Allergies, body mass, and hospitalization due to arbovirus infection: A prospective surveillance study in Machala, Ecuador.

Dengue, chikungunya, and Zika are arboviruses that cause 390 million infections annually. Risk factors for hospitalization are poorly understood. Communities affected by these diseases have an escalating prevalence of allergies and obesity, which are linked to immune dysfunction. We assessed the association of allergies or body mass with hospitalization for an arbovirus infection. From 2014 to 2017, we recruited participants with a clinical diagnosis of arbovirus infection. Arbovirus infections were laboratory-confirmed and allergies were self-reported. Mid-upper arm circumference (MUAC), weight, and height were measured. We used two logistic regression models to assess the relationships between hospitalization and allergies and between hospitalization and body mass (MUAC for participants <20 years old and body mass index (BMI) for adults ≥20 years old). Models were stratified by age group and adjusted for confounders. For allergies, 41 of 265 were hospitalized. There was no association between allergies and hospitalization. For body mass, 34 of 251 were hospitalized. There was a 43% decrease in hospitalization odds for each additional centimetre MUAC among children (aOR 0.566, 95% CI 0.252-1.019) and a 12% decrease in hospitalization odds for each additional BMI unit among adults (aOR 0.877, 95% CI 0.752-0.998). Our work encourages the exploration of the underlying mechanisms.

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.

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.

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

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.

Micronutrients, Immunological Parameters, and Dengue Virus Infection in Coastal Ecuador: A Nested Case-Control Study in an Infectious Disease Surveillance Program.

BACKGROUND: Micronutrients are known to modulate host immunity, and there is limited literature on this association in the context of dengue virus infection (DENV). METHODS: Using a nested case-control design in a surveillance program, we measured the following: anthropometry; nutritional biomarkers including serum ferritin, soluble transferrin receptor, retinol-binding protein (RBP), 25-hydroxy vitamin D, folate, and vitamin B12; and a panel of immune response markers. We then compared these measures across 4 illness categories: healthy control, nonfebrile DENV, other febrile illness (OFI), and apparent DENV using multivariate polytomous logistic regression models. RESULTS: Among 142 participants, serum ferritin (ng/mL) was associated with apparent DENV compared to healthy controls (odds ratio [OR], 2.66; confidence interval [CI], 1.53-4.62; P = .001), and RBP concentrations (µmol/L) were associated with apparent DENV (OR, 0.03; CI, 0.00-0.30; P = .003) and OFI (OR, 0.02; CI, 0.00-0.24; P = .003). In a subset of 71 participants, interleukin-15 levels (median fluorescent intensity) were positively associated with apparent DENV (OR, 1.09; CI, 1.03-1.14; P = .001) and negatively associated with nonfebrile DENV (OR, 0.89; CI, 0.80-0.99; P = .03) compared to healthy controls. CONCLUSIONS: After adjusting for the acute-phase response, serum ferritin and RBP concentrations were associated with apparent DENV and may represent biomarkers of clinical importance in the context of dengue illness.

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

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.

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

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.

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.

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.

Assessing the Diversity and Stability of Cellular Immunity Generated in Response to the Candidate Live-Attenuated Dengue Virus Vaccine TAK-003.

The development of an efficacious DENV vaccine has been a long-standing public health priority. However, this effort has been complicated significantly due to the hazard presented by incomplete humoral immunity in mediating immune enhancement of infection and disease severity. Therefore, there is a significant need for DENV vaccine platforms capable of generating broad immune responses including durable cellular immunity, as well as novel analytical tools to assess the magnitude, diversity, and persistence of vaccine-elicited immunity. In this study, we demonstrate that a single dose of the recombinant, tetravalent, live-attenuated DENV vaccine TAK-003 elicits potent and durable cellular immunity against both the structural and non-structural proteins of all four DENV serotypes, which is maintained for at least 4 months post-immunization. Although not contained within the vaccine formulation, significant reactivity against the non-structural (NS) proteins of DENV-1,-3, and-4 is observed following vaccination, to an extent directly proportional to the magnitude of responses to the corresponding vaccine (DENV-2) components. Distinct, quantifiable, and durable patterns of DENV antigen reactivity can be observed in individuals following vaccination. Detailed epitope mapping of T cell reactivity against the DENV-2 proteome using a matrix of overlapping peptide pools demonstrated that TAK-003 elicits a broad response directed across the DENV-2 proteome, with focused reactivity against NS1 and NS3. We conclude that, as measured by an IFN-γ ELISPOT assay, a single dose of TAK-003 generates potent T cell-mediated immunity which is durable in magnitude and breadth through 4 months post-vaccination.

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.

