Publications by authors named "Kathryn B Anderson"

26 Publications

  • Page 1 of 1

Knowledge gaps in the epidemiology of severe dengue impede vaccine evaluation.

Lancet Infect Dis 2021 Jul 12. Epub 2021 Jul 12.

Dengue Branch, Centers for Disease Control and Prevention, San Juan, PR, USA; United States Public Health Service, Silver Springs, MD, USA.

The most severe consequences of dengue virus infection include shock, haemorrhage, and major organ failure; however, the frequency of these manifestations varies, and the relative contribution of pre-existing anti-dengue virus antibodies, virus characteristics, and host factors (including age and comorbidities) are not well understood. Reliable characterisation of the epidemiology of severe dengue first depends on the use of consistent definitions of disease severity. As vaccine trials have shown, severe dengue is a crucial interventional endpoint, yet the infrequency of its occurrence necessitates the inclusion of thousands of study participants to appropriately compare its frequency among participants who have and have not been vaccinated. Hospital admission is frequently used as a proxy for severe dengue; however, lack of specificity and variability in clinical practices limit the reliability of this approach. Although previous infection with a dengue virus is the best characterised risk factor for developing severe dengue, the influence of the timing between dengue virus infections and the sequence of dengue virus infections on disease severity is only beginning to be elucidated. To improve our understanding of the diverse factors that shape the clinical spectrum of disease resulting from dengue virus infection, prospective, community-based and clinic-based immunological, virological, genetic, and clinical studies across a range of ages and geographical regions are needed.
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http://dx.doi.org/10.1016/S1473-3099(20)30871-9DOI Listing
July 2021

Correlation between reported dengue illness history and seropositivity in rural Thailand.

PLoS Negl Trop Dis 2021 Jun 15;15(6):e0009459. Epub 2021 Jun 15.

State University of New York Upstate Medical University, Syracuse, New York, United States of America.

In the latest World Health Organization (WHO) recommendation for Dengvaxia implementation, either serological testing or a person's history of prior dengue illness may be used as supporting evidence to identify dengue virus (DENV)-immune individuals eligible for vaccination, in areas with limited capacity for laboratory confirmation. This analysis aimed to estimate the concordance between self-reported dengue illness histories and seropositivity in a prospective cohort study for dengue virus infection in Kamphaeng Phet province, a dengue-endemic area in northern Thailand. The study enrolled 2,076 subjects from 516 multigenerational families, with a median age of 30.6 years (range 0-90 years). Individual and family member dengue illness histories were obtained by questionnaire. Seropositivity was defined based on hemagglutination inhibition (HAI) assays. Overall seropositivity for DENV was 86.5% among those aged 9-45 years, which increased with age. 18.5% of participants reported a history of dengue illness prior to enrollment; 30.1% reported a previous DENV infection in the family, and 40.1% reported DENV infection in either themselves or a family member. Relative to seropositivity by HAI in the vaccine candidate group, the sensitivity and specificity of individual prior dengue illness history were 18.5% and 81.6%, respectively; sensitivity and specificity of reported dengue illness in a family member were 29.8% and 68.0%, and of either the individual or a family member were 40.1% and 60.5%. Notably, 13.4% of individuals reporting prior dengue illness were seronegative. Given the high occurrence of asymptomatic and mild DENV infection, self-reported dengue illness history is poorly sensitive for prior exposure and may misclassify individuals as 'exposed' when they were not. This analysis highlights that a simple, highly sensitive, and highly specific test for determining serostatus prior to Dengvaxia vaccination is urgently needed.
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http://dx.doi.org/10.1371/journal.pntd.0009459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8232416PMC
June 2021

Assessment of U.S. health care personnel (HCP) attitudes towards COVID-19 vaccination in a large university health care system.

Clin Infect Dis 2021 Jan 25. Epub 2021 Jan 25.

Department of Public Health and Preventive Medicine, SUNY Upstate Medical University, Syracuse, NY.

Background: As a priority group, healthcare personnel (HCP) will be key to success of COVID-19 vaccination programs. The purpose of this study was to assess HCP willingness to get vaccinated and identify specific concerns that would undermine vaccination efforts.

Methods: We conducted a cross-sectional survey of HCP, including clinical and non-clinical staff, researchers, and trainees between November 23 rd ,2020 and December 5 th ,2020. The survey evaluated attitudes, beliefs and willingness to get vaccinated.

Results: A total of 5287 respondents had a mean age of 42.5 years (SD=13.56), and were 72.8% female (n=3842). Overall 57.5 % of individuals expressed intent to receive COVID-19 vaccine. 80.4% were physicians and scientists representing the largest group. 33.6% of registered nurses, 31.6% of allied health professionals, and 32% of master's level clinicians were unsure they would take the vaccine (p<.001). Respondents who were older, males, White, or Asian were more likely to get vaccinated compared to other groups. Vaccine safety, potential adverse events, efficacy and speed of vaccine development dominated concerns listed by participants. Fewer (54.0%) providers of direct care vs. non-care providers (62.4%), and 52.0% of those who had provided care for COVID-19 patients (vs. 60.6% of those who had not) indicated they would take the vaccine if offered (p<.001).

