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BackgroundThe COVID-19 standard of care (SOC) evolved rapidly during 2020 and 2021, but its cumulative effect over time is unclear.ObjectiveTo evaluate whether recovery and mortality improved as SOC evolved, using data from ACTT (Adaptive COVID-19 Treatment Trial).DesignACTT is a series of phase 3, randomized, double-blind, placebo-controlled trials that evaluated COVID-19 therapeutics from February 2020 through May 2021. ACTT-1 compared remdesivir plus SOC to placebo plus SOC, and in ACTT-2 and ACTT-3, remdesivir plus SOC was the control group. This post hoc analysis compared recovery and mortality between these comparable sequential cohorts of patients who received remdesivir plus SOC, adjusting for baseline characteristics with propensity score weighting. The analysis was repeated for participants in ACTT-3 and ACTT-4 who received remdesivir plus dexamethasone plus SOC. Trends in SOC that could explain outcome improvements were analyzed. (ClinicalTrials.gov: NCT04280705 [ACTT-1], NCT04401579 [ACTT-2], NCT04492475 [ACTT-3], and NCT04640168 [ACTT-4]).Setting94 hospitals in 10 countries (86% U.S. participants).ParticipantsAdults hospitalized with COVID-19.InterventionSOC.Measurements28-day mortality and recovery.ResultsAlthough outcomes were better in ACTT-2 than in ACTT-1, adjusted hazard ratios (HRs) were close to 1 (HR for recovery, 1.04 [95% CI, 0.92 to 1.17]; HR for mortality, 0.90 [CI, 0.56 to 1.40]). Comparable patients were less likely to be intubated in ACTT-2 than in ACTT-1 (odds ratio, 0.75 [CI, 0.53 to 0.97]), and hydroxychloroquine use decreased. Outcomes improved from ACTT-2 to ACTT-3 (HR for recovery, 1.43 [CI, 1.24 to 1.64]; HR for mortality, 0.45 [CI, 0.21 to 0.97]). Potential explanatory factors (SOC trends, case surges, and variant trends) were similar between ACTT-2 and ACTT-3, except for increased dexamethasone use (11% to 77%). Outcomes were similar in ACTT-3 and ACTT-4. Antibiotic use decreased gradually across all stages.LimitationUnmeasured confounding.ConclusionChanges in patient composition explained improved outcomes from ACTT-1 to ACTT-2 but not from ACTT-2 to ACTT-3, suggesting improved SOC. These results support excluding nonconcurrent controls from analysis of platform trials in rapidly changing therapeutic areas.Primary funding sourceNational Institute of Allergy and Infectious Diseases.

Background Clinical trials initiated during emerging infectious disease outbreaks must quickly enroll participants to identify treatments to reduce morbidity and mortality. This may be at odds with enrolling a representative study population especially when the population affected is undefined. Methods We evaluated the utility of CDC COVID-19-Associated Hospitalization Surveillance Network (COVID-NET), COVID-19 Case Surveillance System (CCSS), and 2020 U.S. Census data to determine demographic representation in the four stages of the Adaptive COVID-19 Treatment Trial (ACTT). We compared the cumulative proportion of participants by sex, race, ethnicity, and age enrolled at U.S. ACTT sites, with the respective 95% confidence intervals, to the reference data in forest plots. Results U.S. ACTT sites enrolled 3,509 adults hospitalized with COVID-19. When compared with COVID-NET, ACTT enrolled a similar or higher proportion of Hispanic or Latino and White participants depending on the stage, and a similar proportion of African American participants in all stages. In contrast, ACTT enrolled a higher proportion of these groups when compared with U.S. Census and CCSS. The proportion of participants ages 65 years was either similar or lower than COVID-NET and higher than CCSS and U.S. Census. The proportion of females enrolled in ACTT was lower than the proportion of females in the reference datasets. Conclusions While surveillance data of hospitalized cases may not be available early in an outbreak, it is a better comparator than U.S. Census data and surveillance of all cases, which may not reflect the population affected and at higher risk of severe disease.

We performed a secondary analysis of the National Institutes of Health-sponsored Adaptive COVID-19 Treatment Trial (ACTT-2) randomized controlled trial and found that baricitinib was associated with a 50% reduction in secondary infections after controlling for baseline and postrandomization patient characteristics. This finding provides a novel mechanism of benefit for baricitinib and supports the safety profile of this immunomodulator for the treatment of coronavirus disease 2019.

This post hoc analysis of the Adaptive Coronavirus Disease 2019 (COVID-19) Treatment Trial-1 (ACTT-1) shows a treatment effect of remdesivir (RDV) on progression to invasive mechanical ventilation (IMV) or death. Additionally, we create a risk profile that better predicts progression than baseline oxygen requirement alone. The highest risk group derives the greatest treatment effect from RDV.

INTRODUCTION: Over the past decade, there have been outbreaks associated with high consequence infectious diseases such as Ebola virus disease, Lassa fever, and Monkeypox. The proper handling of clinical waste from patients infected with such pathogens is critical to ensure healthcare personnel and community safety. METHODS: Mock clinical waste bags were created to simulate four distinct waste streams: personal protective equipment (PPE), dry linens, wet linens, and solidified liquids. Pressure and temperature data loggers were buried in the middle of simulated waste loads to record time at a sterilization temperature of 132°C (270°F) to reduce sterilization time. We also validated super rapid biological indicators (BIs) by embedding standard BIs (48 h), rapid BIs (3 h), and super rapid BIs (24 min) within each load. Cycles were validated over a 2-day period, using a total of 36 simulated waste bags (6 bags each for PPE, dry linen, and wet linen, and 18 bags for solidified liquids). RESULTS: All waste bags achieved the target sterilization temperature, all BIs passed and cycle times were substantially decreased. For PPE waste processing, an estimated 15 h was saved for a 24-h period. DISCUSSION: Default factory settings are inadequate to disinfect Category A clinical waste. Reliance on autoclave temperature readings may overestimate time at goal sterilization temperature for actual waste loads. CONCLUSIONS: The data provided by within bag data loggers and BIs allow for the optimization of autoclave parameters to increase throughput and enhance staff safety.

