Publications by authors named "Christopher W Woods"

164 Publications

SARS-CoV-2 vaccination induces neutralizing antibodies against pandemic and pre-emergent SARS-related coronaviruses in monkeys.

bioRxiv 2021 Feb 17. Epub 2021 Feb 17.

Betacoronaviruses (betaCoVs) caused the severe acute respiratory syndrome (SARS) and Middle East Respiratory Syndrome (MERS) outbreaks, and now the SARS-CoV-2 pandemic. Vaccines that elicit protective immune responses against SARS-CoV-2 and betaCoVs circulating in animals have the potential to prevent future betaCoV pandemics. Here, we show that immunization of macaques with a multimeric SARS-CoV-2 receptor binding domain (RBD) nanoparticle adjuvanted with 3M-052-Alum elicited cross-neutralizing antibody responses against SARS-CoV-1, SARS-CoV-2, batCoVs and the UK B.1.1.7 SARS-CoV-2 mutant virus. Nanoparticle vaccination resulted in a SARS-CoV-2 reciprocal geometric mean neutralization titer of 47,216, and robust protection against SARS-CoV-2 in macaque upper and lower respiratory tracts. Importantly, nucleoside-modified mRNA encoding a stabilized transmembrane spike or monomeric RBD protein also induced SARS-CoV-1 and batCoV cross-neutralizing antibodies, albeit at lower titers. These results demonstrate current mRNA vaccines may provide some protection from future zoonotic betaCoV outbreaks, and provide a platform for further development of pan-betaCoV nanoparticle vaccines.
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http://dx.doi.org/10.1101/2021.02.17.431492DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899458PMC
February 2021

Dysregulated transcriptional responses to SARS-CoV-2 in the periphery.

Nat Commun 2021 02 17;12(1):1079. Epub 2021 Feb 17.

Durham Veterans Affairs Medical Center, Durham, NC, USA.

SARS-CoV-2 infection has been shown to trigger a wide spectrum of immune responses and clinical manifestations in human hosts. Here, we sought to elucidate novel aspects of the host response to SARS-CoV-2 infection through RNA sequencing of peripheral blood samples from 46 subjects with COVID-19 and directly comparing them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a powerful transcriptomic response in peripheral blood with conserved components that are heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, which persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95 [95% CI 0.92-0.98]). The transcriptome in peripheral blood reveals both diverse and conserved components of the immune response in COVID-19 and provides for potential biomarker-based approaches to diagnosis.
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http://dx.doi.org/10.1038/s41467-021-21289-yDOI Listing
February 2021

Racial, Ethnic, and Geographic Disparities in Novel Coronavirus (Severe Acute Respiratory Syndrome Coronavirus 2) Test Positivity in North Carolina.

Open Forum Infect Dis 2021 Jan 8;8(1):ofaa413. Epub 2020 Sep 8.

Duke University School of Medicine, Durham, North Carolina, USA.

Background: Emerging evidence suggests that black and Hispanic communities in the United States are disproportionately affected by coronavirus disease 2019 (COVID-19). A complex interplay of socioeconomic and healthcare disparities likely contribute to disproportionate COVID-19 risk.

Methods: We conducted a geospatial analysis to determine whether individual- and neighborhood-level attributes predict local odds of testing positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We analyzed 29 138 SARS-CoV-2 tests within the 6-county catchment area for Duke University Health System from March to June 2020. We used generalized additive models to analyze the spatial distribution of SARS-CoV-2 positivity. Adjusted models included individual-level age, gender, and race, as well as neighborhood-level Area Deprivation Index, population density, demographic composition, and household size.

Results: Our dataset included 27 099 negative and 2039 positive unique SARS-CoV-2 tests. The odds of a positive SARS-CoV-2 test were higher for males (odds ratio [OR], 1.43; 95% credible interval [CI], 1.30-1.58), blacks (OR, 1.47; 95% CI, 1.27-1.70), and Hispanics (OR, 4.25; 955 CI, 3.55-5.12). Among neighborhood-level predictors, percentage of black population (OR, 1.14; 95% CI, 1.05-1.25), and percentage Hispanic population (OR, 1.23; 95% CI, 1.07-1.41) also influenced the odds of a positive SARS-CoV-2 test. Population density, average household size, and Area Deprivation Index were not associated with SARS-CoV-2 test results after adjusting for race.

Conclusions: The odds of testing positive for SARS-CoV-2 were higher for both black and Hispanic individuals, as well as within neighborhoods with a higher proportion of black or Hispanic residents-confirming that black and Hispanic communities are disproportionately affected by SARS-CoV-2.
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http://dx.doi.org/10.1093/ofid/ofaa413DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499753PMC
January 2021

Validation of a host gene expression test for bacterial/viral discrimination in immunocompromised hosts.

Clin Infect Dis 2021 Jan 19. Epub 2021 Jan 19.

Duke Center for Applied Genomics and Precision Medicine, Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

Background: Host gene expression has emerged as a complementary strategy to pathogen detection tests for the discrimination of bacterial and viral infection. The impact of immunocompromise on host response tests remains unknown. We evaluated a host response test discriminating bacterial, viral, and non-infectious conditions in immunocompromised subjects.

Methods: An 81-gene signature was measured using RT-PCR in subjects with immunocompromise (chemotherapy, solid organ transplant, immunomodulatory agents, AIDS) with bacterial infection, viral infection, or noninfectious illness. A regularized logistic regression model trained in immunocompetent subjects was used to estimate the likelihood of each class in immunocompromised subjects.

Results: Accuracy in the 136-subject immunocompetent training cohort was 84.6% for bacterial vs. non-bacterial discrimination and 80.8% for viral vs. non-viral discrimination. Model validation in 134 immunocompromised subjects showed overall accuracy of 73.9% for bacterial infection (p=0.04 relative to immunocompetent subjects) and 75.4% for viral infection (p=0.30). A scheme reporting results by quartile improved test utility. The highest probability quartile ruled-in bacterial and viral infection with 91.4% and 84.0% specificity, respectively. The lowest probability quartile ruled-out infection with 90.1% and 96.4% sensitivity for bacterial and viral infection, respectively. Performance was independent of the type or number of immunocompromising conditions.

