Publications by authors named "Timothy P Endy"

93 Publications

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

Historical Analysis of the Risk of Hepatitis E and Its Complications in Pregnant Women in Nepal, 1996-1998.

Am J Trop Med Hyg 2021 Jun 14. Epub 2021 Jun 14.

6Department of Virus Diseases, Walter Reed Army Institute of Research, Silver Spring, Maryland.

Hepatitis E (HE) during pregnancy can be fatal; there are no prospective risk estimates for HE and its complications during pregnancy. We followed 2,404 pregnant women for HE and pregnancy outcomes from 1996 to 1998. Subjects from Nepal were enrolled at an antenatal clinic with pregnancy of ≤ 24 weeks. Most women (65.1%) were anti-HE virus negative. There were 16 cases of HE (6.7 per 1,000); three mothers died (18.8%) having had intrauterine fetal death (IUFD). Thirteen mothers survived: five preterm and seven full-term deliveries, one IUFD. HE among seronegative women was the sole cause of maternal death and increased the risk of IUFD (relative risk [RR]: 10.6; 95% confidence interval [CI]: 4.29-26.3) and preterm delivery (RR: 17.1, 95% CI 7.56-38.5). HE vaccination of females in at-risk regions before or as they attain reproductive age would reduce their risk for preterm delivery, IUFD, and maternal death.
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http://dx.doi.org/10.4269/ajtmh.20-1007DOI Listing
June 2021

Persistent COVID-19 Symptoms Minimally Impact the Development of SARS-CoV-2-Specific T Cell Immunity.

Viruses 2021 05 15;13(5). Epub 2021 May 15.

Department of Microbiology and Immunology, State University of New York Upstate Medical University, Syracuse, NY 13210, USA.

SARS-CoV-2 represents an unprecedented public health challenge. While the majority of SARS-CoV-2-infected individuals with mild-to-moderate COVID-19 resolve their infection with few complications, some individuals experience prolonged symptoms lasting for weeks after initial diagnosis. Persistent viral infections are commonly accompanied by immunologic dysregulation, but it is unclear if persistent COVID-19 impacts the development of virus-specific cellular immunity. To this end, we analyzed SARS-CoV-2-specific cellular immunity in convalescent COVID-19 patients who experienced eight days or fewer of COVID-19 symptoms or symptoms persisting for 18 days or more. We observed that persistent COVID-19 symptoms were not associated with the development of an overtly dysregulated cellular immune response. Furthermore, we observed that reactivity against the N protein from SARS-CoV-2 correlates with the amount of reactivity against the seasonal human coronaviruses 229E and NL63. These results provide insight into the processes that regulate the development of cellular immunity against SARS-CoV-2 and related human coronaviruses.
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http://dx.doi.org/10.3390/v13050916DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8155927PMC
May 2021

Exploring the utility of social-ecological and entomological risk factors for dengue infection as surveillance indicators in the dengue hyper-endemic city of Machala, Ecuador.

PLoS Negl Trop Dis 2021 03 19;15(3):e0009257. Epub 2021 Mar 19.

Quantitative Disease Ecology and Conservation (QDEC) Lab Group, Department of Geography, University of Florida, Gainesville, Florida, United States of America.

The management of mosquito-borne diseases is a challenge in southern coastal Ecuador, where dengue is hyper-endemic and co-circulates with other arboviral diseases. Prior work in the region has explored social-ecological factors, dengue case data, and entomological indices. In this study, we bring together entomological and epidemiological data to describe links between social-ecological factors associated with risk of dengue transmission at the household level in Machala, Ecuador. Households surveys were conducted from 2014-2017 to assess the presence of adult Aedes aegypti (collected via aspiration) and to enumerate housing conditions, demographics, and mosquito prevention behaviors. Household-level dengue infection status was determined by laboratory diagnostics in 2014-2015. Bivariate analyses and multivariate logistic regression models were used to identify social-ecological variables associated with household presence of female Ae. aegypti and household dengue infection status, respectively. Aedes aegypti presence was associated with interruptions in water service and weekly trash collection, and household air conditioning was protective against mosquito presence. Presence of female Ae. aegypti was not associated with household dengue infections. We identified shaded patios and head of household employment status as risk factors for household-level dengue infection, while window screening in good condition was identified as protective against dengue infection. These findings add to our understanding of the systems of mosquito-borne disease transmission in Machala, and in the larger region of southern Ecuador, aiding in the development of improved vector surveillance efforts, and targeted interventions.
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http://dx.doi.org/10.1371/journal.pntd.0009257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011822PMC
March 2021

Switched and unswitched memory B cells detected during SARS-CoV-2 convalescence correlate with limited symptom duration.

