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Improved risk stratification and prognosis prediction in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here, we present prognostic models for 30-day mortality generated independently by three scientific groups by using 12 discovery cohorts containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance is validated in five cohorts of community-onset sepsis patients in which the models show summary AUROCs ranging from 0.765–0.89. Similar performance is observed in four cohorts of hospital-acquired sepsis. Combining the new gene-expression-based prognostic models with prior clinical severity scores leads to significant improvement in prediction of 30-day mortality as measured via AUROC and net reclassification improvement index These models provide an opportunity to develop molecular bedside tests that may improve risk stratification and mortality prediction in patients with sepsis., Sepsis is characterized by deregulated host response to infection. Efficient therapies are still needed but a limitation for sepsis treatment is the heterogeneity in patients. Here Sweeney et al. generate prognostic models based on gene expression to improve risk stratification classification and prediction for 30-day mortality of patients.

Background Antimicrobial stewardship programs (ASPs) have been shown to improve the appropriate use of antimicrobials, especially in high-income countries. However, ASPs are relatively less well implemented in low-or-middle income countries. To improve the effectiveness of ASPs in these settings, it is important to determine the core actions and targets for improving antimicrobial use. We sought to describe the prevalence and patterns of antibiotic use at a tertiary care hospital in Tanzania. Methods Consecutive patients admitted to an adult medical ward at a tertiary care hospital, Kilimanjaro Christian Medical Centre, in Moshi, Tanzania were enrolled from June 2018 to March 2019. The medical record was reviewed for data regarding the type of antibiotics prescribed, indications for use, and microbiologic testing ordered. Results A total of 1103 patients were enrolled during the study period. The majority of patients were males (663, 60.1%), with the median age being 54 years (IQR 39–70). About one-third (390, 35.4%) of the admitted patients received antimicrobials during hospitalization, with pneumonia being the leading indication for antimicrobial use (158, 40.5%). The most commonly used antibiotics included ceftriaxone in 285 (73.1%), metronidazole in 155 (39.7%), and amoxicillin/ ampicillin in 46 (11.8%) patients. The median duration of antimicrobial use was 5 days (IQR 3–7). Few patients on antimicrobials (27, 6.9%) had culture results, of which half (15, 55.6%) were positive for an organism and a minority (8, 29.6%) were susceptible to the antibiotics being used. Overall, mortality in the cohort was 22.7% and the median duration of hospitalization was 5 days (IQR 3–8). Conclusion Antibiotics were used in a substantial proportion of admitted patients. However, in most cases, treatment was empirical with limited use of culture results. Future ASP efforts can target the improved use of microbiologic cultures to target antimicrobial use. Disclosures All authors: No reported disclosures.

A century of advances in infectious disease diagnosis and treatment changed the face of medicine. However, challenges continue to develop including multi-drug resistance, globalization that increases pandemic risks and high mortality from severe infections. These challenges can be mitigated through improved diagnostics, focusing on both pathogen discovery and the host response. Here, we review how 'omics' technologies improve sepsis diagnosis, early pathogen identification and personalize therapy. Such host response diagnostics are possible due to the confluence of advanced laboratory techniques (e.g., transcriptomics, metabolomics, proteomics) along with advanced mathematical modeling such as machine learning techniques. The road ahead is promising, but obstacles remain before the impact of such advanced diagnostic modalities is felt at the bedside.

Influenza accounts for a large burden of acute respiratory tract infections in high-income countries; data from lower-income settings are limited due to lack of confirmatory testing. Consecutive outpatients presenting to the largest tertiary care hospital in southern Sri Lanka were surveyed for influenza-like illness (ILI), defined as acute onset of fever ≥ 38.0°C and cough. Patients were administered a questionnaire and nasal/nasopharyngeal sampling for rapid influenza A/B testing. We enrolled 311 patients with ILI from March to November 2013: 170 (54.7%) children and 172 (55.3%) males. Approximately half (147, 47.3%) tested positive for influenza, but 253 (81.4%) were prescribed antibiotics. On bivariable analysis, symptoms associated with influenza included pain with breathing (P < 0.001), headache (P = 0.005), fatigue (P = 0.003), arthralgias (P = 0.003), and myalgias (P = 0.006) in children and pain with breathing (P = 0.01), vomiting (P = 0.03), and arthralgias (P = 0.03) in adults. Our final clinical predictive models had low sensitivity and fair specificity—50.0% (95% CI: 38.6–61.4%) and 83.2% (95% CI: 73.4–90.0%), respectively, in children and 52.2% (95% CI: 39.9–64.2%) and 81.4% (95% CI: 70.0–89.4%), respectively, in adults. Our study confirms the ability of rapid influenza testing to identify an influenza epidemic in a setting in which testing is not routinely available.

Background The heart is a metabolically active organ, and plasma acylcarnitines are associated with long-term risk for myocardial infarction. We hypothesized that myocardial ischemia from cardiac stress testing will produce dynamic changes in acylcarnitine and amino acid levels compared to levels seen in matched control patients with normal stress tests. Methods We analyzed targeted metabolomic profiles in a pilot study of 20 case patients with inducible ischemia on stress testing from an existing prospectively collected repository of 357 consecutive patients presenting with symptoms of Acute Coronary Syndrome (ACS) in an Emergency Department (ED) observation unit between November 2012 and September 2014. We selected 20 controls matched on age, sex, and body-mass index (BMI). A peripheral blood sample was drawn

The four serotypes of dengue virus (DENV-1, -2, -3, and -4) have had a rapidly expanding geographic range and are now endemic in over 100 tropical and subtropical countries. Sri Lanka has experienced periodic dengue outbreaks since the 1960s, but since 1989 epidemics have become progressively larger and associated with more severe disease. The dominant virus in the 2012 epidemic was DENV-1, but DENV-4 infections were also commonly observed. DENV-4 transmission was first documented in Sri Lanka when it was isolated from a traveler in 1978, but has been comparatively uncommon since dengue surveillance began in the early 1980s. To better understand the molecular epidemiology of DENV-4 infections in Sri Lanka, we conducted whole-genome sequencing on dengue patient samples from two different geographic locations. Phylogenetic analysis indicates that all sequenced DENV-4 strains belong to genotype 1 and are most closely related to DENV-4 viruses previously found in Sri Lanka and those recently found to be circulating in India and Pakistan.