Conclusions: We observed that self-reported willingness to receive vaccination against COVID-19 differs by hospital roles, with physicians and research scientists showing the highest acceptance. These findings highlight important heterogeneity in personal attitudes among HCPs around COVID-19 vaccines and highlight a need for tailored communication strategies.
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http://dx.doi.org/10.1093/cid/ciab054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929026PMC
January 2021

Comparative Analyses of Historical Trends in Confirmed Dengue Illnesses Detected at Public Hospitals in Bangkok and Northern Thailand, 2002-2018.

Am J Trop Med Hyg 2020 Dec 14. Epub 2020 Dec 14.

Department of Virology, Armed Forces Research Institute of Medical Sciences (AFRIMS), Bangkok, Thailand.

Dengue is a re-emerging global public health problem, the most common arbovirus causing human disease in the world, and a major cause of hospitalization in endemic countries causing significant economic burden. Data were analyzed from passive surveillance of hospital-attended dengue cases from 2002 to 2018 at Phramongkutklao Hospital (PMKH) located in Bangkok, Thailand, and Kamphaeng Phet Provincial Hospital (KPPH) located in the lower northern region of Thailand. At PMKH, serotype 1 proved to be the most common strain of the virus, whereas at KPPH, serotypes 1, 2, and 3 were the most common strains from 2006 to 2008, 2009 to 2012, and 2013 to 2015, respectively. The 11-17 years age-group made up the largest proportion of patients impacted by dengue illnesses during the study period at both sites. At KPPH, dengue virus (DENV)-3 was responsible for most cases of dengue fever (DF), whereas it was DENV-1 at PMKH. In cases where dengue hemorrhagic fever was the clinical diagnosis, DENV-2 was the predominant serotype at KPPH, whereas at PMKH, it was DENV-1. The overall disease prevalence remained consistent across the two study sites with DF being the predominant clinical diagnosis as the result of an acute secondary dengue infection, representing 40.7% of overall cases at KPPH and 56.8% at PMKH. The differences seen between these sites could be a result of climate change increasing the length of dengue season and shifts in migration patterns of these populations from rural to urban areas and vice versa.
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http://dx.doi.org/10.4269/ajtmh.20-0396DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7941814PMC
December 2020

Complete Coding Sequences of 22 East/Central/South African Genotype Chikungunya Virus Isolates from Thailand (2018 to 2019).

Microbiol Resour Announc 2020 Oct 15;9(42). Epub 2020 Oct 15.

Department of Virology, U.S. Army Medical Directorate-Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

The coding-complete genome sequences of 22 chikungunya virus strains collected from the 2018-2019 outbreak in Thailand are reported. All sequences belong to the East/Central/South African (ECSA) genotype and contain two mutations, E1:K211E and E2:V264A, which were previously shown to be associated with increased viral infectivity, dissemination, and transmission in .
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http://dx.doi.org/10.1128/MRA.00438-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561681PMC
October 2020

Surveying Health-Related Knowledge, Attitudes, and Behaviors of U.S.-Based Residents Traveling Internationally to Visit Friends and Relatives.

Am J Trop Med Hyg 2020 12 17;103(6):2591-2599. Epub 2020 Sep 17.

Institute for Global Health and Translational Sciences, State University of New York-Upstate Medical University, Syracuse, New York.

U.S. residents traveling internationally to regions with increased risk of infectious diseases infrequently seek pretravel health care. First- and second-generation immigrants traveling to their countries of origin and visiting friends and relatives (VFRs) have increased risk of certain infectious diseases and are more likely to participate in high-risk activities. In an online survey of 994 U.S. residents with two foreign-born parents who went on at least one international trip to an at-risk country (defined as having a typhoid vaccine recommendation) in the prior 3 years, respondents were questioned about their international travel over the previous 3 years and their knowledge and individual risk of disease. Participants reported infrequently seeking pretravel health information (32% of trips) or consulting a healthcare provider before their trips (15% of trips). Participants reported seeking pretravel health information less often for VFR trips home (22%) than to other regions (30%). Perceived risk of disease was directly associated with seeking pretravel health information (82% for the highest and 13% for the lowest perceived risk), consulting a healthcare provider (55% for the highest and 5% for the lowest perceived risk), and reporting travel-associated illness (54% for the highest and 10% for the lowest perceived risk). Respondents were generally knowledgeable about cholera, hepatitis B, malaria, and rabies but had low knowledge of hepatitis A and typhoid. Understanding where VFR travelers lack understanding of disease transmission and which travelers are ideal targets for interventions has the potential to shape physician recommendations and public health strategy in this vulnerable population.
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http://dx.doi.org/10.4269/ajtmh.20-0508DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7695092PMC
December 2020

Social Distancing Metrics and Estimates of SARS-CoV-2 Transmission Rates: Associations Between Mobile Telephone Data Tracking and R.