In response to the Ebola outbreak of 2014–2016, the US Office of the Assistant Secretary for Preparedness and Response (ASPR) established 10 regional treatment centers, called biocontainment units (BCUs), to prepare and provide care for patients infected with high-consequence pathogens. Many of these BCUs were among the first units to activate for coronavirus disease 2019 (COVID-19) patient care. The activities of the Johns Hopkins BCU helped prepare the Johns Hopkins Health System for COVID-19 in the 3 domains of containment care: (1) preparedness planning, education and training, (2) patient care and unit operations, and (3) research and innovation. Here, we describe the role of the JH BCU in the Hopkins COVID-19 response to illustrate the value of BCUs in the current pandemic and their potential role in preparing healthcare facilities and health systems for future infectious disease threats.

The biocontainment unit at Johns Hopkins Hospital is a specially designed, inactive high-level isolation unit designated to care for patients infected with high-consequence pathogens. The unit team designed a facility-specific readiness scale and checklist that focus on infrastructure, consumable supplies, and staffing to assess activation readiness of the biocontainment unit. Over a period of 50 days and 14 days, these tools were used as part of a routine risk assessment to first identify barriers and then tier the impact of these barriers into activation categories of "Ready," "Ready with Considerations," and "Not Ready." The assessment identified the greatest risks to activation readiness were staffing and waste management capabilities. Assessing threats to activation readiness and the risk of not being ready should be a priority for maintaining facility, regional, and national capacity to safely isolate and care for patients infected with high-consequence pathogens while maintaining healthcare worker safety.

Summary Background Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19. Methods We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov , NCT04492475 . Findings Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87–1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3–7%) in the interferon beta-1a plus remdesivir group and 3% (2–6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69–2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group. Interpretation Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo. Funding The National Institute of Allergy and Infectious Diseases (USA).

Infectious diseases (ID) physicians play a crucial role in public health in a variety of settings. Unfortunately, much of this work is undercompensated despite the proven efficacy of public health interventions such as hospital acquired infection prevention, antimicrobial stewardship, disease surveillance, and outbreak response. The lack of compensation makes it difficult to attract the best and the brightest to the field of ID, threatening the future of the ID workforce. Here, we examine compensation data for ID physicians compared to their value in population and public health settings and suggest policy recommendations to address the pay disparities that exist between cognitive and procedural specialties that prevent more medical students and residents from entering the field. All ID physicians should take an active role in promoting the value of the subspecialty to policymakers and influencers as well as trainees., Infectious diseases (ID) physicians perform valuable roles protecting public health, but many of their activities are poorly compensated. Compensation policy changes are needed to allow the ID field to continue to attract the best and brightest medical students and residents.

Introduction International travellers contribute to the rapid spread of Zika virus (ZIKV) and its sentinel identification globally. We describe ZIKV infections among international travellers seen at GeoSentinel sites with a focus on ZIKV acquired in the Americas and the Caribbean, describe countries of exposure and traveller characteristics, and assess ZIKV diagnostic testing by site. Methods Records with an international travel-related diagnosis of confirmed or probable ZIKV from January 2012 through December 2019 reported to GeoSentinel with a recorded illness onset date were included to show reported cases over time. Records from March 2016 through December 2019 with an exposure region of the Americas or the Caribbean were included in the descriptive analysis. A survey was conducted to assess the availability, accessibility and utilization of ZIKV diagnostic tests at GeoSentinel sites. Results GeoSentinel sites reported 525 ZIKV cases from 2012 through 2019. Between 2012 and 2014, eight cases were reported, and all were acquired in Asia or Oceania. After 2014, most cases were acquired in the Americas or the Caribbean, a large decline in ZIKV cases occurred in 2018–19. Between March 2016 and December 2019, 423 patients acquired ZIKV in the Americas or the Caribbean, peak reporting to these regions occurred in 2016 [330 cases (78%)]. The median age was 36 years (range: 3–92); 63% were female. The most frequent region of exposure was the Caribbean (60%). Thirteen travellers were pregnant during or after travel; one had a sexually acquired ZIKV infection. There was one case of fetal anomaly and two travellers with Guillain-Barré syndrome. GeoSentinel sites reported various challenges to diagnose ZIKV effectively. Conclusion ZIKV should remain a consideration for travellers returning from areas with risk of ZIKV transmission. Travellers should discuss their travel plans with their healthcare providers to ensure ZIKV prevention measures are taken.

Background Travelers to international mass gatherings may be exposed to conditions which increase their risk of acquiring infectious diseases. Most existing data come from single clinical sites seeing returning travelers, or relate to single events. Methods Investigators evaluated ill travelers returning from a mass gathering, and presenting to a GeoSentinel site between August 2015 and April 2019, and collected data on the nature of the event and the relation between final diagnoses and the mass gathering. Results Of 296 ill travelers, 51% were female and the median age was 54 years (range: 1–88). Over 82% returned from a religious mass gathering, most frequently Umrah or Hajj. Only 3% returned from the Olympics in Brazil or South Korea. Other mass gatherings included other sporting events, cultural or entertainment events, and conferences. Respiratory diseases accounted for almost 80% of all diagnoses, with vaccine preventable illnesses such as influenza and pneumonia accounting for 26% and 20% of all diagnoses respectively. This was followed by gastrointestinal illnesses, accounting for 4.5%. Sixty-three percent of travelers reported having a pre-travel encounter with a healthcare provider. Conclusions Despite this surveillance being limited to patients presenting to GeoSentinel sites, our findings highlight the importance of respiratory diseases at mass gatherings, the need for pre-travel consultations before mass gatherings, and consideration of vaccination against influenza and pneumococcal disease.