We previously showed that chromosome 8 of A/J mice was associated with susceptibility to S. aureus infection. However, the specific genes responsible for this susceptibility are unknown. Chromosome substitution strain 8 (CSS8) mice, which have chromosome 8 from A/J but an otherwise C57BL/6J genome, were used to identify the genetic determinants of susceptibility to S. aureus on chromosome 8. Quantitative trait loci (QTL) mapping of S. aureus-infected N2 backcross mice (F1 [C8A] × C57BL/6J) identified a locus 83180780-88103009 (GRCm38/mm10) on A/J chromosome 8 that was linked to S. aureus susceptibility. All genes on the QTL (n~ 102) were further analyzed by three different strategies: 1) different expression in susceptible (A/J) and resistant (C57BL/6J) mice only in response to S. aureus, 2) consistently different expression in both uninfected and infected states between the two strains, and 3) damaging non-synonymous SNPs in either strain. Eleven candidate genes from the QTL region were significantly differently expressed in patients with S. aureus infection vs healthy human subjects. Four of these 11 genes also exhibited significantly different expression in S. aureus-challenged human neutrophils: Ier2, Crif1, Cd97 and Lyl1. CD97 ligand binding was evaluated within peritoneal neutrophils from A/J and C57BL/6J. CD97 from A/J had stronger CD55 but weaker integrin α5β1 ligand binding as compared with C57BL/6J. Because CD55/CD97 binding regulates immune cell activation and cytokine production, and integrin α5β1 is a membrane receptor for fibronectin, which is also bound by S. aureus, strain-specific differences could contribute to susceptibility to S. aureus. Down-regulation of Crif1 with siRNA was associated with increased host cell apoptosis among both naïve and S. aureus-infected bone marrow-derived macrophages. Specific genes in A/J chromosome 8, including Cd97 and Crif1, may play important roles in host defense against S. aureus.

The substrate of the methionine salvage pathway, methylthioadenosine, is a predictor of death in sepsis patients., Sepsis is a deleterious inflammatory response to infection with high mortality. Reliable sepsis biomarkers could improve diagnosis, prognosis, and treatment. Integration of human genetics, patient metabolite and cytokine measurements, and testing in a mouse model demonstrate that the methionine salvage pathway is a regulator of sepsis that can accurately predict prognosis in patients. Pathway-based genome-wide association analysis of nontyphoidal Salmonella bacteremia showed a strong enrichment for single-nucleotide polymorphisms near the components of the methionine salvage pathway. Measurement of the pathway’s substrate, methylthioadenosine (MTA), in two cohorts of sepsis patients demonstrated increased plasma MTA in nonsurvivors. Plasma MTA was correlated with levels of inflammatory cytokines, indicating that elevated MTA marks a subset of patients with excessive inflammation. A machine-learning model combining MTA and other variables yielded approximately 80% accuracy (area under the curve) in predicting death. Furthermore, mice infected with Salmonella had prolonged survival when MTA was administered before infection, suggesting that manipulating MTA levels could regulate the severity of the inflammatory response. Our results demonstrate how combining genetic data, biomolecule measurements, and animal models can shape our understanding of disease and lead to new biomarkers for patient stratification and potential therapeutic targeting.

Infection of respiratory mucosa with viral pathogens triggers complex immunologic events in the affected host. We sought to characterize this response through proteomic analysis of nasopharyngeal lavage in human subjects experimentally challenged with influenza A/H3N2 or human rhinovirus, and to develop targeted assays measuring peptides involved in this host response allowing classification of acute respiratory virus infection. Unbiased proteomic discovery analysis identified 3285 peptides corresponding to 438 unique proteins, and revealed that infection with H3N2 induces significant alterations in protein expression. These include proteins involved in acute inflammatory response, innate immune response, and the complement cascade. These data provide insights into the nature of the biological response to viral infection of the upper respiratory tract, and the proteins that are dysregulated by viral infection form the basis of signature that accurately classifies the infected state. Verification of this signature using targeted mass spectrometry in independent cohorts of subjects challenged with influenza or rhinovirus demonstrates that it performs with high accuracy (0.8623 AUROC, 75% TPR, 97.46% TNR). With further development as a clinical diagnostic, this signature may have utility in rapid screening for emerging infections, avoidance of inappropriate antibacterial therapy, and more rapid implementation of appropriate therapeutic and public health strategies.

Respiratory viral infections (RVI) are a frequent cause of morbidity and mortality in hematopoietic stem cell transplant (HSCT) patients. We examined clinical characteristics and respiratory viral detection in asymptomatic pediatric HSCT pre-transplant patients and symptomatic post-transplant patients. Coxsackie/echovirus (most common virus detected pre and post-transplant), rhinovirus, and coronavirus were detected pre-transplant and at the first post-transplant event suggesting persistent detection. None of the clinical characteristics examined were associated with viral detection and there was no increase in mortality noted with asymptomatic viral detection.

Rationale: Sepsis is a leading cause of morbidity and mortality. Currently, early diagnosis and the progression of the disease are difficult to make. The integration of metabolomic and transcriptomic data in a primate model of sepsis may provide a novel molecular signature of clinical sepsis. Objectives: To develop a biomarker panel to characterize sepsis in primates and ascertain its relevance to early diagnosis and progression of human sepsis. Methods: Intravenous inoculation of Macaca fascicularis with Escherichia coli produced mild to severe sepsis, lung injury, and death. Plasma samples were obtained before and after 1, 3, and 5 days of E. coli challenge and at the time of killing. At necropsy, blood, lung, kidney, and spleen samples were collected. An integrative analysis of the metabolomic and transcriptomic datasets was performed to identify a panel of sepsis biomarkers. Measurements and Main Results: The extent of E. coli invasion, respiratory distress, lethargy, and mortality was dependent on the bacterial dose. Metabolomic and transcriptomic changes characterized severe infections and death, and indicated impaired mitochondrial, peroxisomal, and liver functions. Analysis of the pulmonary transcriptome and plasma metabolome suggested impaired fatty acid catabolism regulated by peroxisome-proliferator activated receptor signaling. A representative four-metabolite model effectively diagnosed sepsis in primates (area under the curve, 0.966) and in two human sepsis cohorts (area under the curve, 0.78 and 0.82). Conclusions: A model of sepsis based on reciprocal metabolomic and transcriptomic data was developed in primates and validated in two human patient cohorts. It is anticipated that the identified parameters will facilitate early diagnosis and management of sepsis.

Background: Bartonella species are important emerging pathogens in human and veterinary medicine. In the context of their daily activities, veterinary professionals have frequent animal contact and arthropod exposures. Detection of Bartonella spp. using traditional culture methods has been limited by poor sensitivity, making it difficult to determine the prevalence of infection in this population. We have developed a detection method combining enrichment culture and molecular amplification, which increases testing sensitivity. Methods: We performed a cross-sectional study to determine the prevalence of detectable Bartonella spp. in the blood of veterinary personnel and nonveterinary control subjects. Bartonella was detected by enrichment blood culture with conventional PCR followed by DNA sequencing. Results were correlated with epidemiological variables and symptoms. Results: We detected DNA from at least one Bartonella species in 32 (28%) of the 114 veterinary subjects. After DNA sequencing, the Bartonella species could be determined for 27 of the 32 infected subjects, including B. henselae in 15 (56%), B. vinsonii subsp. berkhoffii in seven (26%), B. koehlerae in six (22%), and a B. volans–like sequence in one (4%). Seventy percent of Bartonella-positive subjects described headache compared with 40% of uninfected veterinarians (p=0.009). Irritability was also reported more commonly by infected subjects (68% vs. 43%, p=0.04). Conclusions: Our study supports an emerging body of evidence that cryptic Bartonella bloodstream infection may be more frequent in humans than previously recognized and may induce symptoms. Longitudinal studies are needed to determine the natural course and clinical features of Bartonella infection.