J Public Health Manag Pract 2020 Nov/Dec;26(6):606-612

Department of Public Health & Preventive Medicine (Drs Morley, Shaw, Stewart, and Wang), Department of Family Medicine (Dr Morley), Department of Psychiatry & Behavioral Sciences (Dr Morley), Department of Medicine (Drs Anderson and Thomas), Institute for Global Health & Translational Science (Drs Anderson and Thomas), Department of Microbiology and Immunology (Drs Anderson and Thomas), Department of Pediatrics, Division of Pediatric Infectious Disease (Dr Shaw), Department of Urology (Dr Stewart), and Department of Geriatrics (Dr Stewart), SUNY Upstate Medical University, Syracuse, New York.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease 2019 (COVID-19). In the absence of robust preventive or curative strategies, the implementation of social distancing has been a key component of limiting the spread of the virus.

Methods: Daily estimates of R(t) were calculated and compared with measures of social distancing made publicly available by Unacast. Daily generated variables representing an overall grade for distancing, changes in distances traveled, encounters between individuals, and daily visitation, were modeled as predictors of average R value for the following week, using linear regression techniques for 8 counties surrounding the city of Syracuse, New York. Supplementary analysis examined differences between counties.

Results: A total of 225 observations were available across the 8 counties, with 166 meeting the mean R(t) < 3 outlier criterion for the regression models. Measurements for distance (β = 1.002, P = .012), visitation (β = .887, P = .017), and encounters (β = 1.070, P = .001) were each predictors of R(t) for the following week. Mean R(t) drops when overall distancing grades move from D+ to C-. These trends were significant (P < .001 for each).

Conclusions: Social distancing, when assessed by free and publicly available measures such as those shared by Unacast, has an impact on viral transmission rates. The scorecard may also be useful for public messaging about social distance, in hospital planning, and in the interpretation of epidemiological models.
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http://dx.doi.org/10.1097/PHH.0000000000001240DOI Listing
October 2020

Key Findings and Comparisons From Analogous Case-Cluster Studies for Dengue Virus Infection Conducted in Machala, Ecuador, and Kamphaeng Phet, Thailand.

Front Public Health 2020 12;8. Epub 2020 Feb 12.

Department of Medicine, SUNY Upstate Medical University, Syracuse, NY, United States.

Dengue viruses (DENV) pose a significant and increasing threat to human health across broad regions of the globe. Currently, prevention, control, and treatment strategies are limited. Promising interventions are on the horizon, including multiple vaccine candidates under development and a renewed and innovative focus on controlling the vector, . However, significant gaps persist in our understanding of the similarities and differences in DENV epidemiology across regions of potential implementation and evaluation. In this manuscript, we highlight and compare findings from two analogous cluster-based studies for DENV transmission and pathogenesis conducted in Thailand and Ecuador to identify key features and questions for further pursuit. Despite a remarkably similar incidence of DENV infection among enrolled neighborhood contacts at the two sites, we note a higher occurrence of secondary infection and severe illness in Thailand compared to Ecuador. A higher force of infection in Thailand, defined as the incidence of infection among susceptible individuals, is suggested by the higher number of captured mosquitoes per household, the increasing proportion of asymptomatic infections with advancing age, and the high proportion of infections identified as secondary-type infections by serology. These observations should be confirmed in long-term, parallel prospective cohort studies conducted across regions, which would advantageously permit characterization of baseline immune status (susceptibility) and contemporaneous assessment of risks and risk factors for dengue illness.
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http://dx.doi.org/10.3389/fpubh.2020.00002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7028768PMC
May 2021

An Innovative, Prospective, Hybrid Cohort-Cluster Study Design to Characterize Dengue Virus Transmission in Multigenerational Households in Kamphaeng Phet, Thailand.

Am J Epidemiol 2020 07;189(7):648-659

Difficulties inherent in the identification of immune correlates of protection or severe disease have challenged the development and evaluation of dengue vaccines. There persist substantial gaps in knowledge about the complex effects of age and sequential dengue virus (DENV) exposures on these correlations. To address these gaps, we were conducting a novel family-based cohort-cluster study for DENV transmission in Kamphaeng Phet, Thailand. The study began in 2015 and is funded until at least 2023. As of May 2019, 2,870 individuals in 485 families were actively enrolled. The families comprise at least 1 child born into the study as a newborn, 1 other child, a parent, and a grandparent. The median age of enrolled participants is 21 years (range 0-93 years). Active surveillance is performed to detect acute dengue illnesses, and annual blood testing identifies subclinical seroconversions. Extended follow-up of this cohort will detect sequential infections and correlate antibody kinetics and sequence of infections with disease outcomes. The central goal of this prospective study is to characterize how different DENV exposure histories within multigenerational family units, from DENV-naive infants to grandparents with multiple prior DENV exposures, affect transmission, disease, and protection at the level of the individual, household, and community.
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http://dx.doi.org/10.1093/aje/kwaa008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393304PMC
July 2020

Longitudinal Analysis of Memory B and T Cell Responses to Dengue Virus in a 5-Year Prospective Cohort Study in Thailand.

Front Immunol 2019 13;10:1359. Epub 2019 Jun 13.

