118. Nasopharyngeal (NP) Bacterial Detection in Infants With Respiratory Syncytial Virus (RSV) Infection: Impact on Clinical Outcomes

Abstract Background Previous studies suggest that RSV increases NP bacterial colonization and may facilitate infection. However, the role of NP colonization with potentially pathogenic bacteria (PPB) in the pathogenesis of RSV bronchiolitis is not well understood. We sought to determine the frequency, type, and density of NP PPB detection in infants with RSV infection compared with healthy controls (HC), and its association with clinical outcomes. Methods Single-center, prospective study of previously healthy infants with RSV infection and age-matched HC. Inpatients (IP) were enrolled within 24 hours of hospitalization, outpatients (OP) at the ED or primary clinics and HC at well-child visits. RSV infection and the following PPB: [S. pneumoniae, M. catarrhalis, H. influenzae, and S. aureus] were detected and quantified by PCR. We compared demographic, clinical characteristics, and outcomes of care according to NP PPB detection. Results From 2010 to 2018, we enrolled 815 infants: 664 with RSV infection [IP, 560; OP, 104] and 151 HC. RSV+ OP (6.1 [3.7–10.7] months) and HC (6.9 [3.8–10.8] months) were older than IP (2.5 [1.4–5.4] months; P < 0.001). Identification of ≥1 PPB was 89% in RSV+ infants [IP, 88%; OP, 90%] versus 63% of HC (P < 0.0001). While H. influenzae or >1 PPB detection was higher in RSV infection (P < 0.001), S. aureus detection predominated in HC (P < 0.05; Figure 1). Frequency of S. pneumoniae detection was comparable between groups; however, S. pneumoniae loads were one log higher in RSV+ infants versus HC (P = 0.001) adjusted for antibiotic use. Differences in colonization rates remained different in RSV+ infants versus HC across age ranges (<3, 3–6, >6–12, and >12–24 months; Figure 2). Last, RSV patients (both IP and OP) with S. pneumoniae or H. influenzae detection had fever more frequently (70%–74% vs. 25%–47%; P < 0.0001), higher clinical disease severity scores (P = 0.01), and higher blood neutrophil counts (34%–36% vs. 16%–19%; P < 0.001), versus those with M. catarrhalis, S. aureus detection or PCR negative. In addition, NP detection of H. influenzae in RSV children was associated with higher frequency of atelectasis/consolidation by chest X-ray (P < 0.005). Conclusion These data suggest that NP colonization with PPB is high in infants with RSV infection independent of age, and that specific bacteria, namely S. pneumoniae and H. influenzae, are associated with enhanced clinical disease severity. Disclosures A. Leber, Nationwide Children’s Hospital: Research Contractor, Research support. O. Ramilo, Janssen Scientific Affairs, LLC: Consultant, Consulting fee. A. Mejias, Janssen: Grant Investigator and Scientific Advisor, Consulting fee and Research grant. Abbvie: CME talks, Speaker honorarium.

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Nasopharyngeal Codetection of H. influenzae and S. pneumoniae and Respiratory Syncytial Virus Disease Outcomes in Children

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab481 ◽

2021 ◽

Author(s):

Alejandro Diaz-Diaz ◽

Eleonora Bunsow ◽

Cristina Garcia-Maurino ◽

Melissa Moore-Clingenpeel ◽

Jeffrey Naples ◽

...