PLoS One 2021 28;16(1):e0244855. Epub 2021 Jan 28.

Department of Microbiology and Immunology, Upstate Medical University, Syracuse, New York, United States of America.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic human respiratory illness COVID-19, is a global health emergency. While severe acute disease has been linked to an expansion of antibody-secreting plasmablasts, we sought to identify B cell responses that correlated with positive clinical outcomes in convalescent patients. We characterized the peripheral blood B cell immunophenotype and plasma antibody responses in 40 recovered non-hospitalized COVID-19 subjects that were enrolled as donors in a convalescent plasma treatment study. We observed a significant negative correlation between the frequency of peripheral blood memory B cells and the duration of symptoms for convalescent subjects. Memory B cell subsets in convalescent subjects were composed of classical CD24+ class-switched memory B cells, but also activated CD24-negative and natural unswitched CD27+ IgD+ IgM+ subsets. Memory B cell frequency was significantly correlated with both IgG1 and IgM responses to the SARS-CoV-2 spike protein receptor binding domain (RBD) in most seropositive subjects. IgM+ memory, but not switched memory, directly correlated with virus-specific antibody responses, and remained stable over 3 months. Our findings suggest that the frequency of memory B cells is a critical indicator of disease resolution, and that IgM+ memory B cells may play an important role in SARS-CoV-2 immunity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0244855PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7843013PMC
February 2021

Mobilization and Activation of the Innate Immune Response to Dengue Virus.

Front Cell Infect Microbiol 2020 3;10:574417. Epub 2020 Nov 3.

Department of Microbiology and Immunology, State University of New York (SUNY) Upstate Medical University, Syracuse, NY, United States.

Dengue virus is an important human pathogen, infecting an estimated 400 million individuals per year and causing symptomatic disease in a subset of approximately 100 million. Much of the effort to date describing the host response to dengue has focused on the adaptive immune response, in part because of the well-established roles of antibody-dependent enhancement and T cell original sin as drivers of severe dengue upon heterotypic secondary infection. However, the innate immune system is a crucial factor in the host response to dengue, as it both governs the fate and vigor of the adaptive immune response, and mediates the acute inflammatory response in tissues. In this review, we discuss the innate inflammatory response to dengue infection, focusing on the role of evolutionarily conserved innate immune cells, their effector functions, and clinical course.
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http://dx.doi.org/10.3389/fcimb.2020.574417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7670994PMC
June 2021

Immunogenicity of a Live-Attenuated Dengue Vaccine Using a Heterologous Prime-Boost Strategy in a Phase 1 Randomized Clinical Trial.

J Infect Dis 2021 May;223(10):1707-1716

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

Background: Dengue is a global health problem and the development of a tetravalent dengue vaccine with durable protection is a high priority. A heterologous prime-boost strategy has the advantage of eliciting immune responses through different mechanisms and therefore may be superior to homologous prime-boost strategies for generating durable tetravalent immunity.

Methods: In this phase 1 first-in-human heterologous prime-boost study, 80 volunteers were assigned to 4 groups and received a tetravalent dengue virus (DENV-1-4) purified inactivated vaccine (TDENV-PIV) with alum adjuvant and a tetravalent dengue virus (DENV-1-4) live attenuated vaccine (TDENV-LAV) in different orders and dosing schedules (28 or 180 days apart).

Results: All vaccination regimens had acceptable safety profiles and there were no vaccine-related serious adverse events. TDEN-PIV followed by TDEN-LAV induced higher neutralizing antibody titers and a higher rate of tetravalent seroconversions compared to TDEN-LAV followed by TDEN-PIV. Both TDEN-PIV followed by TDEN-LAV groups demonstrated 100% tetravalent seroconversion 28 days following the booster dose, which was maintained for most of these subjects through the day 180 measurement.

Conclusions: A heterologous prime-boost vaccination strategy for dengue merits additional evaluation for safety, immunogenicity, and potential for clinical benefit.