Institute for Immunology and Informatics, University of Rhode Island, Providence, RI, United States.

Prior exposure to dengue virus (DENV) has a profound impact on the outcome of infection, which varies according to the interval between infections. Antibodies secreted by B cells and cytokines secreted by T cells are thought to contribute both to protective immunity against DENV and the pathogenesis of dengue disease. We analyzed peripheral blood mononuclear cells (PBMC) collected from Thai children over a 5-year prospective cohort study to define the dynamics of DENV-specific memory B and T cell responses and the impact of symptomatic or subclinical DENV infections. To measure B cell responses, PBMC were stimulated with IL-2 plus R848 and culture supernatants were tested for DENV-binding antibodies by ELISA. To measure T cell responses, PBMC were stimulated in dual-color ELISPOT assays with overlapping peptide pools of structural and non-structural proteins from the four DENV types. B cell responses were low to one or more DENV types prior to symptomatic infection and increased with reactivity to all four types after infection. Subjects who had a subclinical infection or who did not experience a DENV infection during the study period showed strong memory B cell responses to all four DENV types. T cell responses to DENV peptides demonstrated a cytokine hierarchy of IFN-γ > IL-2 > IFN-γ/IL-2. T cell responses were low or absent prior to secondary infections. The trends in T cell responses to DENV peptides over 3 year post-infection were highly variable, but subjects who had experienced a secondary DENV1 infection showed higher cytokine responses compared to subjects who had experienced a secondary DENV2 or subclinical infection. The longitudinal nature of our study demonstrates persistent memory B cell responses over years and a lasting but variable impact of secondary DENV infection on DENV-specific T cell responses.
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http://dx.doi.org/10.3389/fimmu.2019.01359DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6585174PMC
October 2020

Model-based assessment of public health impact and cost-effectiveness of dengue vaccination following screening for prior exposure.

PLoS Negl Trop Dis 2019 07 1;13(7):e0007482. Epub 2019 Jul 1.

Department of Biological Sciences and Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN, United States of America.

The tetravalent dengue vaccine CYD-TDV (Dengvaxia) is the first licensed vaccine against dengue, but recent findings indicate an elevated risk of severe disease among vaccinees without prior dengue virus (DENV) exposure. The World Health Organization currently recommends CYD-TDV only for individuals with serological confirmation of past DENV exposure. Our objective was to evaluate the potential health impact and cost-effectiveness of vaccination following serological screening. To do so, we used an agent-based model to simulate DENV transmission with and without vaccination over a 10-year timeframe. Across a range of values for the proportion of vaccinees with prior DENV exposure, we projected the proportion of symptomatic and hospitalized cases averted as a function of the sensitivity and specificity of serological screening. Scenarios about the cost-effectiveness of screening and vaccination were chosen to be representative of Brazil and the Philippines. We found that public health impact depended primarily on sensitivity in high-transmission settings and on specificity in low-transmission settings. Cost-effectiveness could be achievable from the perspective of a public payer provided that sensitivity and the value of a disability-adjusted life-year were both high, but only in high-transmission settings. Requirements for reducing relative risk and achieving cost-effectiveness from an individual perspective were more restricted, due to the fact that those who test negative pay for screening but receive no benefit. Our results predict that cost-effectiveness could be achieved only in high-transmission areas of dengue-endemic countries with a relatively high per capita GDP, such as Panamá (13,680 USD), Brazil (8,649 USD), México (8,201 USD), or Thailand (5,807 USD). In conclusion, vaccination with CYD-TDV following serological screening could have a positive impact in some high-transmission settings, provided that screening is highly specific (to minimize individual harm), at least moderately sensitive (to maximize population benefit), and sufficiently inexpensive (depending on the setting).
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http://dx.doi.org/10.1371/journal.pntd.0007482DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6625736PMC
July 2019

Protective versus pathologic pre-exposure cytokine profiles in dengue virus infection.

PLoS Negl Trop Dis 2018 12 17;12(12):e0006975. Epub 2018 Dec 17.

Institute for Immunology and Informatics, Department of Cell and Molecular Biology, University of Rhode Island, Providence, Rhode Island, United States of America.

Background: Hyperendemic circulation of all four types of dengue virus (DENV-1-4) has expanded globally, fueling concern for increased incidence of severe dengue. While the majority of DENV infections are subclinical, epidemiologic studies suggest that type-cross-reactive immunity can influence disease outcome in subsequent infections. The mechanisms controlling these differential clinical outcomes remain poorly defined.

Methodology/principal Findings: Blood samples were collected from a cohort of school-aged Thai children who subsequently experienced a subclinical DENV infection or developed dengue illness. PBMC collected prior to infection were stimulated in vitro with DENV and the secretion of 30 cytokines was measured using a multiplexed, bead-based array. Significant differences were found in cytokine production based on both the type of DENV used for stimulation and the occurrence of clinical illness. Secretion of IL-15 and MCP-1 was significantly higher by PBMC of subjects who later developed symptomatic DENV infection. In addition, IL-6 was produced by PBMC from all subjects who subsequently developed symptomatic infection, versus 59% of subjects who had subclinical infection. Secretion of IL-12, IL-2R, MIP-1α, RANTES, GM-CSF, and TNFα was significantly lower by PBMC from subjects with symptomatic infection.

