bluuebunny/crossref_metadata_2025_split huggingface dataset:
2593. Human Monoclonal Antibodies Potently Neutralize Enterovirus D68 in both a Clade-Specific and -Independent Manner
Authors: Vogt Matthew R , Kose Nurgun , Williamson Lauren , Bochkov Yury A , Gern James E , Crowe James E 
Published: October 2019

Abstract

Background
Enterovirus D68 (EV-D68) causes worldwide outbreaks of human respiratory illness with spacio-temporally related outbreaks of acute flaccid myelitis (AFM), a polio-like illness. Numerous seroepidemiology studies show that nearly all humans older than 2 years have EV-D68-neutralizing antibodies in their serum, even in serum collected prior to large outbreaks. However, little else is known about the human antibody response to this virus. We sought to isolate human monoclonal antibodies (mAbs) from B cells in peripheral blood mononuclear cells (PBMCs) of immune subjects, induced by natural infection, to understand human humoral immunity to EV-D68.

Methods
We obtained PBMCs from donors with known infection during the largest ever recorded outbreak, which occurred in the United States in 2014. We used EV-D68 virus isolates from this outbreak in an indirect ELISA to screen immortalized PBMCs for antigen-specificity, then fused them with myeloma cells to create hybridomas.

Results
To date, we have isolated > 60 naturally occurring anti-EV-D68 human mAbs from the B cells of subjects with documented infection. These mAbs exhibit diverse binding affinities when compared across different clades of recent EV-D68 isolates. Many mAbs neutralize EV-D68 quite potently in vitro, with [ng/mL] half maximal effective concentrations. Some mAbs neutralize diverse clades of EV-D68, whereas others are highly clade-specific. Binding of antibodies to at least three, but likely more, major antigenic sites on the virus leads to neutralization.

Conclusion
We observed a qualitative difference among antibodies isolated from patients who had natural infection. These differences could contribute to certain individuals being susceptible to respiratory disease and AFM. Our studies of humoral immunity are especially important for a disease with nearly universal apparent seroprotection, in which the virus somehow persistently causes outbreaks across the world. Furthermore, no licensed vaccines or treatments exist for EV-D68. Given the ability of human intravenous immune globulin to protect mice from AFM, these mAbs are being tested for therapeutic benefit in vivo, and may have promise in the prevention and/or treatment of EV-D68-related diseases.

Disclosures
All authors: No reported disclosures.
2595. Murine Models for the Host Response to Typical and Atypical Pneumonia
Authors: Khan Kirin , Betancourt-Quiroz Marisol , Zaas Aimee K , Treece Amy E , Que Loretta G , Henao Ricardo , Suchindran Sunil , McClain Micah T , Woods Chris W , Ginsburg Geoffrey S , Tsalik Ephraim L , Tsalik Ephraim L 
Published: October 2019

Abstract

Background
The etiology of pneumonia is difficult to diagnose, with typical bacterial, atypical bacterial, and viral infections being the most common. However, diagnostics that discriminate these infectious etiologies are limited. We, therefore, focused on the host response to identify possible diagnostic markers and better understand these infections. However, atypical bacterial pneumonia is challenging to identify in humans precisely because of this diagnostic difficulty. Therefore, we utilized murine models to define host response differences between typical bacterial, atypical bacterial, and viral pneumonia.

Methods
Mice were intranasally inoculated with S. pneumoniae (n = 38), M. pneumoniae (n = 27), H1N1 pr8 (n = 19), or saline as a control (n = 42). RNA was extracted from peripheral blood collected at 24, 48, 72, 120, or 168 hours and subjected to microarray analysis. Diagnostic signatures were generated using lasso logistic regression and accuracy was assessed using nested leave-one-out cross-validation with feature selection repeated within each iteration. Differentially expressed genes were used to perform gene set enrichment analysis. These murine-derived signatures were externally validated in silico in 487 human subjects found across 5 publicly available data sets.

Results
We generated pathogen-specific murine disease signatures that performed with 91–100% accuracy. Pathway analysis revealed that animals with pneumococcal pneumonia had a robust immune response by 48 hours that continued to 72 hours post-infection. In contrast, animals infected with M. pneumoniae did not show evidence of a strong immune response until 72-hours post-infection. Additionally, the immune response to M. pneumoniae bared greater similarity to the viral response than it did to the host pneumococcal response. H1N1-infected mice showed an anti-viral response at 120 hours that resolved by 168 hours post-infection. The AUC values resulting from independent human validation of our murine signatures ranged from 89 to 98%.