Conclusion: A host gene expression test discriminated bacterial, viral, and non-infectious etiologies at a lower overall accuracy in immunocompromised patients compared to immunocompetent patients, though this difference was only significant for bacterial infection classification. With modified interpretive criteria, a host response strategy may offer clinically useful diagnostic information for patients with immunocompromise.
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http://dx.doi.org/10.1093/cid/ciab043DOI Listing
January 2021

The functions of SARS-CoV-2 neutralizing and infection-enhancing antibodies in vitro and in mice and nonhuman primates.

bioRxiv 2021 Jan 2. Epub 2021 Jan 2.

SARS-CoV-2 neutralizing antibodies (NAbs) protect against COVID-19, making them a focus of vaccine design. A safety concern regarding SARS-CoV-2 antibodies is whether they mediate disease enhancement. Here, we isolated potent NAbs against the receptor-binding domain (RBD) and the N-terminal domain (NTD) of SARS-CoV-2 spike protein from individuals with acute or convalescent SARS-CoV-2 or a history of SARS-CoV-1 infection. Cryo-electron microscopy of RBD and NTD antibodies demonstrated function-specific modes of antibody binding. Select RBD NAbs also demonstrated Fc receptor-γ (FcγR)-mediated enhancement of virus infection , while five non-neutralizing NTD antibodies mediated FcγR-independent infection enhancement. However, both neutralizing and infection-enhancing RBD or infection-enhancing NTD antibodies protected from SARS-CoV-2 challenge in non-human primates and mice. One of 30 monkeys infused with enhancing antibodies had lung pathology and bronchoalveolar lavage cytokine evidence suggestive of enhanced disease. Thus, these assessments of enhanced antibody-mediated infection do not necessarily indicate biologically relevant infection enhancement.
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http://dx.doi.org/10.1101/2020.12.31.424729DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7805451PMC
January 2021

An atlas connecting shared genetic architecture of human diseases and molecular phenotypes provides insight into COVID-19 susceptibility.

medRxiv 2020 Dec 22. Epub 2020 Dec 22.

While genome-wide associations studies (GWAS) have successfully elucidated the genetic architecture of complex human traits and diseases, understanding mechanisms that lead from genetic variation to pathophysiology remains an important challenge. Methods are needed to systematically bridge this crucial gap to facilitate experimental testing of hypotheses and translation to clinical utility. Here, we leveraged cross-phenotype associations to identify traits with shared genetic architecture, using linkage disequilibrium (LD) information to accurately capture shared SNPs by proxy, and calculate significance of enrichment. This shared genetic architecture was examined across differing biological scales through incorporating data from catalogs of clinical, cellular, and molecular GWAS. We have created an interactive web database (interactive Cross-Phenotype Analysis of GWAS database (iCPAGdb); http://cpag.oit.duke.edu ) to facilitate exploration and allow rapid analysis of user-uploaded GWAS summary statistics. This database revealed well-known relationships among phenotypes, as well as the generation of novel hypotheses to explain the pathophysiology of common diseases. Application of iCPAGdb to a recent GWAS of severe COVID-19 demonstrated unexpected overlap of GWAS signals between COVID-19 and human diseases, including with idiopathic pulmonary fibrosis driven by the locus. Transcriptomics from peripheral blood of COVID-19 patients demonstrated that was induced in SARS-CoV-2 compared to healthy controls or those with bacterial infection. Further investigation of cross-phenotype SNPs with severe COVID-19 demonstrated colocalization of the GWAS signal of the locus with plasma protein levels of a reported receptor of SARS-CoV-2, CD209 (DC-SIGN), pointing to a possible mechanism whereby glycosylation of CD209 by may regulate COVID-19 disease severity. Thus, connecting genetically related traits across phenotypic scales links human diseases to molecular and cellular measurements that can reveal mechanisms and lead to novel biomarkers and therapeutic approaches.
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http://dx.doi.org/10.1101/2020.12.20.20248572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781346PMC
December 2020

Chromatin remodeling in peripheral blood cells reflects COVID-19 symptom severity.

bioRxiv 2020 Dec 5. Epub 2020 Dec 5.

SARS-CoV-2 infection triggers highly variable host responses and causes varying degrees of illness in humans. We sought to harness the peripheral blood mononuclear cell (PBMC) response over the course of illness to provide insight into COVID-19 physiology. We analyzed PBMCs from subjects with variable symptom severity at different stages of clinical illness before and after IgG seroconversion to SARS-CoV-2. Prior to seroconversion, PBMC transcriptomes did not distinguish symptom severity. In contrast, changes in chromatin accessibility were associated with symptom severity. Furthermore, single-cell analyses revealed evolution of the chromatin accessibility landscape and transcription factor motif occupancy for individual PBMC cell types. The most extensive remodeling occurred in CD14+ monocytes where sub-populations with distinct chromatin accessibility profiles were associated with disease severity. Our findings indicate that pre-seroconversion chromatin remodeling in certain innate immune populations is associated with divergence in symptom severity, and the identified transcription factors, regulatory elements, and downstream pathways provide potential prognostic markers for COVID-19 subjects.
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http://dx.doi.org/10.1101/2020.12.04.412155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724678PMC
December 2020

Outbreak of severe acute respiratory infection in Southern Province, Sri Lanka in 2018: a cross-sectional study.

BMJ Open 2020 11 6;10(11):e040612. Epub 2020 Nov 6.

Medicine, Duke University School of Medicine, Durham, North Carolina, USA

Objectives: To determine aetiology of illness among children and adults presenting during outbreak of severe respiratory illness in Southern Province, Sri Lanka, in 2018.

Design: Prospective, cross-sectional study.

Setting: 1600-bed, public, tertiary care hospital in Southern Province, Sri Lanka.

Participants: 410 consecutive patients, including 371 children and 39 adults, who were admitted with suspected viral pneumonia (passive surveillance) or who met case definition for acute respiratory illness (active surveillance) in May to June 2018.

Results: We found that cocirculation of influenza A (22.6% of cases), respiratory syncytial virus (27.8%) and adenovirus (AdV) (30.7%; type B3) was responsible for the outbreak. Mortality was noted in 4.5% of paediatric cases identified during active surveillance. Virus type and viral coinfection were not significantly associated with mortality.