Conclusions/significance: These data demonstrate significant differences in pre-existing immune responses to DENV associated with the clinical outcome of subsequent infection. The finding of higher levels of some cytokines in subjects with symptomatic infection and higher levels of other cytokines in subjects with subclinical infection supports the existence of both protective and pathologic immune profiles. Clinical-immunological correlations identified in the context of natural DENV infection may be useful for evaluating immune responses to dengue vaccines.
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http://dx.doi.org/10.1371/journal.pntd.0006975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6312351PMC
December 2018

Association between semi-quantitative microbial load and respiratory symptoms among Thai military recruits: a prospective cohort study.

BMC Infect Dis 2018 Sep 14;18(1):462. Epub 2018 Sep 14.

Phramongkutklao Hospital, Bangkok, 10400, Thailand.

Background: Multiplex real-time polymerase chain reaction assays have improved diagnostic sensitivity for a wide range of pathogens. However, co-detection of multiple agents and bacterial colonization make it difficult to distinguish between asymptomatic infection or illness aetiology. We assessed whether semi-quantitative microbial load data can differentiate between symptomatic and asymptomatic states for common respiratory pathogens.

Methods: We obtained throat and nasal swab samples from military trainees at two Thai Army barracks. Specimens were collected at the start and end of 10-week training periods (non-acute samples), and from individuals who developed upper respiratory tract infection during training (acute samples). We analysed the samples using a commercial multiplex respiratory panel comprising 33 bacterial, viral and fungal targets. We used random effects tobit models to compare cycle threshold (Ct) value distributions from non-acute and acute samples.

Results: We analysed 341 non-acute and 145 acute swab samples from 274 participants. Haemophilus influenzae type B was the most commonly detected microbe (77.4% of non-acute and 64.8% of acute samples). In acute samples, nine specific microbe pairs were detected more frequently than expected by chance. Regression models indicated significantly lower microbial load in non-acute relative to acute samples for H. influenzae non-type B, Streptococcus pneumoniae and rhinovirus, although it was not possible to identify a Ct-value threshold indicating causal etiology for any of these organisms.

Conclusions: Semi-quantitative measures of microbial concentration did not reliably differentiate between illness and asymptomatic colonization, suggesting that clinical symptoms may not always be directly related to microbial load for common respiratory infections.
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http://dx.doi.org/10.1186/s12879-018-3358-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6137728PMC
September 2018

Epidemiology and Transmission of Respiratory Infections in Thai Army Recruits: A Prospective Cohort Study.

Am J Trop Med Hyg 2018 10;99(4):1089-1095

Phramongkutklao Hospital, Bangkok, Thailand.

Military recruits are at high risk of respiratory infections. However, limited data exist on military populations in tropical settings, where the epidemiology of respiratory infections differs substantially from temperate settings. We enrolled recruits undertaking a 10-week military training at two Royal Thai Army barracks between May 2014 and July 2015. We used a multiplex respiratory panel to analyze nose and throat swabs collected at the start and end of the training period, and from participants experiencing respiratory symptoms during follow-up. Paired sera were tested for influenza seroconversion using a hemagglutinin inhibition assay. Overall rates of upper respiratory illness and influenza-like illness were 3.1 and 2.0 episodes per 100 person-weeks, respectively. A pathogen was detected in 96% of samples. The most commonly detected microbes were type B (62.7%) or non-type B (58.2%) and rhinovirus (22.4%). At baseline, bacterial colonization was high and included type B (82.3%), non-type B (31.5%), (14.6%), (8.5%), and (8.5%). At the end of follow-up, colonization with non-type B had increased to 74.1%, and to 33.6%. In the serology subset, the rate of influenza infection was 3.4 per 100 person-months; 58% of influenza infections resulted in clinical disease. Our study provides key data on the epidemiology and transmission of respiratory pathogens in tropical settings. Our results emphasize the need for improved infection prevention and control in military environments, given the high burden of illness and potential for intense transmission of respiratory pathogens.
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http://dx.doi.org/10.4269/ajtmh.18-0219DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6159564PMC
October 2018

The dynamic role of dengue cross-reactive immunity: changing the approach to defining vaccine safety and efficacy.

Lancet Infect Dis 2018 10 18;18(10):e333-e338. Epub 2018 May 18.