Leptospirosis is a potentially fatal emerging zoonosis with worldwide distribution and a broad range of clinical presentations and exposure risks. It typically affects vulnerable populations in (sub)tropical countries but is increasingly reported in travelers as well. Diagnostic methods are cumbersome and require further improvement. Here, we describe leptospirosis among travelers presenting to the GeoSentinel Global Surveillance Network. We performed a descriptive analysis of leptospirosis cases reported in GeoSentinel from January 1997 through December 2016. We included 180 travelers with leptospirosis (mostly male; 74%; mostly tourists; 81%). The most frequent region of infection was Southeast Asia (52%); the most common source countries were Thailand (N = 52), Costa Rica (N = 13), Indonesia, and Laos (N = 11 each). Fifty-nine percent were hospitalized; one fatality was reported. We also distributed a supplemental survey to GeoSentinel sites to assess clinical and diagnostic practices. Of 56 GeoSentinel sites, three-quarters responded to the survey. Leptospirosis was reported to have been most frequently considered in febrile travelers with hepatic and renal abnormalities and a history of freshwater exposure. Serology was the most commonly used diagnostic method, although convalescent samples were reported to have been collected infrequently. Within GeoSentinel, leptospirosis was diagnosed mostly among international tourists and caused serious illness. Clinical suspicion and diagnostic workup among surveyed GeoSentinel clinicians were mainly triggered by a classical presentation and exposure history, possibly resulting in underdiagnosis. Suboptimal usage of available diagnostic methods may have resulted in additional missed, or misdiagnosed, cases. Published version

A strategic multilateral dialogue related to biosecurity risks in Southeast Asia, established in 2014, now includes participants from Singapore, Malaysia, Indonesia, Thailand, Philippines, and the United States. This dialogue is conducted at the nonministerial level, enabling participants to engage without the constraints of operating in their official capacities. Participants reflect on mechanisms to detect, mitigate, and respond to biosecurity risks and highlight biosecurity issues for national leadership. Participants have also identified factors to improve regional and global biosecurity, including improved engagement and collaboration across relevant ministries and agencies, sustainable funding for biosecurity programs, enhanced information sharing for communicable diseases, and increased engagement in international biosecurity forums.

High-consequence pathogens create a unique problem. To provide effective treatment for infected patients while providing safety for the community, a series of 10 high-level isolation units have been created across the country; they are known as Regional Ebola and Special Pathogen Treatment Centers (RESPTCs). The activation of a high-level isolation unit is a highly resource-intensive activity, with effects that ripple across the healthcare system. The incident command system (ICS), a standard tool for command, control, and coordination in domestic emergencies, is a command structure that may be useful in a biocontainment event. A version of this system, the hospital emergency incident command system, provides an adaptable all-hazards approach in healthcare delivery systems. Here we describe its utility in an operational response to safely care for a patient(s) infected with a high-consequence pathogen on a high-level isolation unit. The Johns Hopkins Hospital created a high-level isolation unit to manage the comprehensive and complex needs of patients with high-consequence infectious diseases, including Ebola virus disease. The unique challenges of and opportunities for providing care in this high-level isolation unit led the authors to modify the hospital incident command system model for use during activation. This system has been tested and refined during full-scale functional and tabletop exercises. Lessons learned from the after-action reviews of these exercises led to optimization of the structure and implementation of ICS on the biocontainment unit, including improved job action sheets, designation of physical location of roles, and communication approaches. Overall, the adaptation of ICS for use in the high-level isolation unit setting may be an effective approach to emergency management during an activation.

UNLABELLED The ideal dengue vaccine will provide protection against all serotypes of dengue virus and will be economical and uncomplicated in its administration. To determine the ability of a single dose of the live attenuated tetravalent dengue vaccine TV003 to induce a suitable neutralizing antibody response, a placebo-controlled clinical trial was performed in 48 healthy adults who received 2 doses of vaccine or placebo administered 12 months apart. Evaluation of safety, vaccine viremia, and neutralizing antibody response after each dose indicated that the first dose of vaccine was capable of preventing infection with the second dose, thus indicating that multiple doses are unnecessary. CLINICAL TRIALS REGISTRATION NCT01782300.

Background: The number of US students studying abroad more than tripled during the past 20 years. As study abroad programmes' destinations diversify, students increasingly travel to resource-limited countries, placing them at risk for infectious diseases. Data describing infections acquired by US students while travelling internationally are limited. We describe illnesses among students who returned from international travel and suggest how to prevent illness among these travellers. Methods: GeoSentinel is a global surveillance network of travel and tropical medicine providers that monitors travel-related morbidity. This study included the records of US resident student international travellers, 17-24 years old, who returned to the USA, had a confirmed travel-related illness at one of 15 US GeoSentinel sites during 2007-17 and had a documented exposure region. Records were analysed to describe demographic and travel characteristics and diagnoses. Results: The study included 432 students. The median age was 21 years; 69% were female. More than 70% had a pre-travel consultation with a healthcare provider. The most common exposure region was sub-Saharan Africa (112; 26%). Students were most commonly exposed in India (44; 11%), Ecuador (28; 7%), Ghana (25; 6%) and China (24; 6%). The median duration of travel abroad was 40 days (range: 1-469) and presented to a GeoSentinel site a median of 8 days (range: 0-181) after travel; 98% were outpatients. Of 581 confirmed diagnoses, the most common diagnosis category was gastrointestinal (45%). Acute diarrhoea was the most common gastrointestinal diagnosis (113 of 261; 43%). Thirty-one (7%) students had vector-borne diseases [14 (41%) malaria and 11 (32%) dengue]. Three had vaccine-preventable diseases (two typhoid; one hepatitis A); two had acute human immunodeficiency virus infection. Conclusions: Students experienced travel-related infections, despite the majority having a pre-travel consultation. US students should receive pre-travel advice, vaccinations and chemoprophylaxis to prevent gastrointestinal, vector-borne, sexually transmitted and vaccine-preventable infections.