Conclusion
There are discrete host responses to typical bacterial, atypical bacterial, and viral etiologies of pneumonia in mice. These signatures validate well in humans, highlighting the conserved nature of the host response to these pathogen classes.

Disclosures
Ephraim L. Tsalik, MD MHS PhD, Immunexpress: Consultant; Predigen, Inc.: Officer or Board Member, Research Grant.
2598. Macrophage Migration Inhibitory Factor May Contribute to Disseminated Coccidioidomycosis Susceptibility
Authors: Odio Camila D , Leng Lin , Siu Edwin , Piecychna Marta , Galgiani John N , Holland Steven M , Bucala Richard 
Published: October 2019

Abstract

Background
Disseminated coccidioidomycosis occurs in <1% of cases, and genetic polymorphisms may account for some of the variability in infection severity. Macrophage migration inhibitory factor (MIF) is an inflammatory cytokine with two promoter polymorphisms linked to variability in expression. High expression MIF polymorphisms have been associated with granulomatosis with polyangitis (GPA), sarcoidosis and tuberculosis. Despite the overlap between MIF and Coccidioides immunity, MIF has never been studied in coccidioidomycosis.

Methods
A549 cells transfected with MIF promoter/luciferase plasmids of 0 or 8 CATT repeats were stimulated with 50 µg/mL of inactivated C. posadasii spherule lysate, and luciferase expression was measured as relative units (RU) of luminescence. Genomic DNA from patients with disseminated coccidioidomycosis (n = 37) and healthy controls (n = 371) was analyzed for the 794 CATT5-8 microsatellite and the -173 G/C SNP. Cohorts were divided into self-identified African Americans and Caucasians, and allele frequencies were compared using Fisher exact test. Plasma MIF levels were analyzed by enzyme-linked immunosorbant assay using specific antibodies, and levels were compared by T-test.

Results
Human lung epithelial cells exposed to Coccidioides spherules had significantly higher MIF expression than unexposed cells (3.94 ± 0.44 vs. 3.02 ± 0.24 RU, P = 0.0162). Among Caucasians (n = 26), the high MIF expression −173C containing genotype was present in 50% of the coccidioidomycosis patients vs. 40% of healthy controls (P = 0.396). The -794 CATT7 containing genotype was present in 40% of patients vs. 27% of controls (p = 0.240). Plasma MIF levels were higher in coccidoidomycosis patients with high- vs. low-expression alleles (P = 0.008), but lower in patients vs. controls (P < 0.0001).

Conclusion
Coccoidioides spherules stimulated MIF expression in human lung epithelial cells supporting the hypothesis that MIF is involved in immunity against this pathogen. In Caucasian subjects, the higher MIF expression genotypes were more common in patients with disseminated coccidioidomycosis when compared with healthy controls, although significance was limited by sample size. This is consistent with high expression MIF alleles associated with other granulomatous diseases, and may reflect destruction of the granuloma with pathogen dissemination.

Disclosures
All authors: No reported disclosures.
153. A Review of Ten Cases of Pulmonic Valve Infective Endocarditis
Authors: Hicklin Harry E , Huang Glen , Davis Kyle A , Barnes Erin W , Peacock James E 
Published: October 2019

Abstract

Background
Pulmonic valve (PV) infective endocarditis (IE) is a rare entity, accounting for ~1.5–2% of all cases of IE. As a result, published literature describing the diagnosis and management of patients with PVIE is limited.

Methods
A retrospective review of patients ≥18 years old admitted to Wake Forest Baptist Medical Center from 2012 to 2017 with a diagnosis of PVIE based on the modified Duke criteria was performed.