State University of New York Upstate Medical University, Syracuse, NY, USA. Electronic address:

Dengue virus infections cause a substantial public health burden in tropical and subtropical regions. A single dengue vaccine has been approved by regulatory authorities in 19 countries, but concerns regarding vaccine safety in people who are dengue naive at the time of immunisation has introduced uncertainty into the vaccine's future. As other dengue vaccines complete or enter large-scale efficacy trials, we argue that foundational work by Sabin, historic epidemiological observations of dengue outbreaks, and prospective cohort studies in Asia and the Americas indicate that modifications must be made to the methods of assessing dengue vaccines. In this Personal View, we review and relate previous data that supports a dynamic role of cross-protective dengue immunity to the goals and challenges of measuring and interpreting dengue vaccine immunogenicity, efficacy, and safety in clinical trials. We suggest that for partly protective vaccines, temporary cross-protective immunity could lead to overestimation of vaccine safety and efficacy in the early years following vaccination. We recommend that assessment of dengue vaccines should span several years, involve active surveillance to clinically characterise incident infections and regular blood draws to define kinetic changes in immunological profiles, and include sample sizes that are large enough to support detailed analyses of vaccine trial subgroups, such as individuals who are dengue naive.
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http://dx.doi.org/10.1016/S1473-3099(18)30126-9DOI Listing
October 2018

Finding the Signal in the Noise in the Serologic Diagnosis of Flavivirus Infections.

J Infect Dis 2018 07;218(4):516-518

State University of New York Upstate Medical University, Syracuse.

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http://dx.doi.org/10.1093/infdis/jiy166DOI Listing
July 2018

Clinical and laboratory predictors of influenza infection among individuals with influenza-like illness presenting to an urban Thai hospital over a five-year period.

PLoS One 2018 7;13(3):e0193050. Epub 2018 Mar 7.

Viral Disease Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, United States of America.

Early diagnosis of influenza infection maximizes the effectiveness of antiviral medicines. Here, we assess the ability for clinical characteristics and rapid influenza tests to predict PCR-confirmed influenza infection in a sentinel, cross-sectional study for influenza-like illness (ILI) in Thailand. Participants meeting criteria for acute ILI (fever > 38°C and cough or sore throat) were recruited from inpatient and outpatient departments in Bangkok, Thailand, from 2009-2014. The primary endpoint for the study was the occurrence of virologically-confirmed influenza infection (based upon detection of viral RNA by RT-PCR) among individuals presenting for care with ILI. Nasal and throat swabs were tested by rapid influenza test (QuickVue) and by RT-PCR. Vaccine effectiveness (VE) was calculated using the case test-negative method. Classification and Regression Tree (CART) analysis was used to predict influenza RT-PCR positivity based upon symptoms reported. We enrolled 4572 individuals with ILI; 32.7% had detectable influenza RNA by RT-PCR. Influenza cases were attributable to influenza B (38.6%), A(H1N1)pdm09 (35.1%), and A(H3N2) (26.3%) viruses. VE was highest against influenza A(H1N1)pdm09 virus and among adults. The most important symptoms for predicting influenza PCR-positivity among patients with ILI were cough, runny nose, chills, and body aches. The accuracy of the CART predictive model was 72.8%, with an NPV of 78.1% and a PPV of 59.7%. During epidemic periods, PPV improved to 68.5%. The PPV of the QuickVue assay relative to RT-PCR was 93.0% overall, with peak performance during epidemic periods and in the absence of oseltamivir treatment. Clinical criteria demonstrated poor predictive capability outside of epidemic periods while rapid tests were reasonably accurate and may provide an acceptable alternative to RT-PCR testing in resource-limited areas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193050PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841736PMC
June 2018

The Emergence of Zika Virus: A Narrative Review.

Ann Intern Med 2016 Aug 3;165(3):175-83. Epub 2016 May 3.

Zika virus (ZIKV) is yet another arbovirus that is rapidly emerging on a global scale, on the heels of a chikungunya epidemic in the Americas that began in 2013. A ZIKV epidemic that began in Brazil in 2015 has now spread rapidly to more than 30 countries in the Americas and the Caribbean, infecting more than 2 million inhabitants. This epidemic currently continues unabated. The explosive nature of recent outbreaks and concerning links to Guillain-Barré syndrome and microcephaly are incompletely understood. Also unknown is the relative importance of sexual transmission of ZIKV and asymptomatic ZIKV infections to the overall burden of transmission. The limited understanding of ZIKV presents an enormous challenge for responses to this rapidly emerging threat to human health. This article reviews the existing literature on ZIKV and proposes critical questions for vaccine development and other areas of needed research.
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http://dx.doi.org/10.7326/M16-0617DOI Listing
August 2016

Chikungunya: acute fever, rash and debilitating arthralgias in a returning traveler from Haiti.

J Travel Med 2014 Nov-Dec;21(6):418-20. Epub 2014 Aug 28.

Department of Internal Medicine, School of Medicine.

The following case report details a case of chikungunya fever in a returning traveler from Haiti. The report highlights the clinical presentation and natural history of the disease, and emphasizes that chikungunya has become established in the western hemisphere, with a resultant need for heightened provider awareness.
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http://dx.doi.org/10.1111/jtm.12159DOI Listing
July 2015

A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand.

J Infect Dis 2014 Feb 20;209(3):360-8. Epub 2013 Aug 20.

Department of Medicine, University of Minnesota Medical School, Minneapolis.