Background. The 4 serotypes of dengue virus, DENV-1–4, are the leading cause of arboviral disease globally. The ideal dengue vaccine would provide protection against all serotypes after a single dose. Methods. Two randomized, placebo-controlled trials were performed with 168 flavivirus-naive adults to demonstrate the safety and immunogenicity of a live attenuated tetravalent dengue vaccine (TV003), compared with those of a second tetravalent vaccine with an enhanced DENV-2 component (TV005), and to evaluate the benefit of a booster dose at 6 months. Safety data, viremia, and neutralizing antibody titers were evaluated. Results. A single dose of TV005 elicited a tetravalent response in 90% of vaccinees by 3 months after vaccination and a trivalent response in 98%. Compared with TV003, the higher-dose DENV-2 component increased the observed frequency of immunogenicity to DENV-2 in the TV005 trial. Both the first and second doses were well tolerated. Neither vaccine viremia, rash, nor a significant antibody boost were observed following a second dose. Conclusions. A single subcutaneous dose of TV005 dengue vaccine is safe and induces a tetravalent antibody response at an unprecedented frequency among vaccinees. A second dose has limited benefit and appears to be unnecessary. Studies to confirm these findings and assess vaccine efficacy will now move to populations in regions where DENV transmission is endemic. Clinical Trials Registration. NCT01072786 and NCT01436422.

Background There is increasing recognition of the contribution of community-acquired cases to the global burden of Clostridium difficile infection (CDI). The epidemiology of CDI among international travellers is poorly understood, and factors associated with international travel, such as antibiotic use and changes in gut microbiota, could potentially put travellers at higher risk. Methods We summarized demographic, travel-associated and geographic characteristics of travellers with CDI in the GeoSentinel database from 1997 to 2015. We also surveyed GeoSentinel sites to compare various testing indications, approaches, and diagnostic modalities. Results We identified 260 GeoSentinel records, including 187 that satisfied criteria for analysis (confirmed cases in non-immigrant travellers aged >2 years, seen

To understand geographic variation in travel-related illness acquired in distinct African regions, we used the GeoSentinel Surveillance Network database to analyze records for 16,893 ill travelers returning from Africa over a 14-year period. Travelers to northern Africa most commonly reported gastrointestinal illnesses and dog bites. Febrile illnesses were more common in travelers returning from sub-Saharan countries. Eleven travelers died, 9 of malaria; these deaths occurred mainly among male business travelers to sub-Saharan Africa. The profile of illness varied substantially by region: malaria predominated in travelers returning from Central and Western Africa; schistosomiasis, strongyloidiasis, and dengue from Eastern and Western Africa; and loaisis from Central Africa. There were few reports of vaccine-preventable infections, HIV infection, and tuberculosis. Geographic profiling of illness acquired during travel to Africa guides targeted pretravel advice, expedites diagnosis in ill returning travelers, and may influence destination choices in tourism.

International audience; Background: Zika virus has spread rapidly in the Americas and has been imported into many nonendemic countries by travelers. Objective: To describe clinical manifestations and epidemiology of Zika virus disease in travelers exposed in the Americas. Design: Descriptive, using GeoSentinel records. Setting: 63 travel and tropical medicine clinics in 30 countries. Patients: Ill returned travelers with a confirmed, probable, or clinically suspected diagnosis of Zika virus disease seen between January 2013 and 29 February 2016. Measurements: Frequencies of demographic, trip, and clinical characteristics and complications. Results: Starting in May 2015, 93 cases of Zika virus disease were reported. Common symptoms included exanthema (88%), fever (76%), and arthralgia (72%). Fifty-nine percent of patients were exposed in South America; 71% were diagnosed in Europe. Case status was established most commonly by polymerase chain reaction (PCR) testing of blood and less often by PCR testing of other body fluids or serology and plaque-reduction neutralization testing. Two patients developed Guillain-Barre syndrome, and 3 of 4 pregnancies had adverse outcomes (microcephaly, major fetal neurologic abnormalities, and intrauterine fetal death). Limitation: Surveillance data collected by specialized clinics may not be representative of all ill returned travelers, and denominator data are unavailable. Conclusion: These surveillance data help characterize the clinical manifestations and adverse outcomes of Zika virus disease among travelers infected in the Americas and show a need for global standardization of diagnostic testing. The serious fetal complications observed in this study highlight the importance of travel advisories and prevention measures for pregnant women and their partners. Travelers are sentinels for global Zika virus circulation and may facilitate further transmission.