Respiratory infections can be due to a multitude of etiologies and are common throughout the world. Most are viral and self-limited, yet these infections are commonly treated with antibiotics thus contributing to the increase in resistance. Historically, infectious disease diagnostics have focused on identification of the microbial culprit at the site of infection but the specificity of host response as measured by the host transcriptome, now enables us to classify the etiology of infection agnostic to pathogen class. The ability to rapidly determine whether a similar set of symptoms is due to a virus, bacteria, or other agent from a common specimen (blood) will have far-reaching public health benefits, and further research is warranted to transfer this technology into the clinical setting.

Improved risk stratification and prognosis in sepsis is a critical unmet need. Clinical severity scores and available assays such as blood lactate reflect global illness severity with suboptimal performance, and do not specifically reveal the underlying dysregulation of sepsis. Here three scientific groups were invited to independently generate prognostic models for 30-day mortality using 12 discovery cohorts (N=650) containing transcriptomic data collected from primarily community-onset sepsis patients. Predictive performance was validated in 5 cohorts of community-onset sepsis patients (N=189) in which the models showed summary AUROCs ranging from 0.765-0.89. Similar performance was observed in 4 cohorts of hospital-acquired sepsis (N=282). Combining the new gene-expression-based prognostic models with prior clinical severity scores led to significant improvement in prediction of 30-day mortality (p

Introduction: Mucormycosis is a rare fungal infection, but can cause substantial morbidity and mortality in both immunocompromised and immunocompetent patients. Apophysomyces is a mucormycetes species ubiquitous in nature, particularly in soil, decaying wood and other organic matter. Apophysomyces is known to cause cutaneous fungal infections, particularly after penetrating trauma. Septic arthritis is a rare clinical manifestation. Case presentation: We describe a case of Apophysomyces trapeziformis causing septic arthritis of the knee of a patient with multiple myeloma. He was treated multiple times for bacterial septic arthritis with minimal improvement. Surgical tissue specimens finally grew mucoraceous mould, and DNA sequencing and morphological assessment of spores identified the mould as A. trapeziformis. The patient was treated with amphotericin B and posaconazole, but ultimately required an above-the-knee amputation for definitive treatment. Conclusion: This case illustrates the need to evaluate for fungal infection in a persistent septic arthritis that is culture negative and refractory to empiric antibiotics, particularly in an immunocompromised individual. It also shows the importance of a thorough social history and adequate tissue specimens for culture.

Emerging pandemic infectious threats, inappropriate antibacterial use contributing to multidrug resistance, and increased morbidity and mortality from diagnostic delays all contribute to a need for improved diagnostics in the field of infectious diseases. Historically, diagnosis of infectious diseases has relied on pathogen detection; however, a novel concept to improve diagnostics in infectious diseases relies instead on the detection of changes in patterns of gene expression in circulating white blood cells in response to infection. Alterations in peripheral blood gene expression in the infected state are robust and reproducible, yielding diagnostic and prognostic information to help facilitate patient treatment decisions.

This cohort study examines the 5-year incidence of community-acquired and health care facility–associated Clostridioides difficile infection among patients in US community hospitals., Key Points Question What are the current trends in incidence rates of community-acquired and health care facility–associated Clostridioides difficile in US community hospitals? Findings In this multicenter cohort study of 2 025 678 admissions and 21 254 cases of Clostridioides difficile infection, the incidence of health care facility–associated C difficile infection decreased from 2013 to 2017, whereas the incidence of community-acquired C difficile infection during the same period showed no statistically significant change. The proportion of cases classified as community acquired increased over time. Meaning The findings suggest that the proportion of community-acquired C difficile infections is increasing over time and warrants further study to identify the factors behind this trend., Importance Clostridioides difficile infection (CDI) remains a leading cause of health care facility–associated infection. A greater understanding of the regional epidemiologic profile of CDI could inform targeted prevention strategies. Objectives To assess trends in incidence of health care facility–associated and community-acquired CDI among hospitalized patients over time and to conduct a subanalysis of trends in the NAP1 strain of CDI over time. Design, Setting, and Participants This long-term multicenter cohort study reviewed records of patients (N = 2 025 678) admitted to a network of 43 regional community hospitals primarily in the southeastern United States from January 1, 2013, through December 31, 2017. Generalized linear mixed-effects models were used to adjust for potential clustering within facilities and changing test method (nucleic acid amplification testing or toxin enzyme immunoassay) over time. Main Outcomes and Measures Clostridioides difficile infection incidence rates were counted as cases per 1000 admissions for community-acquired and total CDI cases or cases per 10 000 patient-days for health care facility–associated CDI. Long-term trends in the proportion of cases acquired in the community and in NAP1 strain incidence were also evaluated. Results A total of 2 025 678 admissions and 21 254 CDI cases were included (12 678 [59.6%] female; median [interquartile range] age, 69 [55-80] years). Median (interquartile range) total CDI incidence increased slightly from 7.9 (3.5-12.4) cases per 1000 admissions in 2013 to 9.3 (4.9-13.7) cases per 1000 admissions in 2017. After adjustment, the overall incidence of health care facility–associated CDI declined (incidence rate ratio [IRR], 0.995; 95% CI, 0.990-0.999; P = .03), whereas insufficient evidence was found for either an increase or a decrease in community-acquired CDI (IRR, 1.004; 95% CI, 0.999-1.009; P = .14). The proportion of cases classified as community acquired increased over time from a mean (SD) of 0.49 (0.28) in 2013 to 0.61 (0.26) in 2017 (odds ratio, 1.010 per month; 95% CI, 1.006-1.015; P

Background The global emergence of antimicrobial resistance poses a major public health threat. However, there are little data regarding antimicrobial use from many low- or middle-income countries. In this study, we determined the prevalence and patterns of antibiotic prescription among outpatients at a tertiary healthcare facility in Sri Lanka. Methods The study was conducted at the Outpatient Department (OPD) of the largest public tertiary care center in Southern Province, Sri Lanka. This is a free walk-in clinic serving upwards of 1,000 patients per day. Adult and pediatric OPD patients were recruited for a cross-sectional survey in February–April 2019. Pre-visit and post-visit questionnaires were verbally administered to obtain information regarding participants’ demographics and presenting illness. The OPD pharmacy’s electronic prescribing system was queried to calculate the prevalence of antibiotic prescriptions among enrolled patients. Logistic regression was performed to identify features associated with antibiotic prescription. Results Of 408 patients surveyed, 246 (62.9%) were female and 88 (21.7%) were children Conclusion We show a high prevalence of outpatient antibiotic prescription despite limited diagnostic evaluation at a tertiary medical facility in Southern Province, Sri Lanka. Antibiotic stewardship efforts, especially targeting respiratory illness, may help improve antibiotic use in this setting. Disclosures All authors: No reported disclosures.