Conclusions: This is the first report of intense cocirculation of multiple respiratory viruses as a cause of an outbreak of severe acute respiratory illness in Sri Lanka, and the first time that AdV has been documented as a cause of a respiratory outbreak in the country. Our results emphasise the need for continued vigilance in surveying for known and emerging respiratory viruses in the tropics.
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http://dx.doi.org/10.1136/bmjopen-2020-040612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7651749PMC
November 2020

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.

Clin Infect Dis 2020 Nov 3. Epub 2020 Nov 3.

Department of Pediatrics, Division of Infectious Diseases, Duke University School of Medicine, Durham, NC.

Background: Children with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children.

Methods: We conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay.

Results: Of 382 children, 293 (77%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have asthma (p=0.005), and more likely to have an infected sibling contact (p=0.001) than uninfected children. Children ages 6-13 years were frequently asymptomatic (39%) and had respiratory symptoms less often than younger children (29% vs. 48%; p=0.01) or adolescents (29% vs. 60%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p<0.0001), gastrointestinal (27% vs. 9%; p=0.002), and sensory symptoms (42% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.01]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children.

Conclusions: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.
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http://dx.doi.org/10.1093/cid/ciaa1693DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7665428PMC
November 2020

A blood-based host gene expression assay for early detection of respiratory viral infection: an index-cluster prospective cohort study.

Lancet Infect Dis 2021 Mar 24;21(3):396-404. Epub 2020 Sep 24.

Center for Applied Genomics and Precision Medicine, Duke University Medical Center, Durham, NC, USA; Division of Infectious Diseases, Duke University Medical Center, Durham, NC, USA; Durham VA Medical Center, Durham, NC, USA.

Background: Early and accurate identification of individuals with viral infections is crucial for clinical management and public health interventions. We aimed to assess the ability of transcriptomic biomarkers to identify naturally acquired respiratory viral infection before typical symptoms are present.

Methods: In this index-cluster study, we prospectively recruited a cohort of undergraduate students (aged 18-25 years) at Duke University (Durham, NC, USA) over a period of 5 academic years. To identify index cases, we monitored students for the entire academic year, for the presence and severity of eight symptoms of respiratory tract infection using a daily web-based survey, with symptoms rated on a scale of 0-4. Index cases were defined as individuals who reported a 6-point increase in cumulative daily symptom score. Suspected index cases were visited by study staff to confirm the presence of reported symptoms of illness and to collect biospecimen samples. We then identified clusters of close contacts of index cases (ie, individuals who lived in close proximity to index cases, close friends, and partners) who were presumed to be at increased risk of developing symptomatic respiratory tract infection while under observation. We monitored each close contact for 5 days for symptoms and viral shedding and measured transcriptomic responses at each timepoint each day using a blood-based 36-gene RT-PCR assay.

Findings: Between Sept 1, 2009, and April 10, 2015, we enrolled 1465 participants. Of 264 index cases with respiratory tract infection symptoms, 150 (57%) had a viral cause confirmed by RT-PCR. Of their 555 close contacts, 106 (19%) developed symptomatic respiratory tract infection with a proven viral cause during the observation window, of whom 60 (57%) had the same virus as their associated index case. Nine viruses were detected in total. The transcriptomic assay accurately predicted viral infection at the time of maximum symptom severity (mean area under the receiver operating characteristic curve [AUROC] 0·94 [95% CI 0·92-0·96]), as well as at 1 day (0·87 [95% CI 0·84-0·90]), 2 days (0·85 [0·82-0·88]), and 3 days (0·74 [0·71-0·77]) before peak illness, when symptoms were minimal or absent and 22 (62%) of 35 individuals, 25 (69%) of 36 individuals, and 24 (82%) of 29 individuals, respectively, had no detectable viral shedding.

Interpretation: Transcriptional biomarkers accurately predict and diagnose infection across diverse viral causes and stages of disease and thus might prove useful for guiding the administration of early effective therapy, quarantine decisions, and other clinical and public health interventions in the setting of endemic and pandemic infectious diseases.

Funding: US Defense Advanced Research Projects Agency.
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http://dx.doi.org/10.1016/S1473-3099(20)30486-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7515566PMC
March 2021

SARS-CoV-2 Infections Among Children in the Biospecimens from Respiratory Virus-Exposed Kids (BRAVE Kids) Study.

medRxiv 2020 Sep 1. Epub 2020 Sep 1.

Department of Pediatrics, Division of Infectious Diseases, Duke University School of Medicine, Durham, NC.

Background: Children with SARS-CoV-2 infection typically have mild symptoms that do not require medical attention, leaving a gap in our understanding of the spectrum of illnesses that the virus causes in children.

Methods: We conducted a prospective cohort study of children and adolescents (<21 years of age) with a SARS-CoV-2-infected close contact. We collected nasopharyngeal or nasal swabs at enrollment and tested for SARS-CoV-2 using a real-time PCR assay.

Results: Of 382 children, 289 (76%) were SARS-CoV-2-infected. SARS-CoV-2-infected children were more likely to be Hispanic (p<0.0001), less likely to have a history of asthma (p=0.009), and more likely to have an infected sibling contact (p=0.0007) than uninfected children. Children ages 6-13 years were frequently asymptomatic (38%) and had respiratory symptoms less often than younger children (30% vs. 49%; p=0.008) or adolescents (30% vs. 59%; p<0.0001). Compared to children ages 6-13 years, adolescents more frequently reported influenza-like (61% vs. 39%; p=0.002), gastrointestinal (26% vs. 9%; p=0.003), and sensory symptoms (43% vs. 9%; p<0.0001), and had more prolonged illnesses [median (IQR) duration: 7 (4, 12) vs. 4 (3, 8) days; p=0.004]. Despite the age-related variability in symptoms, we found no differences in nasopharyngeal viral load by age or between symptomatic and asymptomatic children.

Conclusions: Hispanic ethnicity and an infected sibling close contact are associated with increased SARS-CoV-2 infection risk among children, while a history of asthma is associated with decreased risk. Age-related differences in the clinical manifestations of SARS-CoV-2 infection must be considered when evaluating children for COVID-19 and in developing screening strategies for schools and childcare settings.
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http://dx.doi.org/10.1101/2020.08.18.20166835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7480040PMC
September 2020

Improved empiric antibiotic prescribing for acute cystitis with use of local urinary antibiogram and clinical decision support system.