Background The number of US students studying abroad has more than tripled over the past 20 years. As study abroad programs diversify their destinations, more students are traveling to developing regions, increasing their risk of infectious diseases. Few data exist describing infections acquired by US students while traveling internationally. We describe the spectrum of disease among students who have returned from international travel and suggest how to reduce illness among these travelers. Methods GeoSentinel is a global network of travel and tropical medicine providers that monitors travel-related morbidity. Records of US resident student travelers, 17–24 years old, who returned to the United States and were given a confirmed travel-related diagnosis at one of 15 US GeoSentinel sites during 2007–2017. Those without ascertainable exposure regions were excluded. Records were analyzed to describe demographic and travel characteristics and diagnoses. Results There were 432 students included. The median age was 21 years; 69% were female. Over 70% had a pretravel consultation with a healthcare provider. The most common exposure region was sub-Saharan Africa (112 travelers; 26%); the most common exposure countries were India (44 students; 11%), Ecuador (28; 7%), Ghana (25; 6%), and China (24; 6%). Students presented to a GeoSentinel site a median of 8 days (range: 0–181) after travel; 98% were outpatients. The most common diagnosis categories were gastrointestinal (45%) and dermatologic (17%). Of 581 confirmed diagnoses, diarrheal illnesses were most common (165; 28%). Thirty-one (7%) students had a vector-borne disease; 14 (41%) of these were diagnosed with malaria (13 had a pretravel consultation) and 11 (32%) with dengue. Two students were diagnosed with acute HIV. Three had a vaccine-preventable disease (two typhoid; one hepatitis A). Conclusion Students experienced travel-related infections despite a large proportion receiving pretravel consultations. Students (especially those traveling to a less developed region) should receive specific pretravel instructions (including suggestions for behavioral modification, vaccination, and medication prophylaxis when applicable) to prevent gastrointestinal, vector-borne, sexually transmitted, and vaccine-preventable diseases. Disclosures All authors: No reported disclosures.

Background. Dengue virus (DENV) causes hundreds of millions of infections annually. Four dengue serotypes exist, and previous infection with one serotype increases the likelihood of severe disease with a second, heterotypic DENV infection. Methods. In a randomized, placebo-controlled study, the safety and immunogenicity of 4 different admixtures of a live attenuated tetravalent (LATV) dengue vaccine were evaluated in 113 flavivirus-naive adults. Serum neutralizing antibody levels to all 4 dengue viruses were measured on days 0, 28, 42, and 180. Results. A single dose of each LATV admixture induced a trivalent or better neutralizing antibody response in 75%–90% of vaccinees. There was no significant difference in the incidence of adverse events between vaccinees and placebo-recipients other than rash. A trivalent or better response correlated with rash and with non-black race (P< .0001). Black race was significantly associated with a reduced incidence of vaccine viremia. Conclusions. TV003 induced a trivalent or greater antibody response in 90% of flavivirus-naive vaccinees and is a promising candidate for the prevention of dengue. Race was identified as a factor influencing the infectivity of the LATV viruses, reflecting observations of the effect of race on disease severity in natural dengue infection. Clinical Trials Registration. NCT01072786.

Author(s): Frank, Gregory M; Adalja, Amesh; Barbour, Alan; Casadevall, Arturo; Dormitzer, Philip R; Duchin, Jeff; Hayden, Frederick G; Hirsch, Martin S; Hynes, Noreen A; Lipsitch, Marc; Pavia, Andrew T; Relman, David A

To describe patient characteristics and disease spectrum among foreign visitors to Haiti before and after the 2010 earthquake, we used GeoSentinel Global Surveillance Network data and compared 1 year post-earthquake versus 3 years pre-earthquake. Post-earthquake travelers were younger, predominantly from the United States, more frequently international assistance workers, and more often medically counseled before their trip than pre-earthquake travelers. Work-related stress and upper respiratory tract infections were more frequent post-earthquake; acute diarrhea, dengue, and Plasmodium falciparum malaria were important contributors of morbidity both pre- and post-earthquake. These data highlight the importance of providing destination- and disaster-specific pre-travel counseling and post-travel evaluation and medical management to persons traveling to or returning from a disaster location, and evaluations should include attention to the psychological wellbeing of these travelers. For travel to Haiti, focus should be on mosquito-borne illnesses (dengue and P. falciparum malaria) and travelers' diarrhea.

A dengue human challenge model can be an important tool to identify candidate dengue vaccines that should be further evaluated in large efficacy trials in endemic areas. Dengue is responsible for about 390 million infections annually. Protective efficacy results for the most advanced dengue vaccine candidate (CYD) were disappointing despite its ability to induce neutralizing antibodies against all four dengue virus (DENV) serotypes. TV003 is a live attenuated tetravalent DENV vaccine currently in phase 2 evaluation. To better assess the protective efficacy of TV003, a randomized double-blind, placebo-controlled trial in which recipients of TV003 or placebo were challenged 6 months later with a DENV-2 strain, rDEN2Δ30, was conducted. The primary endpoint of the trial was protection against dengue infection, defined as rDEN2Δ30 viremia. Secondary endpoints were protection against rash and neutropenia. All 21 recipients of TV003 who were challenged with rDEN2Δ30 were protected from infection with rDEN2Δ30. None developed viremia, rash, or neutropenia after challenge. In contrast, 100% of the 20 placebo recipients who were challenged with rDEN2Δ30 developed viremia, 80% developed rash, and 20% developed neutropenia. TV003 induced complete protection against challenge with rDEN2Δ30 administered 6 months after vaccination. TV003 will be further evaluated in dengue-endemic areas. The controlled dengue human challenge model can accelerate vaccine development by evaluating the protection afforded by the vaccine, thereby eliminating poor candidates from further consideration before the initiation of large efficacy trials.