Keyword(s):

Disease Severity ◽

Pathogenic Bacteria ◽

Virus Disease ◽

Severe Disease ◽

Quantitative Detection ◽

Healthy Controls ◽

Upper Respiratory Tract ◽

Severity Scores ◽

Rsv Infection ◽

Co Detection

Abstract Background The role of nasopharyngeal bacteria on RSV disease has been underestimated. We measured the frequency and quantitative detection of potentially pathogenic bacteria in the upper respiratory tract of infants with RSV infection over seven respiratory seasons, and their impact on clinical outcomes. Methods Children <2 years old with mild (outpatients; n=115) or severe (inpatients; n=566) RSV infection, and matched healthy controls (n=161) were prospectively enrolled. Nasopharyngeal samples were obtained for RSV, S. pneumoniae, S. aureus, M. catarrhalis, and H. influenzae detection and quantitation by PCR. Multivariable models were constructed to identify variables predictive of severe disease. Results S. pneumoniae, H. influenzae, and M. catarrhalis, but not S. aureus, were detected more frequently in RSV-infected children (84%) than healthy controls (46%; p<0.001). Detection of S. pneumoniae and/or H. influenzae was associated with fever, more frequent antibiotic treatment, worse radiologic findings, and higher neutrophil counts (p<0.01). In adjusted analyses S. pneumoniae/H. influenzae co-detection was associated with greater odds (OR; 95% CI) of hospitalization (2.25 [1.07-4.74), higher disease severity scores (1.93 [1.14-3.26]), prolonged oxygen administration (2.23 [1.01-4.91]), and longer hospitalization (2.53 [1.33-4.79]). Conclusions Nasopharyngeal co-detection of S. pneumoniae and H. influenzae in infants with RSV infection is associated with increased disease severity.

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Viral Load Dynamics and Clinical Disease Severity in Infants With Respiratory Syncytial Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiy655 ◽

2018 ◽

Vol 219 (8) ◽

pp. 1207-1215 ◽

Cited By ~ 23

Author(s):

Cristina Garcia-Mauriño ◽

Melissa Moore-Clingenpeel ◽

Jessica Thomas ◽

Sara Mertz ◽

Daniel M Cohen ◽

...

Keyword(s):

Viral Load ◽

Respiratory Syncytial Virus ◽

Virus Infection ◽

Disease Severity ◽

Respiratory Syncytial Virus Infection ◽

Clinical Disease ◽

Syncytial Virus

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Clinical impact of respiratory syncytial virus infection on children hospitalized for pertussis

10.21203/rs.3.rs-85375/v1 ◽

2020 ◽

Author(s):

Ruimu Zhang ◽

Jikui Deng

Keyword(s):

Respiratory Syncytial Virus ◽

Hospital Stay ◽

Antibiotic Use ◽

Immunofluorescence Assay ◽

Clinical Impact ◽

Chest Auscultation ◽

Lactam Antibiotic ◽

Rsv Infection ◽

Polymerase Chain ◽

Syncytial Virus

Abstract Background: Although Respiratory syncytial virus (RSV) is one of the common pathogens in children with pertussis and viral coinfection, the clinical impact of RSV infection on pertussis remains unclear. We compared clinical characteristics and sought differences between infants with single Bordetella pertussis (B. pertussis) infection and those with RSV coinfection.Methods: We enrolled 80 patients with pertussis who were hospitalized in Shenzhen Children’s Hospital from January 2017 to December 2019. Respiratory tract samples were tested for B. pertussis with real-time polymerase chain reaction and respiratory viruses with immunofluorescence assay. Clinical data were obtained from hospital records and collected using a structured questionnaire.Results: Thirty-seven of 80 patients had B. pertussis infection alone (pertussis group) and 43 had RSV-pertussis coinfection (coinfection group). No significant differences were found with regard to sex, body weight, preterm birth history, pertussis vaccination, symptoms, presence of pneumonia, or lymphocyte count between the 2 groups. Patients with RSV coinfection were older; received more β-lactam antibiotic treatment; had higher rates of wheezes and rales on chest auscultation, a higher rate of readmission, and a longer hospital stay.Conclusions: RSV coinfection increases β-lactam antibiotic use, readmission rate, and hospital stay in children hospitalized for pertussis. RSV infection should be suspected when wheezes or rales are present on auscultation of the chest in these patients. Early detection of RSV may avoid unnecessary antibiotic use.