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, N = 324) were referred from five Ministry of Health clinical sites. A subset of DENV-positive index cases (N = 44) were selected, and individuals from the index household and four neighboring homes within 200 m were recruited (N = 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.

Spatiotemporal Variation in Environmental Vibrio cholerae in an Estuary in Southern Coastal Ecuador.

Cholera emergence is strongly linked to local environmental and ecological context. The 1991-2004 pandemic emerged in Perú and spread north into Ecuador's El Oro province, making this a key site for potential re-emergence. Machala, El Oro, is a port city of 250,000 inhabitants, near the Peruvian border. Many livelihoods depend on the estuarine system, from fishing for subsistence and trade, to domestic water use. In 2014, we conducted biweekly sampling for 10 months in five estuarine locations, across a gradient of human use, and ranging from inland to ocean. We measured water-specific environmental variables implicated in cholera growth and persistence: pH, temperature, salinity, and algal concentration, and evaluated samples in five months for pathogenic and non-pathogenic Vibrio cholerae, by polymerase chain reaction (PCR). We found environmental persistence of pandemic strains O1 and O139, but no evidence for toxigenic strains. Vibrio cholerae presence was coupled to algal and salinity concentration, and sites exhibited considerable seasonal and spatial heterogeneity. This study indicates that environmental conditions in Machala are optimal for cholera re-emergence, with risk peaking during September, and higher risk near urban periphery low-income communities. This highlights a need for surveillance of this coupled cholera-estuarine system to anticipate potential future cholera outbreaks.

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

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.

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.

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.

Phase 2a, Open-Label, 4-Escalating-Dose, Randomized Multicenter Study Evaluating the Safety and Activity of Ferroquine (SSR97193) Plus Artesunate, versus Amodiaquine Plus Artesunate, in African Adult Men with Uncomplicated Plasmodium falciparum Malaria.

Artemisinin-based combination therapies are recommended as first-line agents for treating uncomplicated Plasmodium falciparum malaria. Ferroquine, a 4-aminoquinolone, is a novel long-acting combination partner for fast-acting drugs like artesunate (AS). We did a small phase 2a, multicenter, open-label, safety-focused dose-ranging randomized study of ferroquine at three African hospitals: two Gabonese and one Kenyan. We recruited adult men with symptomatic uncomplicated P. falciparum monoinfection. Four escalating doses of ferroquine (100, 200, 400, and 600 mg) were assessed in sequence, versus an amodiaquine comparator. After a 2:1 randomization (block size three, equating to N = 12 for each ferroquine dose and N = 6 for each of four amodiaquine comparator groups) patients received daily for three consecutive days, either ferroquine + AS (200 mg/day) or amodiaquine (612 mg/day) + AS (200 mg/day). Safety, electrocardiograms, parasite clearance times, efficacy, and pharmacokinetics were assessed to day 28. Seventy-two patients were randomized. Ferroquine + AS showed generally mild increases (Grade 1 toxicity) in alanine aminotransferase (ALT) levels with a dose trend starting at 400 mg. There were two Grade 2 ALT events: one patient receiving 200 mg (3.8 upper limit of normal [ULN], day 7) and one receiving 600 mg (3.3 ULN, day 14), both without increased bilirubin. One ferroquine 100 mg + AS patient after one dose was withdrawn after developing a QTcF interval prolongation > 60 milliseconds over baseline. Parasitemias in all patients cleared quickly, with no recurrence through day 28. Hepatic, as well as cardiac, profiles should be monitored closely in future trials. (ClinicalTrials.gov: NCT00563914).

Successful malaria elimination in the Ecuador-Peru border region: epidemiology and lessons learned.

BACKGROUND: In recent years, malaria (Plasmodium vivax and Plasmodium falciparum) has been successfully controlled in the Ecuador-Peru coastal border region. The aim of this study was to document this control effort and to identify the best practices and lessons learned that are applicable to malaria control and to other vector-borne diseases. A proximal outcome evaluation was conducted of the robust elimination programme in El Oro Province, Ecuador, and the Tumbes Region, Peru. Data collection efforts included a series of workshops with local public health experts who played central roles in the elimination effort, review of epidemiological records from Ministries of Health, and a review of national policy documents. Key programmatic and external factors are identified that determined the success of this eradication effort. CASE DESCRIPTION: From the mid 1980s until the early 2000s, the region experienced a surge in malaria transmission, which experts attributed to a combination of ineffective anti-malarial treatment, social-ecological factors (e.g., El Niño, increasing rice farming, construction of a reservoir), and political factors (e.g., reduction in resources and changes in management). In response to the malaria crisis, local public health practitioners from El Oro and Tumbes joined together in the mid-1990s to forge an unofficial binational collaboration for malaria control. Over the next 20 years, they effectively eradicated malaria in the region, by strengthening surveillance and treatment strategies, sharing of resources, operational research to inform policy, and novel interventions. DISCUSSION AND EVALUATION: The binational collaboration at the operational level was the fundamental component of the successful malaria elimination programme. This unique relationship created a trusting, open environment that allowed for flexibility, rapid response, innovation and resilience in times of crisis, and ultimately a sustainable control programme. Strong community involvement, an extensive microscopy network and ongoing epidemiologic investigations at the local level were also identified as crucial programmatic strategies. CONCLUSION: The results of this study provide key principles of a successful malaria elimination programme that can inform the next generation of public health professionals in the region, and serve as a guide to ongoing and future control efforts of other emerging vector borne diseases globally.