Over the past 3 decades, dengue has spread rapidly and has emerged as one of the world's most common mosquitoborne viral diseases. Although often found in tropical and semitropical areas, dengue is capable of being transmitted in temperate climates as well. Dengue is currently endemic to Mexico, most other Latin American countries, and parts of the Caribbean, and it has the potential to become reestablished as an endemic disease in the United States. In fact, sustained transmission of dengue has occurred in Florida within the past year. Conditions exist in the U.S. that could facilitate sustained dengue transmission, including environmental factors, competent mosquito vectors, limited vector and dengue surveillance, increased domestic outdoor daytime activities in warmer months, and low public awareness of the disease. If dengue were to be reestablished in the U.S., it could have significant medical, public health, and economic consequences for the country. The impact of dengue as a public health threat could be lessened through enhanced awareness and reporting of cases, increased support for vector surveillance and control programs, and a greater focus on vaccine development.

An increasing number of immunocompromised individuals are pursuing international travel, and a better understanding of their international travel patterns and pretravel health care is needed. We evaluated the clinical features, itineraries, and pretravel health care of 486 immunocompromised international travelers seen at Global TravEpiNet sites from January 2009 to June 2012. We used bivariate analyses and logistic regressions using random intercept models to compare demographic and travel characteristics, vaccines administered, and medications prescribed for immunocompromised travelers versus 30,702 immunocompetent travelers. Immunocompromised travelers pursued itineraries that were largely similar to those of immunocompetent travelers, with nearly one-third of such travelers visiting countries with low human development indices. Biological agents, including tumor necrosis factor blockers, were commonly used immunosuppressive medications among immunocompromised travelers. A strong collaboration between travel-medicine specialists, primary care doctors, and specialist physicians is needed to prepare immunocompromised people for international travel. Incorporating routine questioning and planning regarding travel into the primary care visits of immunocompromised people may be useful.

Background: The largest-ever outbreak of Ebola virus disease (EVD), ongoing in West Africa since late 2013, has led to export of cases to Europe and North America. Clinicians encountering ill travelers arriving from countries with widespread Ebola virus transmission must be aware of alternate diagnoses associated with fever and other nonspecific symptoms. Objective: To define the spectrum of illness observed in persons returning from areas of West Africa where EVD transmission has been widespread. Design: Descriptive, using GeoSentinel records. Setting: 57 travel or tropical medicine clinics in 25 countries. Patients: 805 ill returned travelers and new immigrants from Sierra Leone, Liberia, or Guinea seen between September 2009 and August 2014. Measurements: Frequencies of demographic and travel-related characteristics and illnesses reported. Results: The most common specific diagnosis among 770 non-immigrant travelers was malaria (n = 310 [40.3%]), with Plasmodium falciparum or severe malaria in 267 (86%) and non-P. falciparum malaria in 43 (14%). Acute diarrhea was the second most common diagnosis among nonimmigrant travelers (n = 95 [12.3%]). Such common diagnoses as upper respiratory tract infection, urinary tract infection, and influenza-like illness occurred in only 26, 9, and 7 returning travelers, respectively. Few instances of typhoid fever (n = 8), acute HIV infection (n = 5), and dengue (n = 2) were encountered. Limitation: Surveillance data collected by specialist clinics may not be representative of all ill returned travelers. Conclusion: Although EVD may currently drive clinical evaluation of ill travelers arriving from Sierra Leone, Liberia, and Guinea, clinicians must be aware of other more common, potentially fatal diseases. Malaria remains a common diagnosis among travelers seen at GeoSentinel sites. Prompt exclusion of malaria and other life-threatening conditions is critical to limiting morbidity and mortality

International travelers engaging in casual sex are at risk for acquiring sexually transmitted diseases (STDs), including HIV. The frequency of international travel emphasizes the need for a travel sexual activity history to be included in the clinical assessment of any returned traveler. When formulating a differential diagnosis, the STD prevalence rates at the travel destination and the risk profile of the traveler and the sexual partner need to be considered. Casual sex with host country nationals residing in tropical and subtropical areas of the developing world increases the traveler's risk for acquiring STDs rarely seen in industrialized countries, particularly bacterial genital ulcer diseases. Pretravel counseling needs to include education on STD prevention. A post-travel STD diagnostic evaluation is indicated when casual sexual activity has occurred during travel, regardless of whether symptoms are present.

A system designed to rapidly identify an infectious disease outbreak or bioterrorism attack and provide important demographic and geographic information is lacking in most health departments nationwide. The Department of Defense Global Emerging Infections System sponsored a meeting and workshop in May 2000 in which participants discussed prototype systems and developed recommendations for new surveillance systems. The authors provide a summary of the group’s findings, including expectations and recommendations for new surveillance systems. The consensus of the group was that a nationally led effort in developing health indicator surveillance methods is needed to promote effective, innovative systems.