Infect Control Hosp Epidemiol 2020 Nov 19;41(11):1351-1353. Epub 2020 Aug 19.

Division of Infectious Diseases, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.

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http://dx.doi.org/10.1017/ice.2020.357DOI Listing
November 2020

Dysregulated transcriptional responses to SARS-CoV-2 in the periphery support novel diagnostic approaches.

medRxiv 2020 Jul 26. Epub 2020 Jul 26.

Center for Applied Genomics and Precision Medicine, Duke University, Durham, NC.

In order to elucidate novel aspects of the host response to SARS-CoV-2 we performed RNA sequencing on peripheral blood samples across 77 timepoints from 46 subjects with COVID-19 and compared them to subjects with seasonal coronavirus, influenza, bacterial pneumonia, and healthy controls. Early SARS-CoV-2 infection triggers a conserved transcriptomic response in peripheral blood that is heavily interferon-driven but also marked by indicators of early B-cell activation and antibody production. Interferon responses during SARS-CoV-2 infection demonstrate unique patterns of dysregulated expression compared to other infectious and healthy states. Heterogeneous activation of coagulation and fibrinolytic pathways are present in early COVID-19, as are IL1 and JAK/STAT signaling pathways, that persist into late disease. Classifiers based on differentially expressed genes accurately distinguished SARS-CoV-2 infection from other acute illnesses (auROC 0.95). The transcriptome in peripheral blood reveals unique aspects of the immune response in COVID-19 and provides for novel biomarker-based approaches to diagnosis.
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http://dx.doi.org/10.1101/2020.07.20.20155507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386527PMC
July 2020

Previously Derived Host Gene Expression Classifiers Identify Bacterial and Viral Etiologies of Acute Febrile Respiratory Illness in a South Asian Population.

Open Forum Infect Dis 2020 Jun 26;7(6):ofaa194. Epub 2020 May 26.

Department of Medicine, Duke University School of Medicine, Durham, North Carolina, USA.

Background: Pathogen-based diagnostics for acute respiratory infection (ARI) have limited ability to detect etiology of illness. We previously showed that peripheral blood-based host gene expression classifiers accurately identify bacterial and viral ARI in cohorts of European and African descent. We determined classifier performance in a South Asian cohort.

Methods: Patients ≥15 years with fever and respiratory symptoms were enrolled in Sri Lanka. Comprehensive pathogen-based testing was performed. Peripheral blood ribonucleic acid was sequenced and previously developed signatures were applied: a pan-viral classifier (viral vs nonviral) and an ARI classifier (bacterial vs viral vs noninfectious).

Results: Ribonucleic acid sequencing was performed in 79 subjects: 58 viral infections (36 influenza, 22 dengue) and 21 bacterial infections (10 leptospirosis, 11 scrub typhus). The pan-viral classifier had an overall classification accuracy of 95%. The ARI classifier had an overall classification accuracy of 94%, with sensitivity and specificity of 91% and 95%, respectively, for bacterial infection. The sensitivity and specificity of C-reactive protein (>10 mg/L) and procalcitonin (>0.25 ng/mL) for bacterial infection were 100% and 34%, and 100% and 41%, respectively.

Conclusions: Previously derived gene expression classifiers had high predictive accuracy at distinguishing viral and bacterial infection in South Asian patients with ARI caused by typical and atypical pathogens.
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http://dx.doi.org/10.1093/ofid/ofaa194DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7314590PMC
June 2020

Pharmacoepidemiology of Ceftazidime-Avibactam Use: A Retrospective Cohort Analysis of 210 US Hospitals.

Clin Infect Dis 2021 Feb;72(4):611-621

Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, Maryland, USA.

Background: Ceftazidime-avibactam has in vitro activity against some carbapenem-resistant gram-negative infections (GNIs), and therefore may be a useful alternative to more toxic antibiotics such as colistin. Understanding ceftazidime-avibactam uptake and usage patterns would inform hospital formularies, stewardship, and antibiotic development.

Methods: A retrospective cohort study assessed inpatient encounters in the Vizient database. Ceftazidime-avibactam and colistin administrations were categorized into presumed empiric (3 consecutive days of therapy or less with qualifying exclusions) versus targeted therapy (≥4 consecutive days of therapy) for presumed carbapenem-resistant GNIs. Quarterly percentage change (QPC) using modified Poisson regression and relative change in frequency of targeted ceftazidime-avibactam to colistin encounters was calculated. Factors associated with preferentially receiving targeted ceftazidime-avibactam versus colistin were identified using generalized estimating equations.

Results: Between 2015 quarter (q) 1 and 2017q4, ceftazidime-avibactam was administered 21 215 times across 1901 encounters. Inpatient prescriptions for ceftazidime-avibactam increased from 0.44/10 000 hospitalizations in 2015q1 to 7.7/10 000 in 2017q4 (QPC, +11%; 95% CI, 10-13%; P < .01), while conversely colistin prescriptions decreased quarterly by 5% (95% CI, 4-6%; P < .01). Ceftazidime-avibactam therapy was categorized as empiric 25% of the time, targeted 65% of the time, and indeterminate 10% of the time. Patients with chronic kidney disease were twice as likely to receive targeted ceftazidime-avibactam versus colistin (RR, 2.02; 95% CI, 1.82-2.25), whereas those on dialysis were less likely to receive ceftazidime-avibactam than colistin (RR, 0.71; 95% CI, .61-.83).

Conclusions: Since approval in 2015, ceftazidime-avibactam use has grown for presumed carbapenem-resistant GNIs, while colistin has correspondingly declined. Renal function drove the choice between ceftazidime-avibactam and colistin as targeted therapy.
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http://dx.doi.org/10.1093/cid/ciaa061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884805PMC
February 2021

Differences in time-to-testing and time-to-isolation between community-onset and hospital-onset Clostridioides difficile cases at a tertiary care VA medical center.

Am J Infect Control 2020 10 3;48(10):1148-1151. Epub 2020 Jan 3.

Durham VA Health Care System, Durham, NC; Division of Infectious Diseases, Duke University School of Medicine, Durham, NC.