Background Antibiotic resistance is an emerging global public health threat with inappropriate use of antibiotics as one of the major drivers. In Sri Lanka, antibiotic consumption is increasing, while little is known about how patients perceive antibiotics. We conducted a qualitative study to better understand patients’ knowledge, perceptions, and attitudes toward antibiotics. Methods Semi-structured interviews were conducted in the local language (Sinhala) and audio recorded for 18 patients with lower respiratory tract infections (LRTI) admitted to a large, public tertiary care hospital in southern Sri Lanka. Interviews were transcribed and then translated into English. Translated interviews were analyzed for themes regarding care-seeking behavior, patients’ knowledge of disease etiology and treatment of LRTI. Results Almost all patients mentioned multiple care visits and polypharmacy prior to admission. When seeking care, patients mainly focused on finding a quick cure, mostly by visiting several different private physicians. However, self-medication was also common. Patients reused prescriptions for antibiotics, kept antibiotics for later use after prematurely stopping their course of treatment and bought antibiotics over-the-counter. Patients’ knowledge of disease etiology and antibiotics was poor. Most patients described non-microbial causes such as exposure to dust and cold weather for their illness. Only a few patients were aware of antibiotic resistance. Despite the desire to receive more information regarding disease and treatment, transfer of information between patients and physicians was limited and mainly confined to prescription instructions. Conclusion This qualitative study in Sri Lanka suggests inappropriate use of antibiotics is a multifactorial problem. Patients’ poor knowledge of disease and treatment, poor information transfer between physicians and patients, high demand for medicines, overprescribing by physicians, and self-medication were found as possible obstructive factors to improve antibiotic usage. To improve antibiotic use, a multifaceted approach is needed with improvement of awareness by patients, public, and physicians regarding antibiotic use and antibiotic resistance. Disclosures All authors: No reported disclosures.

BackgroundAcute respiratory infections are a common reason for antibiotic overuse. We previously showed that providing Sri Lankan clinicians with positive rapid influenza test results was associated with a reduction in antibiotic prescriptions. The economic impact of influenza diagnostic strategies is unknown.MethodsWe estimated the incremental cost per antibiotic prescription avoided with three diagnostic strategies versus standard care when managing Sri Lankan outpatients with influenza-like illness (ILI): (1) influenza clinical prediction tool, (2) targeted rapid influenza testing and (3) universal rapid influenza testing. We compared findings with literature-based estimates of the cost of antimicrobial resistance attributable to each antibiotic prescription.ResultsStandard care was less expensive than other strategies across all parameter values in one-way sensitivity analyses. The incremental cost per antibiotic prescription avoided with clinical prediction versus standard care was US$3.0, which was lower than the base-case estimate of the cost of antimicrobial resistance per ILI antibiotic prescription (US$12.5). The incremental cost per antibiotic prescription avoided with targeted testing and universal testing versus standard care were both higher than the base-case cost of antimicrobial resistance per ILI antibiotic prescription: US$49.1 and US$138.3, respectively. To obtain a cost-effectiveness ratio lower than US$12.5 with targeted testing versus standard care, the test price must be ConclusionClinical prediction tools and targeted rapid influenza testing may be cost-saving strategies in Sri Lanka when accounting for the societal cost of antimicrobial resistance.

After a short-term fever, complex regional pain syndrome, characterized by hyperalgesia, intermittent swelling, erythema and cyanosis of both feet, was diagnosed in a female veterinarian. The woman was infected with Bartonella koehlerae and she was also Bartonella vinsonii subsp. berkhoffii seroreactive. Having failed other treatments, symptoms resolved following initiation of antibiotics.

Vitamin K deficiency bleeding (VKDB), formerly known as hemorrhagic disease of the newborn (HDN), is a bleeding disorder in neonates that is caused by inadequate serum levels of vitamin K. Vitamin K is a nutrient essential for adequate function of the coagulation cascade. Certain internal and external factors place newborn infants at higher risk for VKDB. Therefore, vitamin K prophylaxis has become the standard of care for newborns. Although the American Academy of Pediatrics recommends the administration of vitamin K to newborns, some parents are choosing to withhold vitamin K administration at birth. This case study describes an infant who developed VKDB in the absence of vitamin K prophylaxis. Although parents ultimately have the right to choose whether or not to administer vitamin K, as healthcare professionals, it is important to provide education regarding the potential complications of withholding vitamin K and the signs of VKDB if vitamin K prophylaxis at birth is withheld.

Background Acute febrile illness is a frequent cause of hospitalization in the tropics and often presents with respiratory symptoms, even when caused by nonrespiratory pathogens. Previously, host-based gene expression signatures accurately identified acute respiratory infections as being bacterial or viral in a U.S. cohort. We determined signature performance in a Sri Lankan cohort with acute febrile respiratory illness (AFRI). Methods We enrolled patients with AFRI in Sri Lanka from July 2012 to May 2013 and collected nasopharygeal swabs, acute/ convalescent sera, and blood in PAXgene RNA tubes. Bacterial (Orientia tsutsugamushi, Leptospira spp.) and viral (influenza A/B, dengue) infections were confirmed using polymerase chain reaction, virus isolation, enzyme immunoassay, and/or microscopic agglutination testing. We extracted total RNA and performed host RNA sequencing (Illumina). We aligned reads to hg38 reference genome using Bowtie2, quantified at isoform level using Express version 1.5.1, and normalized using trimmed-mean normalization. The original model estimated three classes and separate signatures predicted bacterial infections, viral infections, and non-infectious illnesses. Regularized regression was used to predict bacterial and viral infections based on prior signatures. Accuracy was estimated using leave-one-out cross-validation. Results Among 43 patients with viral infections (14 dengue, 29 influenza) and 16 patients with bacterial infections (six Leptospira spp., 10 O. tsutsumagushi), median age was 37 years (IQR 23–51) and 49% were male. Of five respiratory symptoms (cough, sore throat, rhinitis/ congestion, shortness of breath, and pain with breathing), median (IQR) number of symptoms was 2 (1–2) for influenza, 2 (1–2) for dengue, 2 (2–3) for Leptospira spp., and 1.5 (1–2) for O. tsutsumagushi. We observed high predictive accuracy in discriminating bacterial and viral infections: AUROC 0.91 for the bacterial and AUROC 0.81 for the viral model. At enrollment, 65% of viral and 50% of bacterial AFRI patients received antibiotics. Conclusion Host gene expression classifiers performed well in a Sri Lankan population with AFRI, even with nonrespiratory pathogens that may not be readily identified. Host-based diagnostics may play a critical role in improving diagnostic ability and antibiotic use globally. Disclosures E. L. Tsalik, Host Response, Inc.: Founder, Equity. G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth

Background Bacterial and viral infections are difficult to clinically distinguish, leading to antibiotic overuse and resistance. Host response signatures are an alternative to traditional pathogen-detection methods to differentiate these etiologies. Several gene expression signatures have been described although performance in ambiguous clinical phenotypes is unknown. Here, we validate a host response signature and explore its performance in microbiology-negative and co-infection cases. Methods RT-PCR taqman low-density array (TLDA) was used to measure 87 gene targets in a training cohort of 151 samples from patients with microbiologically confirmed and clinically adjudicated phenotypes (48 bacterial; 54 viral; 49 non-infectious illness [NI]). This data were used to construct three distinct classifiers: bacterial vs. nonbacterial; viral vs. nonviral; and non-infectious vs. infectious. This model was then applied to 75 subjects with co-infection and 40 suspected bacterial cases without microbiological confirmation. Results Leave-one-out cross validation on the training cohort demonstrated AUC values of 0.85, 0.89, and 0.88 for bacterial, viral, and NI, respectively. In 40 subjects with microbiology-negative bacterial infections, a bacterial or co-infection signature was present in 72%. Of 75 subjects with co-infection, 53 included a bacterial infection following recent viral infection and 22 were bacterial infections in patients with chronic viral infection (e.g., HCV, HIV). Bacterial infection and co-infection were successfully identified in these varied scenarios. Conclusion This gene expression signature distinguished bacterial, viral, and noninfectious causes of illness. The host response was able to confirm the majority of suspected bacterial infection without confirmatory microbiology but also highlighted a viral response in many. Furthermore, the use of distinct viral and bacterial signatures was capable of identifying co-infection. Such a host gene expression strategy, when translated to a clinically useful platform, can offer new insights into the etiology of both simple and complex cases that are not currently available. Disclosures G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth

Background Asthma exacerbations often occur due to infectious triggers. However, determining whether an infection is present and whether it is bacterial or viral remains clinically challenging leading to antibiotic overuse. A diagnostic strategy that clarifies these uncertainties can enable personalized asthma treatment and mitigate antibiotic resistance. Host gene expression is a promising alternative to pathogen-detection methods. Methods Forty-six patients presenting to the emergency department with asthma exacerbations were enrolled. Cases were clinically adjudicated as having bacterial, viral, or non-infectious etiologies. RT-PCR taqman low density array (TLDA) was used to quantify 87 gene targets, followed by logistic regression modeling to define class. Etiologies were correlated with clinical information including symptoms and antibiotic prescriptions. Results Most clinical parameters were similar between groups including duration of symptoms, presence of sick contacts, and severity of nasal symptoms, cough, headache, throat discomfort, and malaise. Only fever/chills (P = 0.006) and a composite of all symptoms (P = 0.02) were significantly different. In contrast to clinically adjudicated phenotypes, host response signatures identified very few bacterial triggers. Notably, none of the adjudicated bacterial cases had positive confirmatory microbiology. Instead, 29 and 57% were identified as having a viral infection or no infection, respectively. Despite the absence of bacterial infections identified using host gene expression, antibiotics were prescribed in 47.8% of all cases. Conclusion Host response signatures indicated that asthma exacerbation is infrequently caused by bacterial infections, even when clinical adjudications suggest this to be the case. Instead, most are either of viral or non-infectious etiologies. Despite most cases being classified as nonbacterial, empiric antibiotics were prescribed nearly half the time. A host gene expression approach can offer clinically useful diagnostic information to guide more appropriate antibiotic use among patients with asthma exacerbation. Disclosures G. S. Ginsburg, Host Response Inc.: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth < $100). C. W. Woods, Host Response: Founder, Licensing agreement or royalty; Qvella: Collaborator, Research support; BioFire: Collaborator, none. E. L. Tsalik, Host Response, Inc.: Founder, Equity.

Background The inability to reliably discriminate bacterial, viral, and non-infectious illness has led to an epidemic of antibiotic overuse and rising rates of antimicrobial resistance. Host gene expression provides a powerful approach to distinguish infection etiologies and guide appropriate therapy. However, existing platforms for transcriptomic analysis are not amenable for clinical application. The FilmArray platform is a sample-to-answer multiplex RT-PCR system that automates transcriptomic analysis including sample preparation and data analysis. Here we report the validation of a host gene expression FilmArray test to discriminate bacterial, viral, and non-infectious etiologies of illness. Methods Research use only (RUO) FilmArray pouches were manufactured with 45 host response assays previously shown to discriminate bacterial, viral, and non-infectious illness. These pouches were tested on whole blood samples from 226 patients with acute respiratory illness (ARI). Using clinical adjudication as the reference standard, there were 52 bacterial, 100 viral, and 75 non-infectious cases. Quantification cycles were recorded for each assay and normalized to an internal control. A logistic regression model generated probabilities of each condition, which were used to classify subjects. Results Beginning with 100 µL of blood, the FilmArray host response panel provided results in ~45 minutes from sample to answer. Overall accuracy for bacterial ARI relative to clinical adjudication was 85% with an area under the receiver operating characteristic curve (AUC) of 0.92. Accuracy and AUC for viral infection were 85% and 0.91, respectively. Ill patients without infection were correctly identified 86% of the time with an AUC of 0.88. Conclusion These results show that the FilmArray system can rapidLy measure host gene expression to accurately discriminate bacterial, viral, and non-infectious illness. The development of such a system creates a new option to mitigate inappropriate antibiotic use. It also presents opportunities to use host gene expression as a diagnostic modality for a variety of disease states. Disclosures E. L. Tsalik, Host Response, Inc.: Founder, Equity. J. Montgomery, BioFire Diagnostics: Employee, Salary. J. Nawrocki, BioFire Diagnostics, LLC.: Employee, Salary. M. Deneris, BioFire Diagnostics, LLC.: Employee, Salary. C. Gritzen, BioFire Diagnostics, LLC.: Employee, Salary. J. Jones, BioFire Diagnostics, LLC.: Employee, Salary. R. Crisp, BioFire Diagnostics, LLC: Employee, Salary. G. S. Ginsburg, Host Response Inc: Board Member, Founder, Scientific Advisor and Shareholder, Stock (currently worth < $100). A. Hemmert, BioFire Diagnostics, LLC.: Employee and Investigator, Salary. C. W. Woods, Host Response, Inc.: Founder, Equity.

In this paper, we describe a surface-enhanced Raman scattering (SERS)-based detection approach, referred to as “molecular sentinel” (MS) plasmonic nanoprobes, to detect an RNA target related to viral infection. The MS method is essentially a label-free technique incorporating the SERS effect modulation scheme associated with silver nanoparticles and Raman dye-labeled DNA hairpin probes. Hybridization with target sequences opens the hairpin and spatially separates the Raman label from the silver surface thus reducing the SERS signal of the label. Herein, we have developed a MS nanoprobe to detect the human radical S-adenosyl methionine domain containing 2 (RSAD2) RNA target as a model system for method demonstration. The human RSAD2 gene has recently emerged as a novel host-response biomarker for diagnosis of respiratory infections. Our results showed that the RSAD2 MS nanoprobes exhibits high specificity and can detect as low as 1 nM target sequences. With the use of a portable Raman spectrometer and total RNA samples, we have also demonstrated for the first time the potential of the MS nanoprobe technology for detection of host-response RNA biomarkers for infectious disease diagnostics.

Background Antivirals reduce influenza viral replication and illness measures, particularly if initiated early, within 48 h of symptom onset. Whether experimental antivirals that reduce respiratory syncytial virus (RSV) load would also reduce disease is unknown. This study compares viral and disease dynamics in humans experimentally infected with influenza or RSV. Methods Clinical strains of RSV-A and influenza A were inoculated intranasally into 20 and 17 healthy volunteers, respectively, on day 0. Symptom scores and nasal washes were performed twice daily, and daily mucus weights were collected. Viral loads in nasal washes were quantified by culture (plaque assay in HEp-2 cells for RSV and by end point dilution in Madin-Darby canine kidney cells for influenza). Results After influenza inoculation, influenza viral load and illness markers increased simultaneously until day 2. Within individual subjects, peak influenza load occurred 0.4 days (95% CI -0.4, 1.3) before peak symptoms. Influenza viral load and disease declined thereafter. After RSV inoculation, a longer incubation period occurred prior to viral detection and symptom onset. RSV load and disease increased together until day 5. Within individual subjects, peak RSV loads occurred 0.2 days (95% CI -0.7, 1.05) before peak symptoms, after which both illness measures and viral load declined together. Conclusions Viral and disease dynamics in experimental human infections suggest that reducing RSV load, if timed similarly to clinically-effective influenza antivirals, might be expected to have a similar or greater window of opportunity for reducing clinical RSV disease.