Clinical Trials Registration: NCT02239614.
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http://dx.doi.org/10.1093/infdis/jiaa603DOI Listing
May 2021

Switched and unswitched memory B cells detected during SARS-CoV-2 convalescence correlate with limited symptom duration.

medRxiv 2020 Sep 5. Epub 2020 Sep 5.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of the pandemic human respiratory illness COVID-19, is a global health emergency. While severe acute disease has been linked to an expansion of antibody-secreting plasmablasts, we sought to identify B cell responses that correlated with positive clinical outcomes in convalescent patients. We characterized the peripheral blood B cell immunophenotype and plasma antibody responses in 40 recovered non-hospitalized COVID-19 subjects that were enrolled as donors in a convalescent plasma treatment study. We observed a significant negative correlation between the frequency of peripheral blood memory B cells and the duration of symptoms for convalescent subjects. Memory B cell subsets in convalescent subjects were composed of classical CD24+ class-switched memory B cells, but also activated CD24-negative and natural unswitched CD27+ IgD+ IgM+ subsets. Memory B cell frequency was significantly correlated with both IgG1 and IgM responses to the SARS-CoV-2 spike protein receptor binding domain (RBD). IgM+ memory, but not switched memory, directly correlated with virus-specific antibody responses, and remained stable over time. Our findings suggest that the frequency of memory B cells is a critical indicator of disease resolution, and that IgM+ memory B cells play an important role in SARS-CoV-2 immunity.
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http://dx.doi.org/10.1101/2020.09.04.20187724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480039PMC
September 2020

A comparison of passive surveillance and active cluster-based surveillance for dengue fever in southern coastal Ecuador.

BMC Public Health 2020 Jul 6;20(1):1065. Epub 2020 Jul 6.

Institute for Global Health and Translational Science, SUNY Upstate Medical University, 505 Irving Avenue Suite 4200, Syracuse, NY, USA.

Background: Dengue is a major emerging infectious disease, endemic throughout the tropics and subtropics, with approximately 2.5 billion people at risk globally. Active (AS) and passive surveillance (PS), when combined, can improve our understanding of dengue's complex disease dynamics to guide effective, targeted public health interventions. The objective of this study was to compare findings from the Ministry of Health (MoH) PS to a prospective AS arbovirus research study in Machala, Ecuador in 2014 and 2015.

Methods: Dengue cases in the PS system were compared to laboratory confirmed acute dengue illness cases that entered the AS study during the study period. Variables of interest included age class and sex. Outbreak detection curves by epidemiologic week, overall cumulative incidence and age-specific incidence proportions were calculated. Descriptive statistics were tabulated for all variables of interest. Chi-square tests were performed to compare demographic characteristics between the AS and PS data sets in 2014 and 2015.

Results: 177 and 245 cases were identified from 1/1/2014 to 12/31/2015 by PS and AS, respectively; nine cases appeared in both systems. AS identified a greater number of laboratory-confirmed cases in 2014, accounting for more than 60% of dengue cases in the study area. In 2015, the opposite trend was observed with PS identifying 60% of the dengue cases in the study area. Peak transmission time in laboratory confirmed dengue illness, as noted by AS and PS was similar in 2014, whereas earlier detection (7 weeks) was observed by AS in 2015. Younger patients were more frequently identified by PS, while older patients were identified more frequently by AS. The cumulative incidence proportion for laboratory confirmed dengue illness reported via PS to the MoH was 4.12 cases per 10,000 residents in 2014, and 2.21 cases per 10,000 residents in 2015.

Conclusions: Each surveillance system captured distinct demographic subgroups within the Machala population, possibly due to differences in healthcare seeking behaviors, access to care, emerging threats of other viruses transmitted by the same mosquito vector and/or differences in clinical presentation. Integrating AS with pre-existing PS can aid in identifying additional cases in previously underdiagnosed subpopulations, improving our understanding of disease dynamics, and facilitating the implementation of timely public health interventions.
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http://dx.doi.org/10.1186/s12889-020-09168-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7336448PMC
July 2020

Cefiderocol for treatment of an empyema due to extensively drug-resistant : Clinical observations and susceptibility testing considerations.

IDCases 2020 3;21:e00863. Epub 2020 Jun 3.