Background: Delayed identification and isolation of patients with Clostridiodies difficile infection (CDI) may contribute to in-hospital transmission and delay appropriate therapy. To assess potential points for intervention, we conducted a retrospective cohort study to determine differences in time-to-testing and time-to-isolation among community-onset (CO), community-onset healthcare facility-associated (CO-HCFA), and hospital-onset (HO) CDI.

Methods: We compared clinical and demographic data of all CO, CO-HCFA, and HO CDI patients at our institution between October 2011 and September 2015. We then performed bivariable analysis on our cohorts to identify differences in time-to-testing and time-to-isolation for CO versus CO-HCFA versus HO CDI patients.

Results: 355 patients with CDI were hospitalized during the study; 138 (38.9%) with CO CDI, 52 (14.6%) with CO-HCFA CDI, and 165 (46.5%) with HO CDI. 117 (84.8%) CO CDI patients were tested within 1 day of diarrhea onset compared to 41 (78.8%) of CO-HCFA and 113 (68.5%) of HO CDI patients (P < .01). 51 CO CDI patients (36.7%) were placed on empirical isolation precautions at the time of diarrhea onset compared to 22 (43.1%) of CO-HCFA CDI patients and 32 (19.4%) of HO CDI patients (P < .01).

Conclusions: CO CDI patients are more likely to be isolated empirically and tested earlier than HO CDI patients. Further attention should be paid to isolating hospitalized patients who develop diarrhea as an inpatient.
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http://dx.doi.org/10.1016/j.ajic.2019.12.008DOI Listing
October 2020

Geospatial analysis of dengue emergence in rural areas in the Southern Province of Sri Lanka.

Trans R Soc Trop Med Hyg 2020 06;114(6):408-414

Duke Global Health Institute, Durham, NC 27710, USA.

Background: Dengue is a major cause of acute febrile illness in Sri Lanka. Dengue has historically been considered an urban disease. In 2012-2013, we documented that acute dengue was surprisingly associated with self-reported rural residence in the Southern Province of Sri Lanka.

Methods: Patients admitted with an acute febrile illness were enrolled from June 2012-May 2013 in a cross-sectional surveillance study at the largest tertiary care hospital in the Southern Province. Acute dengue was diagnosed by serology and virology testing. Site visits were performed to collect residential geographical coordinates. Spatial variation in odds of acute dengue was modeled using a spatial generalized additive model predicted onto a grid of coordinate pairs covering the Southern Province.

Results: Of 800 patients, 333 (41.6%) had laboratory-confirmed acute dengue. Dengue was spatially heterogeneous (local probability of acute dengue 0.26 to 0.42). There were higher than average odds of acute dengue in the rural northeast of the Southern Province and lower than average odds in the urbanized southwest of the Southern Province, including the city Galle.

Conclusions: Our study further affirms the emergence of dengue in rural southern Sri Lanka and highlights both the need for real-time geospatial analyses to optimize public health activities as well as the importance of strengthening dengue surveillance in non-urban areas.
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http://dx.doi.org/10.1093/trstmh/trz123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7528758PMC
June 2020

Epidemiologic Trends in Clostridioides difficile Infections in a Regional Community Hospital Network.

JAMA Netw Open 2019 10 2;2(10):e1914149. Epub 2019 Oct 2.

Division of Infectious Diseases, Duke University Medical Center, Durham, North Carolina.

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 < .001). Rates of the NAP1 strain of CDI varied widely between facilities, with no statistically significant change in NAP1 strain incidence over time in the community setting (IRR, 1.007; 95% CI, 0.994-1.021) or health care facility setting (IRR, 1.011; 95% CI, 0.990-1.032).

Conclusions And Relevance: The findings suggest that, despite the modest improvement in health care facility-associated CDI rates, a better understanding of community-acquired CDI incidence is needed for future infection prevention efforts.
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http://dx.doi.org/10.1001/jamanetworkopen.2019.14149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6824221PMC
October 2019

Direct-from-blood RNA sequencing identifies the cause of post-bronchoscopy fever.

BMC Infect Dis 2019 Oct 28;19(1):905. Epub 2019 Oct 28.

Austere environments Consortium for Enhanced Sepsis Outcomes (ACESO), Biological Defense Research Directorate, Naval Medical Research Center-Frederick, 8400 Research Plaza, Fort Detrick, MD, 21702, USA.

Background: Antibiotic resistance is rising at disturbing rates and contributes to the deaths of millions of people yearly. Antibiotic resistant infections disproportionately affect those with immunocompromising conditions, chronic colonization, and frequent antibiotic use such as transplant patients or those with cystic fibrosis. However, clinicians lack the diagnostic tools to confidently diagnose and treat infections, leading to widespread use of empiric broad spectrum antimicrobials, often for prolonged duration.

Case Presentation: A 22 year-old Caucasian female with cystic fibrosis received a bilateral orthotopic lung transplantation 5 months prior to the index hospitalization. She underwent routine surveillance bronchoscopy and was admitted for post-procedure fever. A clear cause of infection was not identified by routine methods. Imaging and bronchoscopic lung biopsy did not identify an infectious agent or rejection. She was treated with a prolonged course of antimicrobials targeting known colonizing organisms from prior bronchoalveolar lavage cultures (Pseudomonas, Staphylococcus aureus, and Aspergillus). However, we identified Stenotrophomonas maltophilia in two independent whole blood samples using direct-pathogen sequencing, which was not identified by other methods.

Conclusions: This case represents a common clinical conundrum: identification of infection in a high-risk, complex patient. Here, direct-pathogen sequencing identified a pathogen that would not otherwise have been identified by common techniques. Had results been clinically available, treatment could have been customized, avoiding a prolonged course of broad spectrum antimicrobials that would only exacerbate resistance. Direct-pathogen sequencing is poised to fill a diagnostic gap for pathogen identification, allowing early identification and customization of treatment in a culture-independent, pathogen-agnostic manner.
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http://dx.doi.org/10.1186/s12879-019-4462-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6819639PMC
October 2019

Validation of a host response test to distinguish bacterial and viral respiratory infection.

EBioMedicine 2019 Oct 17;48:453-461. Epub 2019 Oct 17.

Duke University Center for Applied Genomics and Precision Medicine, Durham, NC, USA; Durham Veterans Affairs Health Care System, Durham, NC, USA. Electronic address:

Background: Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases.