Background: Despite the strong association between secondary dengue virus (DENV) infections and dengue hemorrhagic fever (DHF), the majority of secondary infections are subclinical or mild. The determinants of clinical severity remain unclear, though studies indicate a titer-dependent and time-dependent role of cross-protective anti-DENV antibodies.

Methods: Data from 2 sequential prospective cohort studies were analyzed for subclinical and symptomatic DENV infections in schoolchildren in Kamphaeng Phet, Thailand (1998-2002 and 2004-2007). Children experiencing ≥ 1 DENV infection were selected as the population for analysis (contributing 2169 person-years of follow-up).

Results: In total, 1696 children had ≥ 1 DENV infection detected during their enrollment; 268 experienced 2 or more infections. A shorter time interval between infections was associated with subclinical infection in children seronegative for DENV at enrollment, for whom a second-detected DENV infection is more likely to reflect a true second infection (average of 2.6 years between infections for DHF, 1.9 for DF, and 1.6 for subclinical infections).

Conclusions: These findings support a pathogenesis model where cross-reactive antibodies wane from higher-titer, protective levels to lower-titer, detrimental levels. This is one of the first studies of human subjects to suggest a window of cross-protection following DENV infection since Sabin's challenge studies in the 1940s.
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http://dx.doi.org/10.1093/infdis/jit436DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3883164PMC
February 2014

Preexisting Japanese encephalitis virus neutralizing antibodies and increased symptomatic dengue illness in a school-based cohort in Thailand.

PLoS Negl Trop Dis 2011 Oct 4;5(10):e1311. Epub 2011 Oct 4.

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.

Background: Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) have significant cross-reactivity in serological assays; the clinical implications of this remain undefined. An improved understanding of whether and how JEV immunity modulates the clinical outcome of DENV infection is important as large-scale DENV vaccine trials will commence in areas where JEV is co-endemic and/or JEV immunization is routine.

Methods And Findings: The association between preexisting JEV neutralizing antibodies (NAbs) and the clinical severity of DENV infection was evaluated in a prospective school-based cohort in Thailand that captured asymptomatic, non-hospitalized, and hospitalized DENV infections. Covariates considered included age, baseline DENV antibody status, school of attendance, epidemic year, and infecting DENV serotype. 942 children experienced at least one DENV infection between 1998 and 2002, out of 3,687 children who were enrolled for at least one full year. In crude analysis, the presence of JEV NAbs was associated with an increased occurrence of symptomatic versus asymptomatic infection (odds ratio [OR]= 1.55, 95% CI: 1.08-2.23) but not hospitalized illness or dengue hemorrhagic fever (DHF). The association was strongest in children with negative DENV serology (DENV-naive) (OR=2.75, 95% CI: 1.12-6.72), for whom the presence of JEV NAbs was also associated with a symptomatic illness of longer duration (5.4 days for JEV NAb+ versus 2.6 days for JEV NAb-, p=0.048). JEV NAbs were associated with increased DHF in younger children with multitypic DENV NAb profiles (OR=4.05, 95% CI: 1.18 to 13.87). Among those with JEV NAbs, the association with symptomatic illness did not vary by antibody titer.

Interpretation: The prior existence of JEV NAbs was associated with an increased probability of symptomatic as compared to asymptomatic DENV illness. These findings are in contrast to previous studies suggesting an attenuating effect of heterologous flavivirus immunity on DENV disease severity.
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http://dx.doi.org/10.1371/journal.pntd.0001311DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3186763PMC
October 2011

Interference and facilitation between dengue serotypes in a tetravalent live dengue virus vaccine candidate.

J Infect Dis 2011 Aug;204(3):442-50

Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia 30322, USA.

Background: Live, multivalent vaccines have historically exhibited interference in humans; live dengue virus (DENV) vaccines have proven no exception.

Methods: To characterize interactions between DENV serotypes in a tetravalent live-attenuated virus vaccine candidate, we analyzed data from a factorial clinical trial in which all combinations of high- and low-dose DENV serotypes were combined in 16 live-attenuated tetravalent vaccine formulations (N = 64) and administered to flavivirus-naive adult volunteers. Regression models considered the outcomes of reactogenicity and seroconversion, controlling for all serotype doses simultaneously. Additionally, results were compared against earlier evaluations of the same viruses administered as monovalent formulations.

Results: DENV-1 was immunologically dominant in both monovalent and tetravalent formulations. In tetravalent formulations, DENV-1 and DENV-2 antagonized each other, with a high dose of one decreasing seroconversion to the other. However, high-dose DENV-1 significantly increased seroconversion against 3 or more serotypes, increasing seroconversion to DENV-1, DENV-3, and DENV-4. The highest reactogenicity occurred when DENV-1 was at high dose and all others were low; reactogenicity decreased with the incorporation of other high-dose serotypes.

Conclusions: Interference and facilitation occurred between serotypes in the live vaccine candidate evaluated. These analyses suggest that it may be possible to exploit facilitation to increase overall seroconversion.
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http://dx.doi.org/10.1093/infdis/jir279DOI Listing
August 2011

Determinants of inapparent and symptomatic dengue infection in a prospective study of primary school children in Kamphaeng Phet, Thailand.