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

Cefiderocol is a novel siderophore cephalosporin antibacterial with activity against carbapenem-resistant Gram-negative bacteria including . We report a medically complex patient treated with compassionate use cefiderocol for an empyema caused by extensively drug-resistant as well as clinical considerations for cefiderocol use based on our findings. We observed a potential discordance in cefiderocol susceptibility testing results depending if disk diffusion or iron-depleted cation-adjusted Mueller Hinton Broth dilution is used. Furthermore, interpretative criteria differ between the Clinical Laboratory Standards Institute and United States Food and Drug Administration for , which makes cefiderocol interpretation potentially challenging for clinicians. We may have also observed selective pressure from prior cefiderocol exposure given the respective increases and decreases in MIC values and zone diameters for isolates following cefiderocol treatment. Additional data are needed to further describe cefiderocol use, susceptibility testing, and resistance development as real-world clinical use expands.
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http://dx.doi.org/10.1016/j.idcr.2020.e00863DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7300106PMC
June 2020

A Phase 1, Open-Label Assessment of a Dengue Virus-1 Live Virus Human Challenge Strain.

J Infect Dis 2021 Feb;223(2):258-267

Institute for Global Health and Translational Science, Department of Microbiology and Immunology, and Department of Public Health and Preventive Medicine, State University of New York, Upstate Medical University, Syracuse, New York, USA.

Background: Dengue human infection models (DHIM) have been used as a safe means to test the viability of prophylaxis and therapeutics.

Methods: A phase 1 study of 12 healthy adult volunteers using a challenge virus, DENV-1-LVHC strain 45AZ5, was performed. A dose escalating design was used to determine the safety and performance profile of the challenge virus. Subjects were evaluated extensively until 28 days and then out to 6 months.

Results: Twelve subjects received the challenge virus: 6 with 0.5 mL of 6.5 × 103 plaque-forming units (PFU)/mL (low-dose group) and 6 with 0.5 mL of 6.5 × 104 PFU/mL (mid-dose group). All except 1 in the low-dose group developed detectable viremia. For all subjects the mean incubation period was 5.9 days (range 5-9 days) and mean time of viremia was 6.8 days (range 3-9 days). Mean peak for all subjects was 1.6 × 107 genome equivalents (GE)/mL (range 4.6 × 103 to 5 × 107 GE/mL). There were no serious adverse events or long-term safety signals noted.

Conclusions: We conclude that DENV-1-LVHC was well-tolerated, resulted in an uncomplicated dengue illness, and may be a suitable DHIM for therapeutic and prophylactic product testing.

Clinical Trials Registration: NCT02372175.
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http://dx.doi.org/10.1093/infdis/jiaa351DOI Listing
February 2021

Determining the Impact of the Opioid Crisis on a Tertiary-Care Hospital in Central New York to Identify Critical Areas of Intervention in the Local Community.

J Addict 2020 12;2020:3956187. Epub 2020 Mar 12.

Departments of Medicine, Pathology, Public Health and Microbiology and Immunology, State University of New York, Upstate Medical University, Syracuse, USA.

Background: Central New York has been afflicted by the heroin epidemic with an increase in overdose deaths involving opioids.

Objective: The objective of the study was to understand the epidemiology of hospitalizations related to a diagnosis of opioid use (OU).

Design: The study was designed as a retrospective analysis of hospitalized patients admitted from January 1, 2008, to December 30, 2018, using ICD-9 and 10 codes for heroin or opiate use, overdose, or poisoning. . The study was conducted in a tertiary-care and teaching hospital located in Central New York. . Hospitalized patients were included as study participants.

Results: Opioid use-related admissions increased from .05/100 hospital admissions in 2008 to a peak of 2.9/100 in 2018, a 58-fold increase. There were 49 deaths over the 11-year period for an overall case fatality of 1.2 per 100 OU admissions. The median age for all years was 40 years (SD of 13.7 years), and admissions were largely white caucasians (67.0% of all admissions). The mean length of stay was 8.55 days (SD 12 days), with a range of 1 to 153 days. The most frequent discharge diagnosis was due to infections (15.0% of discharge diagnoses) followed by trauma (5.8% of discharge diagnoses). Methicillin-resistant was more common in patients with OU (58.1%) than in patients with non-OU (43%) ( < 0.0001 by chi-square with Yates' correction). Spatial analysis was performed by zip code and demonstrated regional hotspots for OU-related admissions. . The limitations of this study are its retrospective nature and largely numerator-based analysis. The use of ICD codes underrepresents the true burden due to underreporting and failure to code appropriately. This study focuses on patients who are hospitalized for a medical reason with a secondary diagnosis of opioid use and does not include patients who present to the emergency room with an overdose underrepresenting the true burden of the problem.