Adenovirus type 35-vectored tuberculosis vaccine has an acceptable safety and tolerability profile in healthy, BCG-vaccinated, QuantiFERON(®)-TB Gold (+) Kenyan adults without evidence of tuberculosis.

In a Phase 1 trial, we evaluated the safety of AERAS-402, an adenovirus 35-vectored TB vaccine candidate expressing 3 Mycobacterium tuberculosis (Mtb) immunodominant antigens, in subjects with and without latent Mtb infection. HIV-negative, BCG-vaccinated Kenyan adults without evidence of tuberculosis, 10 QuantiFERON(®)-TB Gold In-Tube test (QFT-G)(-) and 10 QFT-G(+), were randomized 4:1 to receive AERAS-402 or placebo as two doses, on Days 0 and 56, with follow up to Day 182. There were no deaths, serious adverse events or withdrawals. For 1 AERAS-402 QFT-G(-) and 1 AERAS-402 QFT-G(+) subject, there were 3 self-limiting severe AEs of injection site pain: 1 after the first vaccination and 1 after each vaccination, respectively. Two additional severe AEs considered vaccine-related were reported after the first vaccination in AERAS-402 QFT-G(+) subjects: elevated blood creatine phosphokinase and neutropenia, the latter slowly improving but remaining abnormal until study end. AERAS-402 was not detected in urine or throat cultures for any subject. In intracellular cytokine staining studies, curtailed by technical issues, we saw modest CD4+ and CD8+ T cell responses to Mtb Ag85A/b peptide pools among both QFT-G(-) and (+) subjects, with trends in the CD4+ T cells suggestive of boosting after the second vaccine dose, slightly more so in QFT-G(+) subjects. CD4+ and CD8+ responses to Mtb antigen TB10.4 were minimal. Increases in Adenovirus 35 neutralizing antibodies from screening to end of study, seen in 50% of AERAS-402 recipients, were mostly minimal. This small study confirms acceptable safety and tolerability profiles for AERAS-402, in line with other Phase 1 studies of AERAS-402, now to include QFT-G(+) subjects.

Klebsiella pneumoniae Liver Abscess: An Emerging Disease.

Most of the cases of Klebsiella pneumoniae liver abscess reported early on were from Asia, predominantly Taiwan, with a significant number of patients being middle aged diabetic men, and developing metastatic complications, especially endophthalmitis. The entity is now being increasingly recognized in the United States. In this article, the authors review those reported cases, and also the literature regarding the pathophysiology of this intriguing syndrome.

Phase 1/2a Trial of Plasmodium vivax Malaria Vaccine Candidate VMP001/AS01B in Malaria-Naive Adults: Safety, Immunogenicity, and Efficacy.

BACKGROUND: A vaccine to prevent infection and disease caused by Plasmodium vivax is needed both to reduce the morbidity caused by this parasite and as a key component in efforts to eradicate malaria worldwide. Vivax malaria protein 1 (VMP001), a novel chimeric protein that incorporates the amino- and carboxy- terminal regions of the circumsporozoite protein (CSP) and a truncated repeat region that contains repeat sequences from both the VK210 (type 1) and the VK247 (type 2) parasites, was developed as a vaccine candidate for global use. METHODS: We conducted a first-in-human Phase 1 dose escalation vaccine study with controlled human malaria infection (CHMI) of VMP001 formulated in the GSK Adjuvant System AS01B. A total of 30 volunteers divided into 3 groups (10 per group) were given 3 intramuscular injections of 15 µg, 30 µg, or 60 µg respectively of VMP001, all formulated in 500 µL of AS01B at each immunization. All vaccinated volunteers participated in a P. vivax CHMI 14 days following the third immunization. Six non-vaccinated subjects served as infectivity controls. RESULTS: The vaccine was shown to be well tolerated and immunogenic. All volunteers generated robust humoral and cellular immune responses to the vaccine antigen. Vaccination did not induce sterile protection; however, a small but significant delay in time to parasitemia was seen in 59% of vaccinated subjects compared to the control group. An association was identified between levels of anti-type 1 repeat antibodies and prepatent period. SIGNIFICANCE: This trial was the first to assess the efficacy of a P. vivax CSP vaccine candidate by CHMI. The association of type 1 repeat-specific antibody responses with delay in the prepatency period suggests that augmenting the immune responses to this domain may improve strain-specific vaccine efficacy. The availability of a P. vivax CHMI model will accelerate the process of P. vivax vaccine development, allowing better selection of candidate vaccines for advancement to field trials.