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Temporal Dysbiosis of Infant Nasal Microbiota Relative to Respiratory Syncytial Virus Infection

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa577 ◽

2020 ◽

Author(s):

Alex Grier ◽

Ann L Gill ◽

Haeja A Kessler ◽

Anthony Corbett ◽

Sanjukta Bandyopadhyay ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Respiratory Disease ◽

Disease Severity ◽

Temporal Dynamics ◽

Disease Risk ◽

Developmental Trajectory ◽

Microbiota Composition ◽

Rsv Infection ◽

Syncytial Virus ◽

Nasal Microbiota

Abstract Rationale Respiratory Syncytial Virus (RSV) is a leading cause of infant respiratory disease. Infant airway microbiota has been associated with respiratory disease risk and severity. The extent to which interactions between RSV and microbiota occur in the airway, and their impact on respiratory disease susceptibility and severity, are unknown. Objectives Characterize temporal associations between microbiota and RSV infection before, during, and after infants’ first respiratory illness. Methods 16S rRNA microbiota profiling of two infant cohorts in the first year of life: 1) a cross-sectional cohort of 89 RSV infected infants sampled during illness and 102 matched healthy controls, and 2) a matched longitudinal cohort of 12 infants who developed RSV infection and 12 who did not, sampled before, during, and after infection. Results We identified 12 taxa significantly associated with RSV infection. All 12 taxa were differentially abundant during infection, with 8 associated with disease severity. Nasal microbiota composition was more discriminative of healthy vs. infected than of disease severity. Conclusions Our findings elucidate the chronology of nasal microbiota dysbiosis and suggest an altered developmental trajectory associated with RSV infection. Microbial temporal dynamics reveal indicators of disease risk, correlates of illness and severity, and impact of RSV infection on microbiota composition.

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Clinical Outcomes of Acute Pancreatitis in Patients with Cirrhosis According to Liver Disease Severity Scores

Digestive Diseases and Sciences ◽

10.1007/s10620-020-06575-x ◽

2020 ◽

Author(s):

C. Roberto Simons-Linares ◽

Suha Abushamma ◽

Carlos Romero-Marrero ◽

Amit Bhatt ◽

Rocio Lopez ◽

...

Keyword(s):

Acute Pancreatitis ◽

Liver Disease ◽

Clinical Outcomes ◽

Disease Severity ◽

Severity Scores ◽

Disease Severity Scores

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Olfactomedin 4 Serves as a Marker for Disease Severity in Pediatric Respiratory Syncytial Virus (RSV) Infection

PLoS ONE ◽

10.1371/journal.pone.0131927 ◽

2015 ◽

Vol 10 (7) ◽

pp. e0131927 ◽

Cited By ~ 30

Author(s):

H. K. Brand ◽

I. M. L. Ahout ◽

D. de Ridder ◽

A. van Diepen ◽

Y. Li ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Disease Severity ◽

Rsv Infection ◽

Syncytial Virus

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1409. Genomic Variation Among Respiratory Syncytial Viruses

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1591 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S712-S712

Author(s):

Christopher S Anderson ◽

Yun Zhang ◽

Anthony Corbett ◽

Chin-Yi Chu ◽

Lu Wang ◽

...

Keyword(s):