Infusion of soybean oil-based Intralipid is a major risk factor for parenteral nutrition (PN)–associated cholestasis that often occurs in infants treated with prolonged PN for short bowel syndrome. Parenteral fish oil–based lipid emulsion (Omegaven) has been reported to treat this condition, but it is not readily available in the United States and still requires a central venous catheter for administration. Enteral administration of Microlipid has been shown to decrease ostomy output and facilitate weight gain in infants with enterostomies. We describe 2 premature infants with short bowel syndrome who received early supplementation with enteral Microlipid and fish oil after bowel resection, and became independent of PN without cholestasis.

Clostridium difficile infection (CDI) is a common cause of nosocomial diarrhea and colitis. The incidence and prognostic significance of thrombocytopenia as related to mode of acquisition (hospital vs. community), NAP1/027 strain, and disease severity has not been examined. We performed a single-institution retrospective analysis of all adult inpatients from 2013 to 2014 diagnosed with CDI during their hospitalization to document the incidence/prevalence of thrombocytopenia and associated outcomes. Severe disease was defined by a composite endpoint of inpatient death, death within 30 days of discharge, presence of septic shock, or need for colectomy during hospitalization. Of the 533 patients diagnosed with CDI, moderate thrombocytopenia (platelet count

Background Rickettsial infections and Q fever present similarly to other acute febrile illnesses, but are infrequently diagnosed because of limited diagnostic tools. Despite sporadic reports, rickettsial infections and Q fever have not been prospectively studied in Central America. Methodology/Principal Findings We enrolled consecutive patients presenting with undifferentiated fever in western Nicaragua and collected epidemiologic and clinical data and acute and convalescent sera. We used ELISA for screening and paired sera to confirm acute (≥4-fold rise in titer) spotted fever and typhus group rickettsial infections and Q fever as well as past (stable titer) infections. Characteristics associated with both acute and past infection were assessed. Conclusions/Significance We enrolled 825 patients and identified acute rickettsial infections and acute Q fever in 0.9% and 1.3%, respectively. Clinical features were non-specific and neither rickettsial infections nor Q fever were considered or treated. Further study is warranted to define the burden of these infections in Central America., Author Summary Rickettsial infections and Q fever cause illness characterized by fever and non-specific symptoms and signs. Not only are these infections difficult to recognize, they are also difficult to diagnose because of limitations in existing tests for them. Despite sporadic reports, rickettsial infections and Q fever have not been prospectively studied in Central America. We enrolled consecutive patients presenting with undifferentiated fever in western Nicaragua and collected data regarding potential risk factors as well as symptoms and signs associated with the illnesses. Additionally, we collected blood samples at the initial visit and 2 to 4 weeks thereafter. We used serologic assays to differentiate new (rising antibody titers) vs. old (stable antibody titers) infections. Characteristics associated with both acute and past infection were assessed. We enrolled 825 patients and identified acute (new) rickettsial infections and acute Q fever in 0.9% and 1.3%, respectively. Clinical features were non-specific and neither rickettsial infections nor Q fever were considered nor treated. Further study is warranted to define the burden of these infections in Central America.

Introduction: Childhood heavy metal exposure is a major environmental health hazard. Some heavy metals (lead, arsenic, and cadmium) are understood to modulate certain immune functions, while the im...

Background. Hepatitis C virus (HCV) infection is a leading cause of cirrhosis and the primary cause of liver transplantation in the United States, and coinfection with human immunodeficiency virus (HIV) increases the risk of comorbidities. However, healthcare utilization (HCU) patterns among HIV/HCV-coinfected patients are poorly understood. This study compared the rates of HCU and reasons for hospital admission among HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans. Methods. Hepatitis C virus- and HIV-infected and HIV/HCV-coinfected veterans in care with the Department of Veterans Affairs (VA) from 1998 to 2009 (n = 335 371, n = 28 179, n = 13 471, respectively) were identified by HIV- and HCV-associated International Classification of Diseases, Ninth Revision codes from the clinical case registry. We assessed rates of HCU using emergency department (ED) visits, outpatient visits, and hospitalization and primary diagnoses associated with hospitalization. Independent risk factors associated with hospitalization were also examined. Results. Rates of outpatient and ED visits increased over the 11-year study period for all groups, with inpatient admission rates remaining stable. The HCU rates were consistently higher for the coinfected than other cohorts. The primary reason for hospital admission for all groups was psychiatric disease/substance use, accounting for 44% of all admissions. Nadir CD4 500 cells/mm3. Conclusions. As the current population of HCV-infected, HIV-infected, and HIV/HCV-coinfected veterans age, they will continue to place a substantial and increasing demand on the US healthcare system, particularly in their utilization of ED and outpatient services. These data suggest the need for an ongoing investment in mental health and primary care within the VA healthcare system.

BACKGROUND Extended-spectrum s-lactamase-producing Enterobacteriaceae (ESBL-PE) are increasingly reported as pathogens in urinary tract infections (UTIs). However, in Sri Lanka, the clinical and molecular epidemiology of ESBL-PE implicated in UTIs has not been well described. MATERIALS AND METHODS We conducted prospective, laboratory-based surveillance from October to December 2013 at a tertiary care hospital in southern Sri Lanka and enrolled patients ≥1 year of age with clinically relevant UTIs due to ESBL-PE. Isolate identity, antimicrobial drug susceptibility, and ESBL production were determined. Presence of s-lactamase genes, bla(SHV), bla(TEM), and bla(CTX-M), was identified by polymerase chain reaction. RESULTS During the study period, Enterobacteriaceae were detected in 184 urine samples, with 74 (40.2%) being ESBL producers. Among 47 patients with ESBL-PE who had medical records available, 38 (80.9%) had clinically significant UTIs. Most UTIs (63.2%) were community acquired and 34.2% were in patients with diabetes. Among 36 cultured ESBL-PE isolates, significant susceptibility (>80%) was only retained to amikacin and the carbapenems. The group 1 bla(CTX-M) gene was present in 90.0% of Escherichia coli isolates and all Klebsiella pneumoniae and Enterobacter cloacae isolates. The bla(SHV) and bla(TEM) genes were more common in K. pneumoniae (75% and 50%) and E. cloacae (50% and 50%) isolates than in E. coli (10% and 20%) isolates, respectively. CONCLUSION The majority of UTIs caused by ESBL-PE were acquired in the community and due to organisms carrying the group 1 CTX-M s-lactamase. Further epidemiologic studies of infections due to ESBL-PE are urgently needed to better prevent and treat these infections in South Asia.