Infection caused by the four serotypes of dengue virus (DENV-1-4) is a leading cause of mosquito-borne disease. Clinically-severe dengue disease is more common when secondary dengue infection occurs following prior infection with a heterologous dengue serotype. Other flaviviruses such as yellow fever virus, Japanese encephalitis virus, and Zika virus, can also elicit antibodies which are cross-reactive to DENV. As candidate dengue vaccines become available in endemic settings and for individuals who have received other flavivirus vaccines, it is important to examine vaccine safety and immunogenicity in these flavivirus-experienced populations. We performed a randomized, controlled trial of the National Institutes of Health live attenuated tetravalent dengue vaccine candidate (TV003) in fifty-eight individuals with prior exposure to flavivirus infection or vaccine. As in prior studies of this vaccine in flavivirus-naive volunteers, flavivirus-experienced subjects received two doses of vaccine six months apart and were followed closely for clinical events, laboratory changes, viremia, and neutralizing antibody titers. TV003 was well tolerated with few adverse events other than rash, which was predominately mild. Following one dose, 87% of vaccinees had an antibody response to all four serotypes (tetravalent response), suggesting a robust immune response. In addition, 76% of vaccinees were viremic; mean peak titers ranged from 0.68–1.1 log10 PFU/mL and did not differ by serotype. The second dose of TV003 was not associated with viremia, rash, or a sustained boost in antibody titers indicating that a single dose of the vaccine is likely sufficient to prevent viral replication and thus protect against disease. In comparison to the viremia and neutralizing antibody response elicited by TV003 in flavivirus-naïve subjects from prior studies, we found that subjects who were flavivirus-exposed prior to vaccination exhibited slightly higher DENV-3 viremia, higher neutralizing antibody titers to DENV-2, -3, and -4, and a higher tetravalent response frequency after TV003 administration. In summary, we demonstrate that the NIH tetravalent dengue vaccine TV003 is well-tolerated in flavivirus-experienced individuals and elicits robust post-vaccination neutralizing antibody titers. Trial registration ClinicalTrials.gov NCT01506570, Author summary As live-attenuated dengue vaccine candidates are developed, it is important to ascertain their safety in all populations, regardless of past exposure to dengue, closely related flaviviruses, or similar vaccines. Each of the four dengue virus (DENV) serotypes can cause clinical disease. Severe dengue disease may be life-threatening and is epidemiologically linked to secondary infection with a serotype distinct from the first infection. Candidate tetravalent dengue vaccines are designed to induce neutralizing antibody responses to all serotypes, but confirmation is needed that vaccination itself, as a secondary exposure, is not associated with the development of enhanced reactogenicity. The National Institutes of Health live attenuated tetravalent dengue vaccine candidate, TV003, has previously been shown to be safe and immunogenic in flavivirus-naïve populations. We performed a randomized, placebo-controlled clinical trial of TV003 in individuals previously exposed to flaviviruses and demonstrated tolerability and strong, broad immunogenicity across serotypes. No subjects experienced any dengue-like illness. Vaccine viremia was self-limited and occurred at acceptably low levels compared to those associated with severe dengue from natural infection. TV003 is well-tolerated in healthy adults, regardless of flavivirus exposure, and will be evaluated next in DENV-endemic settings.

The authors of this commentary discuss how so many health care workers in West Africa could have become infected with Ebola despite the known effectiveness of barrier protection in blocking its tra...

Transmission-blocking vaccines (TBVs) that target sexual stage parasite development could be an integral part of measures for malaria elimination. Pfs25 is a leading TBV candidate, and previous studies conducted in animals demonstrated an improvement of its functional immunogenicity after conjugation to EPA, a recombinant, detoxified ExoProtein A from Pseudomonas aeruginosa. In this report, we describe results of an open-label, dose-escalating Phase 1 trial to assess the safety and immunogenicity of Pfs25-EPA conjugates formulated with Alhydrogel®. Thirty malaria-naïve healthy adults received up to four doses of the conjugate vaccine, with 8, 16, or 47 μg of conjugated Pfs25 mass, at 0, 2, 4, and 10 months. Vaccinations were generally well tolerated. The majority of solicited adverse events were mild in severity with pain at the injection site the most common complaint. Anemia was the most common laboratory abnormality, but was considered possibly related to the study in only a minority of cases. No vaccine-related serious adverse events occurred. The peak geometric mean anti-Pfs25 antibody level in the highest dose group was 88 (95% CI 53, 147) μg/mL two weeks after the 4th vaccination, and declined to near baseline one year later. Antibody avidity increased over successive vaccinations. Transmission blocking activity demonstrated in a standard membrane feeding assay (SMFA) also increased from the second to the third dose, and correlated with antibody titer and, after the final dose, with antibody avidity. These results support the further evaluation of Pfs25-EPA/Alhydrogel® in a malaria-endemic population.

People who travel to areas with high rabies endemicity and have animal contact are at increased risk for rabies exposure. We examined characteristics of international travelers queried regarding rabies vaccination during pretravel consultations at Global TravEpiNet (GTEN) practices during 2009-2010.We performed bivariate and multivariable analyses of data collected from 18 GTEN clinics. Travel destinations were classified by strength level of rabies vaccination recommendation.Of 13,235 travelers, 226 (2%) reported previous rabies vaccination, and 406 (3%) received rabies vaccine at the consultation. Common travel purposes for these 406 travelers were leisure (26%), research/education (17%), and nonmedical service work (14%). Excluding the 226 who were previously vaccinated, 8070 (62%) of 13,009 travelers intended to visit one or more countries with a strong recommendation for rabies vaccination; 1675 (21%) of these 8070 intended to travel for 1 month or more. Among these 1675 travelers, 145 (9%) were vaccinated, 498 (30%) declined vaccination, 832 (50%) had itineraries that clinicians determined did not indicate vaccination, and 200 (12%) remained unvaccinated for other reasons. In both bivariate and multivariate analyses, travelers with trip durations6 months versus 1-3 months (adjusted odds ratio [OR]=4.9 [95% confidence interval [CI] 2.1, 11.4]) and those traveling for "research/education" or to "provide medical care" (adjusted OR=5.1 [95% CI 1.9, 13.7] and 9.5 [95% CI 2.2, 40.8], respectively), compared with leisure travelers, were more likely to receive rabies vaccination.Few travelers at GTEN clinics received rabies vaccine, although many planned trips 1 month long or more to a strong-recommendation country. Clinicians often determined that vaccine was not indicated, and travelers often declined vaccine when it was offered. The decision to vaccinate should take into account the strength of the vaccine recommendation at the destination country, duration of stay, availability of postexposure prophylaxis, potential for exposure to animals, and likelihood of recurrent travel to high-risk destinations.