Conclusions: Our results demonstrate the impact of the opioid epidemic in one tertiary-care center and the need to prepare for the costs and resources to address addiction care for this population.
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http://dx.doi.org/10.1155/2020/3956187DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7091543PMC
March 2020

Dengue virus non-structural protein 1 activates the p38 MAPK pathway to decrease barrier integrity in primary human endothelial cells.

J Gen Virol 2020 05 4;101(5):484-496. Epub 2020 Mar 4.

Department of Microbiology and Immunology, SUNY Upstate Medical University, Syracuse NY, USA.

Dengue virus (DENV) causes an estimated 390 million infections worldwide annually, with severe forms of disease marked by vascular leakage. Endothelial cells (EC) are directly responsible for vascular homeostasis and are highly responsive to circulating mediators but are not commonly infected. DENV encodes seven non-structural (NS) proteins; with only one of those, NS1, secreted from infected cells and accumulating in the blood of patients. NS1 has been implicated in the pathogenesis of vascular permeability, but the mechanism is not completely understood. Here we used primary endothelial cells and an array of approaches to study the effect of NS1 in disease-relevant human ECs. Confocal microscopy demonstrated rapid NS1 internalization by ECs into endosomes with accumulation over time. Transcriptomic and pathway analysis showed significant changes in functions associated with EC homeostasis and vascular permeability. Functional significance of this activation was assessed by trans-endothelial electrical resistance and showed that NS1 induced rapid and transient loss in EC barrier function within 3 h post-treatment. To understand the molecular mechanism by which NS1 induced EC activation, we evaluated the stress-sensing p38 MAPK pathway known to be directly involved in EC permeability and inflammation. WB analysis of NS1-stimulated ECs showed clear activation of p38 MAPK and downstream effectors MAPKAPK-2 and HSP27 with chemical inhibition of the p38 MAP kinase pathway restoring barrier function. Our results suggest that DENV NS1 may be involved in the pathogenesis of severe dengue by activating the p38 MAPK in ECs, promoting increased permeability that characterizes severe disease.
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http://dx.doi.org/10.1099/jgv.0.001401DOI Listing
May 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

Serologic Response of 2 Versus 3 Doses and Intradermal Versus Intramuscular Administration of a Licensed Rabies Vaccine for Preexposure Prophylaxis.

J Infect Dis 2020 04;221(9):1494-1498

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

Background: The World Health Organization recommends intradermal (ID) administration of rabies vaccine for preexposure prophylaxis.

Methods: In a randomized trial in adults assigned to 1 of 6 treatment groups (ID vs intramuscular [IM], 2 vs 3 doses, and controls), rabies neutralizing antibody titers were measured to 1 year postvaccination.

Results: ID vaccination produced acceptable antibody levels in all subjects (2- and 3-dose groups). At day 365, acceptable levels were 40% for IM and 50% for ID 2-dose schedule, and 70% for IM and 60% for ID 3-dose schedule.

Conclusions: ID rabies vaccination induces acceptable antibody titers at a fraction of the dose.

Clinical Trials Registration: NCT02374814.
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http://dx.doi.org/10.1093/infdis/jiz645DOI Listing
April 2020

The Effects of Japanese Encephalitis Vaccine and Accelerated Dosing Scheduling on the Immunogenicity of the Chimeric Yellow Fever Derived Tetravalent Dengue Vaccine: A Phase II, Randomized, Open-Label, Single-Center Trial in Adults Aged 18 to 45 Years in the United States.

J Infect Dis 2020 03;221(7):1057-1069

Institute for Global Health and Translational Sciences, Microbiology and Immunology, and Public Health, State University of New York, Upstate Medical University.

Background: Dengue is a global health problem requiring an effective, safe dengue vaccine.

Methods: We report the results of a phase II, randomized, open-label, single-center trial in adults aged 18 to 45 years in the United States designed to explore the effects of the Chimeric Yellow Fever Derived Tetravalent Dengue Vaccine (CYD-TDV, Dengvaxia) when administered on its designated schedule (months 0, 6, and 12) or on an accelerated dosing schedule (months 0, 2, and 6) and/or given before, or concomitantly with, a vaccine against Japanese encephalitis (JE).