Background Host factors and complications have been associated with higher mortality in infective endocarditis ( IE ). We sought to develop and validate a model of clinical characteristics to predict 6‐month mortality in IE . Methods and Results Using a large multinational prospective registry of definite IE (International Collaboration on Endocarditis [ ICE ]–Prospective Cohort Study [ PCS ], 2000–2006, n=4049), a model to predict 6‐month survival was developed by Cox proportional hazards modeling with inverse probability weighting for surgery treatment and was internally validated by the bootstrapping method. This model was externally validated in an independent prospective registry ( ICE ‐ PLUS , 2008–2012, n=1197). The 6‐month mortality was 971 of 4049 (24.0%) in the ICE ‐ PCS cohort and 342 of 1197 (28.6%) in the ICE ‐ PLUS cohort. Surgery during the index hospitalization was performed in 48.1% and 54.0% of the cohorts, respectively. In the derivation model, variables related to host factors (age, dialysis), IE characteristics (prosthetic or nosocomial IE , causative organism, left‐sided valve vegetation), and IE complications (severe heart failure, stroke, paravalvular complication, and persistent bacteremia) were independently associated with 6‐month mortality, and surgery was associated with a lower risk of mortality (Harrell's C statistic 0.715). In the validation model, these variables had similar hazard ratios (Harrell's C statistic 0.682), with a similar, independent benefit of surgery (hazard ratio 0.74, 95% CI 0.62–0.89). A simplified risk model was developed by weight adjustment of these variables. Conclusions Six‐month mortality after IE is ≈25% and is predicted by host factors, IE characteristics, and IE complications. Surgery during the index hospitalization is associated with lower mortality but is performed less frequently in the highest risk patients. A simplified risk model may be used to identify specific risk subgroups in IE .

Acute respiratory infections caused by bacterial or viral pathogens are among the most common reasons for seeking medical care. Despite improvements in pathogen-based diagnostics, most patients receive inappropriate antibiotics. Host response biomarkers offer an alternative diagnostic approach to direct antimicrobial use. This observational, cohort study determined whether host gene expression patterns discriminate non-infectious from infectious illness, and bacterial from viral causes of acute respiratory infection in the acute care setting. Peripheral whole blood gene expression from 273 subjects with community-onset acute respiratory infection (ARI) or non-infectious illness as well as 44 healthy controls was measured using microarrays. Sparse logistic regression was used to develop classifiers for bacterial ARI (71 probes), viral ARI (33 probes), or a non-infectious cause of illness (26 probes). Overall accuracy was 87% (238/273 concordant with clinical adjudication), which was more accurate than procalcitonin (78%, p

Background Little progress was made in advancing Ebola-specific therapies during the epidemic that began in West Africa in late 2013. Throughout the last quarter of 2014, which saw the greatest numbers of cases, only a handful of clinical trials were underway. Subsequently, as incident cases dwindled, the number of clinical trials increased dramatically, but few, were destined to recruit to their accrual targets. The predictable barriers to implementing clinical trials in resource-constrained settings are compounded by unique characteristics of Ebola — including its high fatality rate, its swift transmission through populations, and the grave risks for exposed health care workers. Methods As members from a group hastily configured as the Ebola Clinical Research Consortium, we sought to implement two clinical trials beginning in late 2014 in Liberia and Sierra Leone: one to evaluate the efficacy and safety of convalescent plasma for Ebola treatment ( ClinicalTrials.gov Identifier: NCT02333578) and another, an adaptive platform protocol to evaluate multiple treatments for Ebola Virus Disease ( ClinicalTrials.gov Identifier: NCT02380625). Results Here, we offer five lessons learned from our experiences that may help inform future efforts to conduct clinical trials targeting Ebola or Ebola-like outbreaks: (1) Research should be an integral part of the public health emergency response in outbreak settings; (2) conducting emergency clinical trials requires experienced research staff at all levels from the start; (3) public health officials should coordinate with scientific leadership to direct resources towards the most meritorious research questions; (4) a platform trial design is well-suited to ethically and efficiently identify effective therapies in the setting of a high-fatality, dynamic outbreak; (5) to advance therapeutics in the midst of an emerging outbreak, academic and research communities need to respond as boldly and as swiftly as the humanitarian community. Conclusions Clinical research to evaluate Ebola therapeutics in the West Africa Ebola epidemic was initiated too late to yield optimal results. In seeking to conduct two clinical studies in this region, we learned valuable lessons and suggest a way forward for implementing therapeutic clinical trials in the next epidemic.

Early, presymptomatic intervention with oseltamivir (corresponding to the onset of a published host-based genomic signature of influenza infection) resulted in decreased overall influenza symptoms (aggregate symptom scores of 23.5 vs 46.3), more rapid resolution of clinical disease (20 hours earlier), reduced viral shedding (total median tissue culture infectious dose [TCID50] 7.4 vs 9.7), and significantly reduced expression of several inflammatory cytokines (interferon-γ, tumor necrosis factor-α, interleukin-6, and others). The host genomic response to influenza infection is robust and may provide the means for early detection, more timely therapeutic interventions, a meaningful reduction in clinical disease, and an effective molecular means to track response to therapy.

We studied rickettsioses in southern Sri Lanka. Of 883 febrile patients with paired serum samples, 156 (17.7%) had acute rickettsioses; rickettsioses were unsuspected at presentation. Additionally, 342 (38.7%) had exposure to spotted fever and/or typhus group rickettsioses and 121 (13.7%) scrub typhus. Increased awareness of rickettsioses and better tests are needed.

Congenital disorders of glycosylation (CDG) are a group of rare genetically inherited disorders that involve the malfunction of attaching sugar molecules to lipids, proteins, or other organic molecules through an enzymatic process. The resulting defect in glycoprotein and glycolipid synthesis often has a heterogeneous range of multisystemic effects ranging from mild dysmorphism to profound organ failure and subsequent death. There are 2 types of CDG, type I and type II, with multiple subtypes within each. This column is a case presentation about an infant who presented with CDG type Ik.

The use of tabletop exercises as a tool in emergency preparedness and response has proven to be an effective means of assessing readiness for unexpected events. Whereas most exercise developers target a population in a defined space (eg, state, county, metropolitan area, hospital), the Southeastern Center for Emerging Biologic Threats (SECEBT) conducted an innovative tabletop exercise involving an unusual foodborne outbreak pathogen, targeting public health agencies and academic institutions in 7 southeastern states. The exercise tested the ability of participants to respond to a simulated foodborne disease outbreak affecting the region. The attendees represented 4 federal agencies, 9 state agencies, 6 universities, 1 nonprofit organization, and 1 private corporation. The goals were to promote collaborative relationships among the players, identify gaps in plans and policies, and identify the unique contributions of each organization—and notably academic institutions—to outbreak recognition, investigation, and control. Participants discussed issues and roles related to outbreak detection and management, risk communication, and coordination of policies and responsibilities before, during, and after an emergency, with emphasis on assets of universities that could be mobilized during an outbreak response. The exercise generated several lessons and recommendations identified by participants and evaluators. Key recommendations included a need to establish trigger points and protocols for information sharing and alerts among public health, academic, and law enforcement; to establish relationships with local, state, and federal stakeholders to facilitate communications during an emergency; and to catalogue and leverage strengths, assets, and priorities of academic institutions to add value to outbreak responses.