Methods: Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin.

Findings: 151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85-0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02).

Interpretation: The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases.
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http://dx.doi.org/10.1016/j.ebiom.2019.09.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6838360PMC
October 2019

Average Weighted Accuracy: Pragmatic Analysis for a Rapid Diagnostics in Categorizing Acute Lung Infections (RADICAL) Study.

Clin Infect Dis 2020 06;70(12):2736-2742

Biostatistics Center, George Washington Milken Institute School of Public Health, Rockville, MD, USA.

Patient management relies on diagnostic information to identify appropriate treatment. Standard evaluations of diagnostic tests consist of estimating sensitivity, specificity, positive/negative predictive values, likelihood ratios, and accuracy. Although useful, these metrics do not convey the tests' clinical value, which is critical to informing decision-making. Full appreciation of the clinical impact of a diagnostic test requires analyses that integrate sensitivity and specificity, account for the disease prevalence within the population of test application, and account for the relative importance of specificity vs sensitivity by considering the clinical implications of false-positive and false-negative results. We developed average weighted accuracy (AWA), representing a pragmatic metric of diagnostic yield or global utility of a diagnostic test. AWA can be used to compare test alternatives, even across different studies. We apply the AWA methodology to evaluate a new diagnostic test developed in the Rapid Diagnostics in Categorizing Acute Lung Infections (RADICAL) study.
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http://dx.doi.org/10.1093/cid/ciz437DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286373PMC
June 2020

Use of clinical algorithms and rapid influenza testing to manage influenza-like illness: a cost-effectiveness analysis in Sri Lanka.

BMJ Glob Health 2019 30;4(2):e001291. Epub 2019 Mar 30.

School of Medicine, Duke University, Durham, North Carolina, USA.

Background: Acute 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.

Methods: We 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.

Results: Standard 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
Conclusion: Clinical prediction tools and targeted rapid influenza testing may be cost-saving strategies in Sri Lanka when accounting for the societal cost of antimicrobial resistance.
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http://dx.doi.org/10.1136/bmjgh-2018-001291DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6441298PMC
March 2019

Mercury Exposure and Poor Nutritional Status Reduce Response to Six Expanded Program on Immunization Vaccines in Children: An Observational Cohort Study of Communities Affected by Gold Mining in the Peruvian Amazon.

Int J Environ Res Public Health 2019 02 21;16(4). Epub 2019 Feb 21.

Nicholas School of the Environment, Duke University, Durham, NC 27710, USA.

Poor nutritional status combined with mercury exposure can generate adverse child health outcomes. Diet is a mediator of mercury exposure and evidence suggests that nutritional status modifies aspects of mercury toxicity. However, health impacts beyond the nervous system are poorly understood. This study evaluates antibody responses to six vaccines from the expanded program on immunization (EPI), including hepatitis B, type B, measles, pertussis, tetanus, and diphtheria in children with variable hair mercury and malnutrition indicators. An observational cohort study ( = 98) was conducted in native and non-native communities in Madre de Dios, Peru, a region with elevated mercury exposure from artisanal and small-scale gold mining. Adaptive immune responses in young (3⁻48 months) and older children (4⁻8 year olds) were evaluated by vaccine type (live attenuated, protein subunits, toxoids) to account for differences in response by antigen, and measured by total IgG concentration and antibody (IgG) concentrations of each EPI vaccine. Mercury was measured from hair samples and malnutrition determined using anthropometry and hemoglobin levels in blood. Generalized linear mixed models were used to evaluate associations with each antibody type. Changes in child antibodies and protection levels were associated with malnutrition indicators, mercury exposure, and their interaction. Malnutrition was associated with decreased measles and diphtheria-specific IgG. A one-unit decrease in hemoglobin was associated with a 0.17 IU/mL (95% CI: 0.04⁻0.30) decline in measles-specific IgG in younger children and 2.56 (95% CI: 1.01⁻6.25) higher odds of being unprotected against diphtheria in older children. Associations between mercury exposure and immune responses were also dependent on child age. In younger children, one-unit increase in log child hair mercury content was associated with 0.68 IU/mL (95% CI: 0.18⁻1.17) higher pertussis and 0.79 IU/mL (95% CI: 0.18⁻1.70) higher diphtheria-specific IgG levels. In older children, child hair mercury content exceeding 1.2 µg/g was associated with 73.7 higher odds (95% CI: 2.7⁻1984.3) of being a non-responder against measles and hair mercury content exceeding 2.0 µg/g with 0.32 IU/mL (95% CI: 0.10⁻0.69) lower measles-specific antibodies. Log hair mercury significantly interacted with weight-for-height z-score, indicating a multiplicative effect of higher mercury and lower nutrition on measles response. Specifically, among older children with poor nutrition (WHZ = -1), log measles antibody is reduced from 1.40 to 0.43 for low (<1.2 µg/g) vs. high mercury exposure, whereas for children with good nutritional status (WHZ = 1), log measles antibody is minimally changed for low vs. high mercury exposure (0.72 vs. 0.81, respectively). Child immune response to EPI vaccines may be attenuated in regions with elevated mercury exposure risk and exacerbated by concurrent malnutrition.
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http://dx.doi.org/10.3390/ijerph16040638DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6406457PMC
February 2019

Pilot study of myocardial ischemia-induced metabolomic changes in emergency department patients undergoing stress testing.

PLoS One 2019 1;14(2):e0211762. Epub 2019 Feb 1.

Center for Applied Genomics & Precision Medicine, Duke University, Durham, North Carolina, United States of America.

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 <1 hour before stress testing and 2 hours after stress testing on each patient. We assayed 60 select acylcarnitines and amino acids by tandem mass spectrometry (MS/MS) using a Quattro Micro instrument (Waters Corporation, Milford, MA). Metabolite values were log transformed for skew. We then performed bivariable analysis for stress test outcome and both individual timepoint metabolite concentrations and stress-delta metabolite ratios (T2/T0). False discovery rates (FDR) were calculated for 60 metabolites while controlling for age, sex, and BMI. We built multivariable regularized linear models to predict stress test outcome from metabolomics data at times 0, 2 hours, and log ratio between these two. We used leave-one-out cross-validation to estimate the performance characteristics of the model.