Results
Ten patients were identified as having PVIE, 9 of whom had isolated PV involvement and 1 of whom had concurrent aortic valve involvement. The diagnosis of IE was definite per the modified Duke criteria in 8 patients. The median age was 41 years and 30% were female. Two patients had pacemakers, 1 had a prosthetic PV, and 1 had congenital heart disease. Six patients were identified as persons who inject drugs (PWID). On admission, 5 patients manifested fever and 5 had a documented murmur. Seven patients had septic pulmonary emboli with 4 of 7 patients manifesting pulmonary hypertension. Transthoracic echocardiography (TTE) revealed vegetations in 4 of 10 patients whereas PV vegetations were demonstrated in all 8 patients undergoing transesophageal echocardiography (TEE). S. aureus was the most common causative organism, accounting for 5 of the cases of PVIE with four of the five isolates being methicillin-resistant. Bacteremia persisted for a median of 3 days. One patient underwent PV replacement. The planned median duration of antimicrobial therapy was 6 weeks. The median length of stay was 18 days. Three patients died during the index hospitalization, 1 of whom was a PWID. No episodes of repeat PVIE occurred within 1 year.

Conclusion
PVIE is a rare disease. Only 40% of our patients had vegetations on TTE in contrast to a reported diagnostic yield of >90% in the literature. As such, PVIE may be underdiagnosed. S aureus was the most common organism isolated, which is in keeping with prior reports. PWID appear to be at high risk for PVIE. In view of the worsening opioid epidemic, more research on PVIE is warranted.

Disclosures
All authors: No reported disclosures.
2603. Biofilm Formation as a Predictive Marker of Prognosis for Escherichia coli Sepsis
Authors: Zhang Kermit , Schneider Daniella , Biswas Rakesh , de la Espriella Mariana Gomez , Rao Jayasimha , Baffoe-Bonnie Anthony 
Published: October 2019

Abstract

Background
Escherichia coli is the Gram-negative organism most commonly associated with bloodstream infections and death due to sepsis. Timely administration of appropriate antibiotic(s) plays a significant role in improving patient outcomes. E. coli expresses virulence factors (VFs) such as biofilm formation and motility phenotypes which play a role in bacterial attachment and dissemination by enabling immune system evasion and host migration. The role of these VFs in bacteremia prognosis is not well characterized. Our study aims to evaluate the clinical characteristics and outcomes of E. coli bacteremia patients specifically in relation to biofilm forming isolates.

Methods
91 E. coli bacteremia clinical isolates were consecutively collected from patients between 2013 to 2015. Virulence factor phenotypes were determined by in vitro biofilm formation, motility, and milk hydrolysis. Clinical patient data associated with the isolates were abstracted from the electronic medical records database and blinded from research team throughout characterization. Descriptive statistics were used for clinical variables and analyzed in a dichotomized fashion based on biofilm formation. The chi-square or Fisher exact test were used for categorical data and the Mann–Whitney U or Student T-test for continuous variables as appropriate.

Results
Of the 91 isolates, 41 had a biofilm-forming phenotype. Of the 87 isolates tested for milk hydrolysis and motility a positive finding was seen in 61 (70%) and 67(77%) isolates, respectively. In the multivariate model, patients with E.coli bacteremia from biofilm producing isolates were at increased risk of death or going into hospice during that hospitalization. ([OR],9.8; 95% CI, 1.1,88.7, P = 0.041)

Conclusion
Patients with biofilm-forming E. coli bacteremia had worse clinical outcomes than their non-biofilm forming counterparts suggesting that this phenotype leads to a more pathogenic organism. A prospective study to confirm this finding is needed as is the design of rapid diagnostics to promptly identify this phenotype in septic patients.

Disclosures
All authors: No reported disclosures.
2605. Mixed Subpopulation of Hemolytic and Non-Hemolytic Phenotype in Clinical Staphylococcus aureus Blood Isolates
Authors: Bae Seongman , Cho Eunbeen , Yang Eunmi , Seo Hyeonji , Kim Eun Sil , Sung Heungsup , Kim Mi-Na , Jung Jiwon , Jae Kim Min , Kim Sung-Han , Lee Sang-Oh , Choi Sang-Ho , Woo Jun Hee , Kim Yang Soo , Chong Yong Pil 
Published: October 2019

Abstract

Background
Agr is a key regulator that controls expression of secreted exoproteins and surface protein in Staphylococcus aureus. It has been reported that mixed status of two different phenotypes including agr functional and nonfunctional subpopulations can coexist in vitro and in vivo. However, data on the natural course and clinical implication of the mixed agr status is limited. We thus investigated the frequency and characteristics of the mixed agr in clinical settings.