Acute dengue may be under-recognized in other regions because of limited studies and tools for rapid diagnosis., Dengue virus (DENV), a globally emerging cause of undifferentiated fever, has been documented in the heavily urbanized western coast of Sri Lanka since the 1960s. New areas of Sri Lanka are now being affected, and the reported number and severity of cases have increased. To study emerging DENV in southern Sri Lanka, we obtained epidemiologic and clinical data and acute- and convalescent-phase serum samples from patients >2 years old with febrile illness. We tested paired serum samples for DENV IgG and IgM and serotyped virus by using isolation and reverse transcription PCR. We identified acute DENV infection (serotypes 2, 3, and 4) in 54 (6.3%) of 859 patients. Only 14% of patients had clinically suspected dengue; however, 54% had serologically confirmed acute or past DENV infection. DENV is a major and largely unrecognized cause of fever in southern Sri Lanka, especially in young adults.

Ehrlichia chaffeensis , the etiologic agent of human monocytic ehrlichiosis (HME), has been extensively studied as a cause of acute febrile illness and an emerging tick-borne zoonosis in the United States. Limited data suggest its presence in other regions, including Central and South America but not Nicaragua to date. Diagnosis of E. chaffeensis infection by indirect immunofluorescence assay (IFA) is the reference standard due to its presumed high sensitivity and specificity, but IFA is impractical, variably reproducible, and cumbersome for large epidemiologic studies and for clinical diagnosis in resource-poor regions. We evaluated a high-throughput, objective peptide-based enzyme-linked immunosorbent assay (ELISA) for use alone or in combination with IFA. We found that it performed best as a screening test (sensitivity, 100%; specificity, 84%) to reduce the proportion of serum samples that were required by the more cumbersome and subjective IFA testing to E. chaffeensis or a serologically and antigenically similar organism as a heretofore unrecognized cause of acute febrile illness in humans in Nicaragua and demonstrated the utility of the peptide ELISA as a screening tool for large-scale clinical studies.

Acute respiratory tract infections (ARTIs) are a common reason for unnecessary antibiotic prescriptions worldwide. Our objective was to determine if providing access to rapid influenza test results could reduce antibiotic prescriptions for ARTIs in a resource-limited setting. We conducted a prospective, pre-post study from March 2013 to October 2014. Outpatients presenting to a hospital in Sri Lanka were surveyed for influenza-like illness-onset of fever ≥ 38.0°C and cough in prior 7 days. Enrolled patients were administered a structured questionnaire, physical examination, and nasal/nasopharyngeal sampling for rapid influenza A/B testing. Influenza test results were released only during phase 2 (January-October 2014). We enrolled 571 patients with ILI-316 in phase 1 and 241 in phase 2. The proportion positive for influenza was 46.5% in phase 1 and 28.6% in phase 2, P < 0.001. Between phases, antibiotic prescriptions decreased from 81.3% to 69.3% (P = 0.001) among all patients and from 83.7% to 62.3% (P = 0.001) among influenza-positive patients. On multivariable analysis, a positive influenza result during phase 2 was associated with lower odds of antibiotic prescriptions (OR = 0.50, 95% CI = 0.26-0.95). This prospective study suggests that providing access to rapid influenza testing may reduce unnecessary antibiotic prescriptions in resource-limited settings.

Background The NHSN recently updated risk adjustment models and “rebaselined” Standardized Infection Ratios (SIRs) for healthcare-associated infections. The CDC expected that hospital SIRs would generally increase. However, the impact of rebaselining on individual hospitals’ SIRs was unknown. Accordingly, we assessed the impact of rebaselining on SIRs in a network of community hospitals. Methods We analyzed 2016 SIR data for CAUTI, MRSA LabID events, CDI LabID events, colon SSIs (COLO), and abdominal hysterectomy SSIs (HYST) from 38 hospitals in the Duke Infection Control Outreach Network (DICON). SIRs calculated using the old and new baselines were compared. Wilcoxon signed rank test was performed to determine whether hospitals’ SIRs changed significantly following rebaselining. Hospitals were ranked by SIR for each metric, and change in rank following rebaselining was determined. Meaningful change in rank was defined as increase or decrease by ≥4 places (greater than a decile). Hospitals that did not have an SIR calculated for a given metric were excluded from that metric’s analysis. Results Median hospital SIRs for CAUTI and CDI increased significantly after rebaselining (0.587 vs 0.307, P Conclusion SIRs increased following rebaselining for CAUTI and CDI but did not change significantly for MRSA, COLO, or HYST. The majority of hospitals’ SIR rank did not change meaningfully following rebaselining. Disclosures D. Sexton, Centers for Disease Control and Prevention: Grant Investigator, Grant recipient; Centers for Disease Control and Prevention Foundation: Grant Investigator, Grant recipient; UpToDate: Collaborator, Royalty Recipient

TOC summary: Clinical impression and serologic tests of acute-phase specimens are insensitive, and rapid, pathogen-based tests are needed., To determine the proportion of fevers caused by leptospirosis, we obtained serum specimens and epidemiologic and clinical data from patients in Galle, Sri Lanka, March–October 2007. Immunoglobulin M ELISA was performed on paired serum specimens to diagnose acute (seroconversion or 4-fold titer rise) or past (titer without rise) leptospirosis and seroprevalence (acute). We compared (individually) the diagnostic yield of acute-phase specimens and clinical impression with paired specimens for acute leptospirosis. Of 889 patients with paired specimens, 120 had acute leptosoirosis and 241 had past leptospirosis. The sensitivity and specificity of acute-phase serum specimens were 17.5% (95% confidence interval [CI] 11.2%–25.5%) and 69.2% (95% CI 65.5%–72.7%), respectively, and of clinical impression 22.9% (95% CI 15.4%–32.0%) and 91.7% (95% CI 89.2%–93.8%), respectively. For identifying acute leptospirosis, clinical impression is insensitive, and immunoglobulin M results are more insensitive and costly. Rapid, pathogen-based tests for early diagnosis are needed.

Staphylococcus aureus is the most common cause of both infective endocarditis (IE) [1] and soft tissue infection (STI) [2] in the industrialized world. The frequency of S. aureus as a human pathogen is thought to be due in part to its diverse armamentarium of virulence-associated genes. Although substantial evidence suggests that clinical manifestations of S. aureus are influenced by the genetic characteristics of the infecting strain [3–7], the association between S. aureus genes and severity of illness is incompletely understood. Previously, we demonstrated a significant association between specific S. aureus isolates genotypes and infection severity [4]. We used multilocus sequence typing (MLST) to show that clonal complex (CC) 5 and CC30 were significantly associated with the presence of IE and bone and joint infection among 371 clinically well-characterized S. aureus isolates from a single geographical region. However, these findings must be confirmed prior to being considered broadly generalizable. The current investigation seeks to externally validate these previously observed associations between bacterial genotype and infection severity in S. aureus. To do this, we used bacterial isolates from 2 large multinational cohorts of patients with distinct forms of staphylococcal disease: IE and STI.