Results: Based on dengue virus serotype-specific neutralizing antibody (NAb), the accelerated dosing schedule was comparable to the 0, 6, and 12-month schedule. Giving JE vaccine concurrently with CYD-TDV did not result in an increase in overall NAb titers. Immunophenotyping of peripheral blood mononuclear cells revealed an increase in activated CD8+ T cells after CYD-TDV vaccination, a phenomenon that was greatest for the JE vaccine primed.

Conclusions: We conclude that an accelerated dosing schedule of CYD-TDV results in essentially equivalent dengue serotype-specific NAb titers as the currently used schedule, and there may be an early benefit in antibody titers and activated CD8+ T cells by the administration of the JE vaccine before CYD-TDV vaccination.
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http://dx.doi.org/10.1093/infdis/jiz592DOI Listing
March 2020

Effect of Antimalarial Drugs on the Immune Response to Intramuscular Rabies Vaccination Using a Postexposure Prophylaxis Regimen.

J Infect Dis 2020 03;221(6):927-933

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

Background: Chloroquine can impair the immune responses to intradermal rabies vaccination. Current guidelines recommend an extra intramuscular dose be given for postexposure prophylaxis in previously unvaccinated persons taking any antimalarial drug.

Methods: We conducted a randomized, open-label, single-site study in 103 previously unvaccinated healthy adults age ≥18 to ≤60 years old to evaluate the effects of chloroquine, atovaquone/proguanil (Malarone), and doxycycline on the antibody response to a purified chick embryo cell vaccine, given on a postexposure prophylaxis schedule. All treatment groups received antimalarials 14 days prior to and during vaccination.

Results: All subjects achieved accepted neutralizing antibody titers of ≥0.5 IU/mL following the second rabies vaccination dose and maintained this protection through the duration of the study. We observed a reduction in rabies antibody geometric mean titer in the chloroquine versus control groups 28 days after vaccination: 2.3 versus 6.87 IU/mL, respectively (P < .001, t test). A significant difference was not observed for those taking Malarone or doxycycline.

Conclusions: We conclude that there is no reduction of rabies antibody response in subjects taking Malarone or doxycycline, but a significant reduction in those taking chloroquine; however, accepted antibody levels were achieved for all 3 antimalarials.

Clinical Trials Registration: NCT02564471.
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http://dx.doi.org/10.1093/infdis/jiz558DOI Listing
March 2020

Detection of Antibodies to Spotted Fever Group Rickettsiae and Arboviral Coinfections in Febrile Individuals in 2014-2015 in Southern Coastal Ecuador.

Am J Trop Med Hyg 2019 11;101(5):1087-1090

State University of New York Upstate Medical University, Syracuse, New York.

Tick-borne diseases (TBDs) are a growing public health threat and are increasingly identified as the cause of undifferentiated febrile illness. There is a significant gap in our understanding of ticks and their associated pathogens in Ecuador. An arboviral surveillance study allowed us to explore potential exposure to TBDs in febrile subjects. We tested plasma samples from 222 febrile subjects for spotted fever group rickettsial (SFGR) antibodies from southern coastal Ecuador in 2014-2015 via ELISA. Fifty-five (25%) subjects had evidence of anti-SFRG IgG or IgM antibodies. Although attempts to detect species in plasma by polymerase chain reaction were unsuccessful, these preliminary data suggest the possibility of endemic SFGR transmission in Ecuador. To better understand the burden and entomological risk for TBDs in Ecuador, future studies should expand TBD surveillance in humans, document common human-biting ticks, and measure pathogen carriage rates in questing ticks.
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http://dx.doi.org/10.4269/ajtmh.19-0157DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838566PMC
November 2019

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

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

Chagas Disease in Southern Coastal Ecuador: Coinfections with Arboviruses and a Comparison of Serological Assays for Chagas Disease Diagnosis.

Am J Trop Med Hyg 2018 12 18;99(6):1530-1533. Epub 2018 Oct 18.

Department of Medicine, SUNY Upstate Medical University, Syracuse, New York.