A global map of suitability for coastal Vibrio cholerae under current and future climate conditions.

Vibrio cholerae is a globally distributed water-borne pathogen that causes severe diarrheal disease and mortality, with current outbreaks as part of the seventh pandemic. Further understanding of the role of environmental factors in potential pathogen distribution and corresponding V. cholerae disease transmission over time and space is urgently needed to target surveillance of cholera and other climate and water-sensitive diseases. We used an ecological niche model (ENM) to identify environmental variables associated with V. cholerae presence in marine environments, to project a global model of V. cholerae distribution in ocean waters under current and future climate scenarios. We generated an ENM using published reports of V. cholerae in seawater and freely available remotely sensed imagery. Models indicated that factors associated with V. cholerae presence included chlorophyll-a, pH, and sea surface temperature (SST), with chlorophyll-a demonstrating the greatest explanatory power from variables selected for model calibration. We identified specific geographic areas for potential V. cholerae distribution. Coastal Bangladesh, where cholera is endemic, was found to be environmentally similar to coastal areas in Latin America. In a conservative climate change scenario, we observed a predicted increase in areas with environmental conditions suitable for V. cholerae. Findings highlight the potential for vulnerability maps to inform cholera surveillance, early warning systems, and disease prevention and control.

Micronutrients and dengue.

Dengue virus infection is the most widespread mosquito-borne viral infection in humans and has emerged as a serious global health challenge. In the absence of effective treatment and vaccine, host factors including nutritional status, which may alter disease progression, need investigation. The interplay between nutrition and other infections is well-established, and modulation of nutritional status often presents a simple low-cost method of interrupting transmission, reducing susceptibility, and/or ameliorating disease severity. This review examines the evidence on the role of micronutrients in dengue virus infection. We found critical issues and often inconsistent results across studies; this finding along with the lack of sufficient literature in this field have limited our ability to make any recommendations. However, vitamins D and E have shown promise in small supplementation trials. In summary, the role of micronutrients in dengue virus infection is an exciting research area and needs to be examined in well-designed studies with larger samples.

Pharmacokinetic evaluation of intravenous artesunate in adults with uncomplicated falciparum malaria in Kenya: a phase II study.

BACKGROUND: Alternatives to treatment for malaria treatment of travellers are needed in the USA and in Europe for travellers who return with severe malaria infections. The objective of this study is to show the pharmacokinetic (PK) profile of intravenous artesunate (AS), which was manufactured under good manufacturing practice (GMP) conditions, in adults with uncomplicated falciparum malaria in Kenya. METHODS: The PK parameters of intravenous AS manufactured under current cGMP were evaluated after a single dose of drug at 2.4 mg/kg infused over 2 min in 28 adults with uncomplicated Plasmodium falciparum malaria. Plasma concentrations of AS and dihydroartemisinin (DHA) were measured using a validated liquid chromatography-mass spectrometry (LC-MS/MS) methodology. Pharmacokinetic data were analysed with a compartmental analysis for AS and DHA. RESULTS: The results suggest there were no drug-related adverse events in any of the patients. After intravenous infusion, the concentration of the parent drug rapidly declined, and the AS was converted to DHA. AS and DHA showed mean elimination half-lives of 0.17 hours and 1.30 hours, respectively. The high mean peak concentration (Cmax) of AS was shown to be 28,558 ng/mL while the Cmax of DHA was determined to be 2,932 ng/mL. Significant variability was noted in the PK profiles of the 28 patients tested. For example, Cmax values of AS were calculated to range from 3,362 to 55,873 ng/mL, and the Cmax value of DHA was noted to vary from 1,493 to 5,569 ng/mL. The mean area under the curve (AUC) of AS was shown to be approximately half that of DHA (1,878 ng · h/mL vs 3,543 ng · h/mL). The DHA/AS ratio observed was 1.94 during the one-day single treatment, and the AUC and half- life measured for DHA were significantly larger and longer than for AS. CONCLUSIONS: Intravenous AS can provide much higher peak concentrations of AS when compared to concentrations achieved with oral therapy; this may be crucial for the rapid elimination of parasites in patients with severe malaria. Given the much longer half-life of DHA compared to the short half-life of AS, DHA also plays a significant role in treatment of severe malaria.