of first and second newborn screens completed was 494,324 and 471,877, respectively. The first screen identified 185 cases of CH (incidence of 1:2,703). The second screen identified an additional 42 cases. Overall, the incidence based on both the first and second screenings was 1:2,174. The false negative rate for the first screen was 15.6%. In the absence of a second screen, one infant with CH out of every 11,111 babies screened would have been missed. The addition of the second screen increased the cost-per-case identified from dollars 6,108 to dollars 9,730. CONCLUSIONS: With only one newborn screen for CH, the number of missed cases is significant and higher than previously reported.

Association between smoking during pregnancy and breastfeeding at about 2 weeks of age.

Maternal smoking during pregnancy may decrease breastfeeding, in part perhaps by decreasing milk supply; furthermore, prenatal smoking is a predictor of postpartum smoking. In this study, birth certificate data, including maternal smoking, for 1998 Oregon resident live births were linked to newborn screening data obtained from Oregon's Newborn Screening Program (NSP), allowing study of risk factors for failure to breastfeed. NSP collects information on infant feeding before newborn discharge and again at about 2 weeks postpartum. Feeding data and risk factor data were available after a probability match of the newborn screening and birth certificate data sets, respectively, for 36,324 (80.3%) of the 45,228 resident live births. Prenatal maternal tobacco use was significantly associated with failure to exclusively breastfeed at about 2 weeks of age (adjusted odds ratio = 2.08, 95% confidence interval = 1.94, 2.21). Women who smoked during pregnancy were less likely to breastfeed than women who did not smoke during pregnancy.

Frequency and clinical manifestations of dengue in urban medellin, Colombia.

A dengue fever surveillance study was conducted at three medical facilities located in the low-income district of San Javier in Medellin, Colombia. During March 2008 to 2009, 781 patients with fever regardless of chief complaint were recruited for acute dengue virus infection testing. Of the 781 tested, 73 (9.3%) were positive for dengue infection. Serotypes DENV-2 (77%) and -3 (23%) were detected by PCR. One patient met the diagnostic criteria for dengue hemorrhagic fever. Only 3 out of 73 (4.1%) febrile subjects testing positive for dengue infection were diagnosed with dengue fever by the treating physician. This study confirms dengue virus as an important cause of acute febrile illness in Medellin, Colombia, but it is difficult to diagnose without dengue diagnostic testing.

Burden of dengue infection and disease in a pediatric cohort in urban Sri Lanka.

Dengue is the most significant arthropod-borne viral infection of humans. Persons infected with dengue viruses (DENV) have subclinical or clinically apparent infections ranging from undifferentiated fever to dengue hemorrhagic fever/shock syndrome. Although recent studies estimated that the Indian subcontinent has the greatest burden of DENV infection and disease worldwide, we do not have reliable, population-based estimates of the incidence of infection and disease in this region. The goal of this study was to follow-up a cohort of 800 children living in a heavily urbanized area of Colombo, Sri Lanka to obtain accurate estimates of the incidence of DENV infection and disease. Annual blood samples were obtained from all children to estimate dengue seroprevalence at enrollment and to identify children exposed to new DENV infections during the study year. Blood was also obtained from any child in whom fever developed over the course of the study year to identify clinically apparent DENV infections. At enrollment, dengue seroprevalence was 53.07%, which indicated high transmission in this population. Over the study year, the incidence of DENV infection and disease were 8.39 (95% confidence interval = 6.56-10.53) and 3.38 (95% confidence interval = 2.24-4.88), respectively, per 100 children per year. The ratio of clinically inapparent to apparent infections was 1.48. These results will be useful for obtaining more accurate estimates of the burden of dengue in the region and for making decisions about testing and introduction of vaccines.

Dengue in the Middle East: a neglected, emerging disease of importance.

Dengue transmission has increased worldwide, particularly in Asia and Latin America since the 1970s, but limited information on the disease is available from the Middle East. Saudi Arabia and Yemen have reported a few epidemics of dengue. Three of the four dengue virus serotypes (DENV-1-3) have been reported in the region. Climate conditions in the Middle East are not favourable for the disease vector, but all other risk factors for dengue are potentially increasing. The existence of a large immigrant work force from dengue-endemic countries, increased travel from and to dengue-endemic countries and increased urbanization are expected to increase the likelihood of the emergence of dengue in the Middle East.

Dengue outbreak in Hadramout, Yemen, 2010: an epidemiological perspective.

We analyzed surveillance data of a dengue outbreak (2010) reported to the Hadramout Health Office (Yemen) and retrospectively analyzed dengue-related epidemiological and entomological events reported in Hadramout from 2005 to 2009. A total of 630 immunoglobulin M (IgM) -confirmed dengue cases of 982 febrile cases was reported during the period from February to June of 2010; 12 cases died, giving case fatality a rate of 1.9%. Among febrile cases, the highest proportion of dengue cases (37.3%) was reported in the 15- to 24-year-old age group. The overall attack rate was 0.89/1,000. The average number of cases reported by month over the preceding 5-year period compared with the 2010 data is consistent with endemicity of dengue in the region and supports epidemic designation for the dengue activity in 2010. Recognition of endemic dengue transmission and potential for substantial dengue epidemics highlight the need for consistent laboratory-based surveillance that can support prevention and control activities accordingly.