Occurrence of Chagas disease and arbovirus coinfections is unknown, despite the vast co-endemic areas throughout the Americas. This study examined the proportion of individuals positive for and coinfections with dengue, chikungunya, and Zika viruses in Machala, Ecuador (January 2014-December 2015). Chagas seropositivity was evaluated with five commercially available assays. Dengue infections were identified by nonstructural protein 1 rapid test and enzyme linked immunosorbent assay (ELISA), immunoglobulin M ELISA, and reverse transcription PCR (RT-PCR); chikungunya and Zika infections were identified by RT-PCR. Of 658 individuals, six were positive for (0.91%), including one /dengue coinfection and one /chikungunya/dengue coinfection. The clinical manifestations of coinfected individuals corresponded to severe dengue and dengue with warning signs, respectively. We observed discrepant results by using the Hemagen Chagas kit and the rapid test Chagas Detect Plus (false positives: 3.9% and 15.4%), highlighting the need to assess diagnostic assays in geographic regions with distinct taxonomic units of
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http://dx.doi.org/10.4269/ajtmh.18-0441DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6283517PMC
December 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

The Burden of Dengue Fever and Chikungunya in Southern Coastal Ecuador: Epidemiology, Clinical Presentation, and Phylogenetics from the First Two Years of a Prospective Study.

Am J Trop Med Hyg 2018 05 1;98(5):1444-1459. Epub 2018 Mar 1.

Department of Microbiology and Immunology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York.

Here, we report the findings from the first 2 years (2014-2015) of an arbovirus surveillance study conducted in Machala, Ecuador, a dengue-endemic region. Patients with suspected dengue virus (DENV) infections (index cases, = 324) were referred from five Ministry of Health clinical sites. A subset of DENV-positive index cases ( = 44) were selected, and individuals from the index household and four neighboring homes within 200 m were recruited ( = 400). Individuals who entered the study, other than the index cases, are referred to as associates. In 2014, 70.9% of index cases and 35.6% of associates had acute or recent DENV infections. In 2015, 28.3% of index cases and 12.8% of associates had acute or recent DENV infections. For every DENV infection captured by passive surveillance, we detected an additional three acute or recent DENV infections in associates. Of associates with acute DENV infections, 68% reported dengue-like symptoms, with the highest prevalence of symptomatic acute infections in children aged less than 10 years. The first chikungunya virus (CHIKV) infections were detected on epidemiological week 12 in 2015; 43.1% of index cases and 3.5% of associates had acute CHIKV infections. No Zika virus infections were detected. Phylogenetic analyses of isolates of DENV from 2014 revealed genetic relatedness and shared ancestry of DENV1, DENV2, and DENV4 genomes from Ecuador with those from Venezuela and Colombia, indicating the presence of viral flow between Ecuador and surrounding countries. Enhanced surveillance studies, such as this, provide high-resolution data on symptomatic and inapparent infections across the population.
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http://dx.doi.org/10.4269/ajtmh.17-0762DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5953373PMC
May 2018

Case Report: An Acute Chikungunya Infection and a Recent Secondary Dengue Infection in a Peripartum Case in Ecuador.

Am J Trop Med Hyg 2018 03 18;98(3):838-840. Epub 2018 Jan 18.

Department of Medicine, SUNY Upstate Medical University, Syracuse, New York.

Dengue virus (DENV) and chikungunya virus (CHIKV) are transmitted by the same mosquito vectors and now co-circulate in many parts of the world; however, coinfections and serial infections are not often diagnosed or reported. A 38-week pregnant woman was admitted to the hospital with a diagnosis of suspected DENV and CHIKV in southern coastal Ecuador. The pregnancy was complicated by mild polyhydramnios and fetal tachycardia, and a healthy newborn was born. The patient was positive for a recent secondary DENV infection (Immunoglobulin M and Immunoglobulin G positive) and an acute CHIKV infection (real-time reverse transcriptase polymerase chain reaction positive) (Asian genotype). The newborn was not tested for either virus. This case resulted in a benign clinical course with a favorable pregnancy outcome.
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http://dx.doi.org/10.4269/ajtmh.17-0781DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5930918PMC
March 2018

Social-ecological factors and preventive actions decrease the risk of dengue infection at the household-level: Results from a prospective dengue surveillance study in Machala, Ecuador.

PLoS Negl Trop Dis 2017 12 18;11(12):e0006150. Epub 2017 Dec 18.

Center for Global Health & Translational Sciences, SUNY Upstate Medical University, Syracuse, NY, United States of America.

Background: In Ecuador, dengue virus (DENV) infections transmitted by the Aedes aegypti mosquito are among the greatest public health concerns in urban coastal communities. Community- and household-level vector control is the principal means of controlling disease outbreaks. This study aimed to assess the impact of knowledge, attitudes, and practices (KAPs) and social-ecological factors on the presence or absence of DENV infections in the household.