Methods
We evaluated isogenic paired MRSA isolates collected from patients with persistent S. aureus bacteremia (SAB) between October 2010 and April 2016, and then prospectively performed surveillance for the presence of mixed agr function in MRSA isolates from patients with SAB between May 2016 and December 2017. The mixed agr status was evaluated by single colony evaluation on sheep blood agar plate containing RN4220 supernatant (β-hemolysin) (Figure 1). Cross-streaking with RN4220 and RNAIII measurement were performed to confirm the agr functionality of each of hemolytic and non-hemolytic colonies, separately. The expression levels of RNAIII, hla, and saeS/saeR were measured by real-time reverse transcription polymerase chain reaction.

Results
A total of 161 first blood isolates were collected during study period, and 6 isolates (4%) displayed mixed phenotype by single colony test. The mixed hemolytic pattern was observed in 5 out of 52 ST72 isolates (10%) and 1 out of 82 ST5 isolates (1%) (Figure 1). No difference was found in the genotypes between hemolytic and non-hemolytic colonies from each isolate. Of the 6 isolates, three lost mixed hemolytic features in the follow-up blood cultures (Table 1). One ST72 and one ST5 isolate showed agr mixed pattern determined by different RNAIII levels, but remaining four ST72 isolates had mixed hemolytic pattern due to different expression of hla correlated with saeS/saeR expression (Figure 2).

Conclusion
The mixture of agr function status among the clinical blood isolates of MRSA was rarely observed and isolates displaying heterogeneous hemolytic phenotype were largely due to differential expression of α-hemolysin. Further investigation is needed to unveil the clinical significance of mixture of different hemolytic phenotypes.

Disclosures
All authors: No reported disclosures.
2609. Escherichia coli Clonal Lineages and Virulence Factors Predict Fecal Colonization within Households
Authors: Fox Teresa C , Thuras Paul , Clabots Connie , Porter Stephen , Johnson James R 
Published: October 2019

Abstract

Background
Extraintestinal Escherichia coli infections are an ever-growing threat, to which specific clonal lineages and virulence factors contribute disproportionately. Despite the gut being the main reservoir for such E. coli strains, relationships between clonal lineages, virulence factors, and fecal colonization patterns are poorly understood. Accordingly, we defined E. coli fecal colonization patterns within households (HHs) and assessed specific lineages and virulence genes (VGs) as predictors of colonization behaviors.

Methods
Veterans with an E. coli clinical isolate (n = 22: 11 fluoroquinoline [FQ]-resistant, 11 FQ-susceptible) and their HH members provided stool samples on 2–6 occasions each. Stools were screened for total and FQ-resistant E. coli. Distinct E. coli strains were resolved by genomic profiling of 10 colonies/sample. Strains underwent molecular lineage identification, VG detection, and comparison with the veteran’s clinical isolate. Clonal lineages and VGs were assessed (Wilcoxon rank-sum test) as predictors of strains’ (i) predominance within the fecal sample, (ii) persistence across serial fecal samples, (iii) within-HH strain sharing, and (iv) overall within-HH colonization prevalence.

Results
From the 22 veterans and 46 HH members (27 humans, 19 pets) we recovered 139 unique-by-household fecal E. coli strains. Sixty-four traits were evaluated (16 clonal lineages, 48 VGs). Of these, 44 exhibited n ≥ 5, so could be analyzed statistically. Among these 44 traits, the proportion significantly associated with ≥ 1 outcome variable was 5/6 (83%) for clonal lineages and 18/38 (47%) for VGs. Additionally, fecal strains that matched the veteran’s clinical isolate exhibited significantly greater sharing, persistence, and overall colonization.

Conclusion
The studied E. coli traits – known for their associations with clinical infections –here were significantly associated with within-HH colonization behavior. These findings support that “virulence factors” may be regarded also (or perhaps best) as “colonization factors,” and “virulent lineages” as “colonizing lineages.” This suggests the possibility that future interventions that disrupt colonization behavior also could prevent E. coli infections.

Disclosures
All authors: No reported disclosures.
2612. Molecular Evidence of Ureaplasma urealyticum and Ureaplasma parvum Colonization in Preterm Infants with Respiratory Distress
Authors: Kumar Surinder , Kashyap Priyanka , Kumar N B , Kashyap Bineeta , Garg Indu Bala , Saigal Sanjeev R 
Published: October 2019

Abstract

Background
Ureaplasma urealyticum and Ureaplasma parvum have been associated with respiratory diseases in premature newborns, but their role in the pathogenesis of the respiratory distress syndrome (RDS) is unclear. The present study was conducted to investigate preterm newborns with respiratory distress for colonization of U. urealyticum and U. parvum in endotracheal fluid (TF)/nasopharyngeal aspirates (NPA) specimens employing culture and polymerase chain reaction (PCR).