Results: Nine of our 20 case subjects were male. Cases' average age was 55.8, with an average BMI 29.5. Bivariable analysis identified 5 metabolites associated with positive stress tests (FDR < 0.2): alanine, C14:1-OH, C16:1, C18:2, C20:4. The multivariable regularized linear models built on T0 and T2 had Area Under the ROC Curve (AUC-ROC) between 0.5 and 0.55, however, the log(T2/T0) model yielded 0.625 AUC, with 65% sensitivity and 60% specificity. The top metabolites selected by the model were: Ala, Arg, C12-OH/C10-DC, C14:1-OH, C16:1, C18:2, C18:1, C20:4 and C18:1-DC.

Conclusions: Stress-delta metabolite analysis of patients undergoing stress testing is feasible. Future studies with a larger sample size are warranted.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211762PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358091PMC
November 2019

An observer blinded, randomized, placebo-controlled, phase I dose escalation trial to evaluate the safety and immunogenicity of an inactivated West Nile virus Vaccine, HydroVax-001, in healthy adults.

Vaccine 2019 07 18;37(30):4222-4230. Epub 2019 Jan 18.

Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA.

Background: West Nile virus (WNV) is the most common mosquito-borne infection in the United States. HydroVax-001 WNV is a hydrogen peroxide inactivated, whole virion (WNV-Kunjin strain) vaccine adjuvanted with aluminum hydroxide.

Methods: We performed a phase 1, randomized, placebo-controlled, double-blind (within dosing group), dose escalation clinical trial of the HydroVax-001 WNV vaccine administered via intramuscular injection. This trial evaluated 1 mcg and 4 mcg dosages of HydroVax-001 WNV vaccine given intramuscularly on day 1 and day 29 in healthy adults. The two dosing groups of HydroVax-001 were enrolled sequentially and each group consisted of 20 individuals who received HydroVax-001 and 5 who received placebo. Safety was assessed at all study days (days 1, 2, 4 and 15 post dose 1, and days 1, 2, 4, 15, 29, 57, 180 and 365 post dose 2), and reactogenicity was assessed for 14 days after administration of each dose. Immunogenicity was measured by WNV-specific plaque reduction neutralization tests (PRNT) in the presence or absence of added complement or by WNV-specific enzyme-linked immunosorbent assays (ELISA).

Results: HydroVax-001 was safe and well-tolerated as there were no serious adverse events or concerning safety signals. At the 1 mcg dose, HydroVax-001 was not immunogenic by PRNT but elicited up to 41% seroconversion by WNV-specific ELISA in the per-protocol population (PP) after the second dose. At the 4 mcg dose, HydroVax-001 elicited neutralizing antibody responses in 31% of the PP following the second dose. In the presence of added complement, PRNT seroconversion rates increased to 50%, and 75% seroconversion was observed by WNV-specific ELISA.

Conclusions: The HydroVax-001 WNV vaccine was found to be modestly immunogenic and well-tolerated at all dose levels.
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http://dx.doi.org/10.1016/j.vaccine.2018.12.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6640644PMC
July 2019

A miRNA Host Response Signature Accurately Discriminates Acute Respiratory Infection Etiologies.

Front Microbiol 2018 11;9:2957. Epub 2018 Dec 11.

Center for Applied Genomics and Precision Medicine, Duke University School of Medicine, Durham, NC, United States.

Acute respiratory infections (ARIs) are the leading indication for antibacterial prescriptions despite a viral etiology in the majority of cases. The lack of available diagnostics to discriminate viral and bacterial etiologies contributes to this discordance. Recent efforts have focused on the host response as a source for novel diagnostic targets although none have explored the ability of host-derived microRNAs (miRNA) to discriminate between these etiologies. In this study, we compared host-derived miRNAs and mRNAs from human H3N2 influenza challenge subjects to those from patients with pneumonia. Sparse logistic regression models were used to generate miRNA signatures diagnostic of ARI etiologies. Generalized linear modeling of mRNAs to identify differentially expressed (DE) genes allowed analysis of potential miRNA:mRNA relationships. High likelihood miRNA:mRNA interactions were examined using binding target prediction and negative correlation to further explore potential changes in pathway regulation in response to infection. The resultant miRNA signatures were highly accurate in discriminating ARI etiologies. Mean accuracy was 100% [88.8-100; 95% Confidence Interval (CI)] in discriminating the healthy state from pneumonia and 91.3% (72.0-98.9; 95% CI) in discriminating pneumonia from influenza infection. Subsequent differential mRNA gene expression analysis revealed alterations in regulatory networks consistent with known biology including immune cell activation and host response to viral infection. Negative correlation network analysis of miRNA:mRNA interactions revealed connections to pathways with known immunobiology such as interferon regulation and MAP kinase signaling. We have developed novel human host-response miRNA signatures for bacterial and viral ARI etiologies. miRNA host response signatures reveal accurate discrimination between pneumonia and influenza etiologies for ARI and integrated analyses of the host-pathogen interface are consistent with expected biology. These results highlight the differential miRNA host response to bacterial and viral etiologies of ARI, offering new opportunities to distinguish these entities.
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http://dx.doi.org/10.3389/fmicb.2018.02957DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6298190PMC
December 2018

Respiratory Viral Infection: An Underappreciated Cause of Acute Febrile Illness Admissions in Southern Sri Lanka.

Am J Trop Med Hyg 2019 03;100(3):672-680

Duke-Ruhuna Collaborative Research Centre, Galle, Sri Lanka.