Neisseria gonorrhoeae, the causative agent of gonococcal infection, is a uniquely human pathogen belonging to the family Nesseriaceae. Up to 50% of women with gonococcal infection are asymptomatic. Its critical epidemiologic feature, silent infection, leads to delayed diagnosis, which, in turn, is associated with an increased period of communicability and increased risk of complications. Furthermore, the risk of acquiring human immunodeficiency virus (HIV) infection from an HIV-infected person is increased among persons coinfected with gonorrhea. In addition, HIV-infected persons coinfected with gonorrhea may be more likely to transmit HIV to an uninfected partner due to increased HIV concentration in their genital secretions. Patients who are infected with N. gonorrhoeae are often coinfected with C. trachomatis, with studies demonstrating coinfection rates among women ranging from 35 to 50%. Routine dual treatment of both infections without testing for chlamydia has been recommended in the setting of presumptive gonococcal infection or when a person presents as the sexual contact of a person with a presumptive or definite diagnosis of gonorrhea from any site. Such an approach was found to be cost effective in populations where chlamydial infection accompanies 20–40% of gonococcal infections.

Conditions that facilitate sustained dengue transmission exist in the United States, and outbreaks have occurred during the past decade in Texas, Hawaii, and Florida. More outbreaks can also be expected in years to come. To combat dengue, medical and public health practitioners in areas with mosquito vectors that are competent to transmit the virus must be aware of the threat of reemergent dengue, and the need for early reporting and control to reduce the impact of dengue outbreaks. Comprehensive dengue control includes human and vector surveillance, vector management programs, and community engagement efforts. Public health, medical, and vector-control communities must collaborate to prevent and control disease spread. Policy makers should understand the role of mosquito abatement and community engagement in the prevention and control of the disease.

Background International travel poses a risk of destination-specific illness and may contribute to the global spread of infectious diseases. Despite this, little is known about the health characteristics and pretravel healthcare of US international travelers, particularly those at higher risk of travel-associated illness. Methods We formed a national consortium (Global TravEpiNet) of 18 US clinics registered to administer yellow fever vaccination. We collected data regarding demographic and health characteristics, destinations, purpose of travel, and pretravel healthcare from 13235 international travelers who sought pretravel consultation at these sites from January 2009 through January 2011. Results The destinations and itineraries of Global TravEpiNet travelers differed from those of the overall population of US international travelers. The majority of Global TravEpiNet travelers were visiting low- or lower-middle-income countries, and Africa was the most frequently visited region. Seventy-five percent of travelers were visiting malaria-endemic countries, and 38% were visiting countries endemic for yellow fever. Fifty-nine percent of travelers reported ≥1 medical condition. Atovaquone/proguanil was the most commonly prescribed antimalarial drug, and most travelers received an antibiotic for self-treatment of travelers' diarrhea. Hepatitis A and typhoid were the most frequently administered vaccines. Conclusions Data from Global TravEpiNet provide insight into the characteristics and pretravel healthcare of US international travelers who are at increased risk of travel-associated illness due to itinerary, purpose of travel, or existing medical conditions. Improved understanding of this epidemiologically significant population may help target risk-reduction strategies and interventions to limit the spread of infections related to global travel.

Background Despite a decreasing incidence of listeriosis in the United States, molecular subtyping has increased the number of recognized outbreaks. In September 2000, the New York City Department of Health identified a cluster of infections caused by Listeria monocytogenes isolates with identical molecular subtypes by pulsed-field gel electrophoresis (PFGE) and ribotyping. Methods To determine the magnitude of the outbreak and identify risk factors for infection, we notified state health departments and conducted a case-control study. A case was defined as a patient or mother-infant pair infected with Listeria monocytogenes whose isolate yielded the outbreak PFGE pattern. Controls were patients infected with Listeria monocytogenes whose isolate yielded a different PFGE pattern. Patients were asked about food and drink consumed during the 30 days before the onset of illness. Results Between May and December 2000, there were 30 clinical isolates of Listeria monocytogenes with identical PFGE patterns identified in 11 US states. Cases of infection caused by these isolates were associated with 4 deaths and 3 miscarriages. A case-control study implicated sliced processed turkey from a delicatessen (Mantel-Haenszel odds ratio, 8.0; 95% confidence interval, 1.2-43.3). A traceback investigation identified a single processing plant as the likely source of the outbreak, and the company voluntarily recalled 16 million pounds of processed meat. The same plant had been identified in a Listeria contamination event that had occurred more than a decade previously. Conclusions Prevention of persistent L. monocytogenes contamination in food processing plants presents a critical challenge to food safety professionals.

Introduction: Herpes simplex virus (HSV) type 1 or 2 can cause chronic genital viral infections, most of which are asymptomatic [1,2]. HSV-2 is the more likely of the two types to cause genital herpes (GHSV) and is more commonly associated with recurrent clinical infection than is HSV-1. HSV-2 is now the leading cause of genital ulcer disease worldwide [3]. For example, in the United States there are approximately 1.6 million new cases each year against a background prevalence of 22% in adults [4]. When coupled with the association of genital ulcer disease with the acquisition and transmission of HIV infection, these high incidence and prevalence rates [5,6] represent a public health imperative to identify effective mechanisms to prevent transmission. Although it is known that acyclovir, its prodrug valacyclovir, and other antivirals can reduce clinical recurrence of GHSV [7] and asymptomatic viral shedding [8], it is unknown if this observed reduction translates into reduced risk for sexual transmission of the virus.