PLoS Negl Trop Dis 2011 Mar 1;5(3):e975. Epub 2011 Mar 1.

Division of Infectious Disease, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.

Background: Dengue viruses are a major cause of morbidity in tropical and subtropical regions of the world. Inapparent dengue is an important component of the overall burden of dengue infection. It provides a source of infection for mosquito transmission during the course of an epidemic, yet by definition is undetected by health care providers. Previous studies of inapparent or subclinical infection have reported varying ratios of symptomatic to inapparent dengue infection.

Methodology/principal Findings: In a prospective study of school children in Northern Thailand, we describe the spatial and temporal variation of the symptomatic to inapparent (S:I) dengue illness ratio. Our findings indicate that there is a wide fluctuation in this ratio between and among schools in a given year and within schools over several dengue seasons. The most important determinants of this S:I ratio for a given school were the incidence of dengue infection in a given year and the incidence of infection in the preceding year. We found no association between the S:I ratio and age in our population.

Conclusions/significance: Our findings point to an important aspect of virus-host interactions at either a population or individual level possibly due to an effect of heterotypic cross-reactive immunity to reduce dengue disease severity. These findings have important implications for future dengue vaccines.
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http://dx.doi.org/10.1371/journal.pntd.0000975DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3046956PMC
March 2011

Factors influencing dengue virus isolation by C6/36 cell culture and mosquito inoculation of nested PCR-positive clinical samples.

Am J Trop Med Hyg 2011 Feb;84(2):218-23

Department of Virology, United States Army Medical Component, Armed Forces Research, Institute of Medical Sciences, Bangkok, Thailand.

Dengue viral isolation is necessary for definitive diagnosis, pathogenesis and evolutionary research, vaccine candidates, and diagnostic materials. Using standardized techniques, we analyzed isolation rates of 1,544 randomly selected polymerase chain reaction (PCR)-positive samples, representing all four dengue serotypes, from patients with serologically confirmed dengue infections and evaluated whether clinical and laboratory results could be predictive of isolation using standard and mosquito isolation techniques. Viruses were isolated from 62.5% of the samples by direct application to C6/36 cells and increased to 79.4% when amplifying C6/36 negative samples by intrathorasic inoculation in Toxyrhynchites splendens mosquitoes. High viremia, measured by reverse transcriptase (RT)-PCR, was a strong predictor for viral isolation by either method. Isolation was most successful in samples collected early in the disease, had low antibody levels, temperatures greater than 38°C, and had a final clinical diagnosis of dengue fever. Dengue serotypes also played a role in the success of viral isolation.
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http://dx.doi.org/10.4269/ajtmh.2011.09-0798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3029170PMC
February 2011

Dengue plaque reduction neutralization test (PRNT) in primary and secondary dengue virus infections: How alterations in assay conditions impact performance.

Am J Trop Med Hyg 2009 Nov;81(5):825-33

Department of Virology, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand.

Dengue virus (DENV) infection is a worsening global health problem. The plaque reduction neutralization test (PRNT) is currently considered to be the "gold standard" to characterize and quantify circulating levels of anti-DENV neutralizing antibody (NAb). Many variations of the PRNT are currently in use and neither the assay nor its performance conditions have been standardized or harmonized between laboratories. We used a well-characterized panel of acute and late convalescent follow-up sera samples from children experiencing primary and secondary DENV infections to evaluate the performance of the dengue PRNT under a variety of testing conditions. Investigators varied cell type, control virus passage, and the use of complement across multiple assay runs of the same sample panel. Our findings indicate wide variation in PRNT titer results in response to varied testing conditions.
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http://dx.doi.org/10.4269/ajtmh.2009.08-0625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2835862PMC
November 2009

Men who target women: specificity of target, generality of aggressive behavior.

Aggress Behav 2008 Nov-Dec;34(6):605-22

Department of Psychology and the Center for the Study of Violence, Iowa State University, Ames, Iowa 50011-3180, USA.

Two studies examined the effects of individual differences identified by the Confluence Model of aggression against women [Malamuth Linz, Hevey et al., 1995] and the General Aggression Model [GAM: Anderson and Carnagey, 2004] as predictors of male-on-female aggression. Study 1, a correlational study, found that hostile masculinity predicts self-reported sexual aggression independently of nonsexual aggression against women, and is itself predicted by proneness to general hostility, masculine gender role stress, and violent attitudes toward women. Furthermore, hostility toward women independently predicted sexual and nonsexual aggression against women, above the effects of general attitudes toward violence and general levels of hostility and aggression. Study 2, an experimental study, found that under high provocation, high hostility toward women predicted increases in male nonsexual aggression against women and slight decreases in male aggression against men. This effect remained significant even after controlling for general attitudes toward violence and for general levels of hostility and aggression, indicating that males who are highly hostile toward women specifically target women and that their aggression toward women generalizes beyond sexual aggression. The findings are discussed in terms of a model that integrates the Confluence Model with GAM.
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http://dx.doi.org/10.1002/ab.20274DOI Listing
December 2008
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