The contribution of respiratory viruses to acute febrile illness (AFI) burden is poorly characterized. We describe the prevalence, seasonality, and clinical features of respiratory viral infection among AFI admissions in Sri Lanka. We enrolled AFI patients ≥ 1 year of age admitted to a tertiary care hospital in southern Sri Lanka, June 2012-October 2014. We collected epidemiologic/clinical data and a nasal or nasopharyngeal sample that was tested using polymerase chain reaction (Luminex NxTAG, Austin, TX). We determined associations between weather data and respiratory viral activity using the Spearman correlation and assessed respiratory virus seasonality using a Program for Appropriate Technology definition. Bivariable and multivariable regression analyses were conducted to identify features associated with respiratory virus detection. Among 964 patients, median age was 26.2 years (interquartile range 14.6-39.9) and 646 (67.0%) were male. One-fifth (203, 21.1%) had respiratory virus detected: 13.9% influenza, 1.4% human enterovirus/rhinovirus, 1.4% parainfluenza virus, 1.1% respiratory syncytial virus, and 1.1% human metapneumovirus. Patients with respiratory virus identified were younger (median 9.8 versus 27.7 years, < 0.001) and more likely to have respiratory signs and symptoms. Influenza A and respiratory viral activity peaked in February-June each year. Maximum daily temperature was associated with influenza and respiratory viral activity ( = 0.03 each). Patients with respiratory virus were as likely as others to be prescribed antibiotics (55.2% versus 52.6%, = 0.51), and none reported prior influenza vaccination. Respiratory viral infection was a common cause of AFI. Improved access to vaccines and respiratory diagnostics may help reduce disease burden and inappropriate antibiotic use.
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http://dx.doi.org/10.4269/ajtmh.18-0699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6402941PMC
March 2019

Point-prevalence study of antimicrobial use in public hospitals in southern Sri Lanka identifies opportunities for improving prescribing practices.

Infect Control Hosp Epidemiol 2019 02 7;40(2):224-227. Epub 2018 Dec 7.

1Duke Global Health Institute,Durham, North Carolina.

A point-prevalence study of antimicrobial use among inpatients at 5 public hospitals in Sri Lanka revealed that 54.6% were receiving antimicrobials: 43.1% in medical wards, 68.0% in surgical wards, and 97.6% in intensive care wards. Amoxicillin-clavulanate was most commonly used for major indications. Among patients receiving antimicrobials, 31.0% received potentially inappropriate therapy.
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http://dx.doi.org/10.1017/ice.2018.321DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353688PMC
February 2019

Evaluating the discriminating capacity of cell death (apoptotic) biomarkers in sepsis.

J Intensive Care 2018 13;6:72. Epub 2018 Nov 13.

1Biological Defense Research Directorate, Naval Medical Research Center, 503 Robert Grant Avenue, Silver Spring, MD 20910 USA.

Background: Sepsis biomarker panels that provide diagnostic and prognostic discrimination in sepsis patients would be transformative to patient care. We assessed the mortality prediction and diagnostic discriminatory accuracy of two biomarkers reflective of cell death (apoptosis), circulating cell-free DNA (cfDNA), and nucleosomes.

Methods: The cfDNA and nucleosome levels were assayed in plasma samples acquired in patients admitted from four emergency departments with suspected sepsis. Subjects with non-infectious systemic inflammatory response syndrome (SIRS) served as controls. Samples were acquired at enrollment (T0) and 24 h later (T24). We assessed diagnostic (differentiating SIRS from sepsis) and prognostic (28-day mortality) predictive power. Models incorporating procalcitonin (diagnostic prediction) and APACHE II scores (mortality prediction) were generated.

Results: Two hundred three subjects were included (107 provided procalcitonin measurements). Four subjects exhibited uncomplicated sepsis, 127 severe sepsis, 35 septic shock, and 24 had non-infectious SIRS. There were 190-survivors and 13 non-survivors. Mortality prediction models using cfDNA, nucleosomes, or APACHEII yielded AUC values of 0.61, 0.75, and 0.81, respectively. A model combining nucleosomes with the APACHE II score improved the AUC to 0.84. Diagnostic models distinguishing sepsis from SIRS using procalcitonin, cfDNA(T0), or nucleosomes(T0) yielded AUC values of 0.64, 0.65, and 0.63, respectively. The three parameter model yielded an AUC of 0.74.

Conclusions: To our knowledge, this is the first head-to-head comparison of cfDNA and nucleosomes in diagnosing sepsis and predicting sepsis-related mortality. Both cfDNA and nucleosome concentrations demonstrated a modest ability to distinguish sepsis survivors and non-survivors and provided additive diagnostic predictive accuracy in differentiating sepsis from non-infectious SIRS when integrated into a diagnostic prediction model including PCT and APACHE II. A sepsis biomarker strategy incorporating measures of the apoptotic pathway may serve as an important component of a sepsis diagnostic and mortality prediction tool.
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http://dx.doi.org/10.1186/s40560-018-0341-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6234551PMC
November 2018

A prospective study of transmission of Multidrug-Resistant Organisms (MDROs) between environmental sites and hospitalized patients-the TransFER study.

Infect Control Hosp Epidemiol 2019 01 14;40(1):47-52. Epub 2018 Nov 14.

1Duke University Health System,Durham,North Carolina.

Objective: Hospital environmental surfaces are frequently contaminated by microorganisms. However, the causal mechanism of bacterial contamination of the environment as a source of transmission is still debated. This prospective study was performed to characterize the nature of multidrug-resistant organism (MDRO) transmission between the environment and patients using standard microbiological and molecular techniques.

Setting: Prospective cohort study at 2 academic medical centers.

Design: A prospective multicenter study to characterize the nature of bacterial transfer events between patients and environmental surfaces in rooms that previously housed patients with 1 of 4 'marker' MDROs: methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, Clostridium difficile, and MDR Acinetobacter baumannii. Environmental and patient microbiological samples were obtained on admission into a freshly disinfected inpatient room. Repeat samples from room surfaces and patients were taken on days 3 and 7 and each week the patient stayed in the same room. The bacterial identity, antibiotic susceptibility, and molecular sequences were compared between organisms found in the environment samples and patient sources.

Results: We enrolled 80 patient-room admissions; 9 of these patients (11.3%) were asymptomatically colonized with MDROs at study entry. Hospital room surfaces were contaminated with MDROs despite terminal disinfection in 44 cases (55%). Microbiological Bacterial Transfer events either to the patient, the environment, or both occurred in 12 patient encounters (18.5%) from the microbiologically evaluable cohort.

Conclusions: Microbiological Bacterial Transfer events between patients and the environment were observed in 18.5% of patient encounters and occurred early in the admission. This study suggests that research on prevention methods beyond the standard practice of room disinfection at the end of a patient's stay is needed to better prevent acquisition of MDROs through the environment.
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http://dx.doi.org/10.1017/ice.2018.275DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6690181PMC
January 2019