Methods: In 2014 and 2015, individuals with DENV infections from sentinel clinics in Machala, Ecuador, were invited to participate in the study, as well as members of their household and members of four neighboring households located within 200 meters. We conducted diagnostic testing for DENV on all study participants; we surveyed heads of households (HOHs) regarding demographics, housing conditions and KAPs. We compared KAPs and social-ecological factors between households with (n = 139) versus without (n = 80) DENV infections, using bivariate analyses and multivariate logistic regression models with and without interactions.

Results: Significant risk factors in multivariate models included proximity to abandoned properties, interruptions in piped water, and shaded patios (p<0.05). Significant protective factors included the use of mosquito bed nets, fumigation inside the home, and piped water inside the home (p<0.05). In bivariate analyses (but not multivariate modeling), DENV infections were positively associated with HOHs who were male, employed, and of younger age than households without infections (p<0.05). DENV infections were not associated with knowledge, attitude, or reported barriers to prevention activities.

Discussion: Specific actions that can be considered to decrease the risk of DENV infections in the household include targeting vector control in highly shaded properties, fumigating inside the home, and use of mosquito bed nets. Community-level interventions include cleanup of abandoned properties, daily garbage collection, and reliable piped water inside houses. These findings can inform interventions to reduce the risk of other diseases transmitted by the Ae. aegypti mosquito, such as chikungunya and Zika fever.
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http://dx.doi.org/10.1371/journal.pntd.0006150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771672PMC
December 2017

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

Improving dengue virus capture rates in humans and vectors in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance strategy.

Am J Trop Med Hyg 2015 Jul 18;93(1):24-32. Epub 2015 May 18.

Viral Diseases Branch, Walter Reed Army Institute of Research, Silver Spring, Maryland; Department of Virology, United States Army Medical Component, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Department of Geography, University at Buffalo, Buffalo, New York; Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand; Bureau of Epidemiology, Department of Disease Control Sciences, Ministry of Public Health, Nonthaburi, Thailand; Department of Entomology, University of California, Davis, Davis, California; Institute for Immunology and Informatics, University of Rhode Island, Providence, Rhode Island; Insect-Virus Interactions Group, Department of Genomes and Genetics, Institut Pasteur, Centre National de la Recherche Scientifique, Paris, France; Department of Infectious Diseases, State University of New York, Syracuse, New York; Fogarty International Center, National Institutes of Health, Bethesda, Maryland.

Dengue is of public health importance in tropical and sub-tropical regions. Dengue virus (DENV) transmission dynamics was studied in Kamphaeng Phet Province, Thailand, using an enhanced spatiotemporal surveillance of 93 hospitalized subjects with confirmed dengue (initiates) and associated cluster individuals (associates) with entomologic sampling. A total of 438 associates were enrolled from 208 houses with household members with a history of fever, located within a 200-m radius of an initiate case. Of 409 associates, 86 (21%) had laboratory-confirmed DENV infection. A total of 63 (1.8%) of the 3,565 mosquitoes collected were dengue polymerase chain reaction positive (PCR+). There was a significant relationship between spatial proximity to the initiate case and likelihood of detecting DENV from associate cases and Aedes mosquitoes. The viral detection rate from human hosts and mosquito vectors in this study was higher than previously observed by the study team in the same geographic area using different methodologies. We propose that the sampling strategy used in this study could support surveillance of DENV transmission and vector interactions.
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http://dx.doi.org/10.4269/ajtmh.14-0242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4497898PMC
July 2015

Case report: Non-invasive management of Madura foot with oral posaconazole and ciprofloxacin.

Am J Trop Med Hyg 2014 Dec 27;91(6):1259-62. Epub 2014 Oct 27.

Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York; Division of Infections Disease, Department of Medicine, State University of New York, Upstate Medical University, Syracuse, New York

Madura foot is a chronic infection caused by fungus and/or bacteria. Traditionally, treatment has been surgical debridement or amputation. Non-invasive management with long-term antimicrobials alone has been reported as successful. We report a case of Madura foot in a Somali refugee successfully managed with oral posaconazole and ciprofloxacin.
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http://dx.doi.org/10.4269/ajtmh.14-0335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4257656PMC
December 2014
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