Methods
Sixty preterm infants, presenting with respiratory distress persisting for more than 24 hours were investigated. Endotracheal fluid or nasopharyngeal aspirates specimens were inoculated in 2mL Ureaplasma broth and Ureaplasma agar for culture identification assay and PCR. DNA extracts were processed for a genus specific PCR (429 base pair region) on urease gene of U. urealyticum/U. parvum and species specific PCR (1305 base pair region) on 16S rRNA gene in U. parvum.

Results
Ureaplasma species colonization was positive in 11 (61.11%) male patients and7 (38.89%) females but there was no statistical association between sex and Ureaplasmaspecies colonization (P = 0.771). Ureaplasma spp. culture identification assay was positive in 7 (11.67%).Ureaplasma genus specific PCR was positive in 14 (23.33%) cases; species specific PCR in 9 (64.28%) infants were identified as U. parvum. Considering culture as diagnostic standard, sensitivity of PCR was 42.86%; specificity 79.24%; positive predictive value 21.43% and negative predictive value 91.30 %; with overall percentage agreement at 75%. Septicemia was positive in 12 (66.67%) infants colonized with Ureaplasmaspecies than in 5 (11.9%) of non colonized infants which was found to be significant (P = 0.00). Twelve (66.67%) patients with Ureaplasmaspecies colonization had lethargy with statistically significant association(P = 0.04).

Conclusion
This study confirms that Ureaplasma species and particularly U. parvum colonization in preterm infants was related to respiratory distress.

Disclosures
All authors: No reported disclosures.
2613. The Epidemiology of Respiratory Syncytial Virus (RSV) in People with Immune Dysfunction Seen at a Tertiary Hospital Between 2010 and 2017
Authors: Li Qiuju , Reekie Joanne , Helleberg Marie , Sengeløv Henrik , Sørensen Søren Schwartz , Jacobsen Søren , Daugaard Gedske , Mocroft Amanda , Lundgren Jens 
Published: October 2019

Abstract

Background
Persons with a compromised immune system are at increased risk of complications related to respiratory syncytial virus (RSV) but the risks are not well defined. We aimed to investigate the prevalence of RSV infection, associated risk factors and complications in a large population of people with immune dysfunction.

Methods
Persons with immune dysfunction, first seen at Copenhagen University Hospital, Rigshospitalet, between January 1, 2010 and February 21, 2017, aged ≥18 were included. RSV testing and positivity (positive PCR or antigen test) was determined through the Danish Microbiology Database. Generalized estimating equations logistic regression was used to investigate the risk factors for RSV positivity; Cox regression was used to assess the impact of RSV positivity (time-updated) on mortality in the first 12 months after first visit.

Results
The study included 42,567 persons, of which 3,356 (7.9%, 95% CI 7.6%-8.1%) were tested for RSV at least once during follow-up, with 2,374 (71%) tested in the first 12 months. Stem cell transplant (HSCT) and solid-organ transplant (SOT) recipients had the highest proportion of persons tested for RSV (66.0%, 95% CI 62.9%–69.1% and 31.6%, 95% CI 29.0%–34.2%, respectively). Of those tested, 256 (7.6%, 95% CI 6.7%–8.5%) had ≥1 positive RSV test (figure). After adjustment, HSCT and SOT recipients, as well as other hematologic and rheumatologic patient groups were more likely to have a positive RSV test compared with persons seen in the infectious disease department. Fifty-seven RSV-related complications were identified in 53/256 (20.7%, 95% CI 15.7%-25.7%) persons positive for RSV (table), of which 24 (45.3%) were HSCT recipients and 18 (34.0%) were other hematologic patients. In the 12 months after first department visit, 9,451 (22%) patients died; persons with RSV had an increased risk of short-term mortality (aHR 1.77, 95% CI 1.19–2.64), adjusting for sex, age, patient group and flu positivity.

Conclusion
Patients with a hematological or rheumatological condition and SOT recipients had the highest odds of contracting RSV, with hematological patients in particular at an excess risk of RSV-related complications. RSV was associated with an increased risk of death in the first 12 months of patient follow-up.

Disclosures
All authors: No reported disclosures.