Protein Structure ◽

Disease Severity ◽

Genomic Variation ◽

Structure Variation ◽

Time Period ◽

Nasal Swabs ◽

Rsv Infection ◽

Respiratory Syncytial Viruses ◽

Syncytial Virus ◽

Over Time

Abstract Background Respiratory Syncytial Virus (RSV) can be easily classified into two subtypes (A and B) based on the nucleic acid sequence of their genome. Phylogenic approaches have shown that within both subtypes separate lineages of viruses exist and new lineages continue to emerge. The role these genomic variations play in disease severity during RSV infection is largely unknown. Methods Next-generation viral RNA sequencing was performed on archived frozen nasal swabs of children infected with RSV in Rochester, NY between 1977-1998. Genomic variation was compared across year-of-isolation, age of host, and inpatient/outpatient status of host. Local RSV genomic variation was compared to variation of publicly available sequences isolated from hosts residing in other parts of the world. Results A and B subtypes demonstrated significant differences in the genetic sequence and primary-protein structure over time. G-protein was the most variable in both subtypes, but they differed in the number of unique genotypes detected. We found a significant association with disease severity (inpatient/outpatient status) and RSV phylogenetic topology, although the magnitude of the association differed by subtype. Variation in the primary protein structure of RSV viral proteins was also significantly associated with disease severity, but depended on which viral protein, and which subtype, was investigated. Lastly, local RSV genomic and protein-structure variation was similar to what was seen globally during this time period. Conclusion Overall, both subtypes demonstrated significant genetic change over time and these changes were associated with disease severity. These results suggest that the genetic variability of RSV may affect RSV disease in humans. Disclosures All Authors: No reported disclosures

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The specific features of the developing T cell compartment of the neonatal lung are a determinant of respiratory syncytial virus immunopathogenesis

PLoS Pathogens ◽

10.1371/journal.ppat.1009529 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009529

Author(s):

Thomas Démoulins ◽

Melanie Brügger ◽

Beatrice Zumkehr ◽

Blandina I. Oliveira Esteves ◽

Kemal Mehinagic ◽

...

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

T Cell ◽

Disease Severity ◽

Early Life ◽

Cell Compartment ◽

Neonatal Lung ◽

Rsv Infection ◽

Syncytial Virus

The human respiratory syncytial virus (RSV) is a major cause of severe lower respiratory tract infections in infants, possibly due to the properties of the immature neonatal pulmonary immune system. Using the newborn lamb, a classical model of human lung development and a translational model of RSV infection, we aimed to explore the role of cell-mediated immunity in RSV disease during early life. Remarkably, in healthy conditions, the developing T cell compartment of the neonatal lung showed major differences to that seen in the mature adult lung. The most striking observation being a high baseline frequency of bronchoalveolar IL-4-producing CD4 and CD8 T cells, which declined progressively over developmental age. RSV infection exacerbated this pro-type 2 environment in the bronchoalveolar space, rather than inducing a type 2 response per se. Moreover, regulatory T cell suppressive functions occurred very early to dampen this pro-type 2 environment, rather than shutting them down afterwards, while γδ T cells dropped and failed to produce IL-17. Importantly, RSV disease severity was related to the magnitude of those unconventional bronchoalveolar T cell responses. These findings provide novel insights in the mechanisms of RSV immunopathogenesis in early life, and constitute a major step for the understanding of RSV disease severity.

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1193. Mucosal Antibody Responses to Respiratory Syncytial Virus (RSV) in Infants and Young Children

Open Forum Infectious Diseases ◽

10.1093/ofid/ofab466.1385 ◽

2021 ◽

Vol 8 (Supplement_1) ◽

pp. S688-S688

Author(s):

Cristina Tomatis Souverbielle ◽

Fang Ye ◽

Sara Mertz ◽

Mark E Peeples ◽

Octavio Ramilo ◽

...

Keyword(s):

Disease Severity ◽

Panel Member ◽

Healthy Children ◽

Upper Respiratory Tract ◽

Limited Information ◽

Research Support ◽

Review Panel ◽

Rsv Infection ◽

Syncytial Virus ◽

Research Grant

Abstract Background The burden associated with RSV infection is substantial. Although RSV initially infects the upper respiratory tract, there is limited information of the mucosal concentrations of antibodies (Abs) directed to RSV specific proteins and whether patient’s age and disease severity influence production of mucosal Abs. Methods From 2017 to2019 we enrolled previously healthy children < 2 years of age hospitalized with RSV infection and obtained acute and convalescent (day; D30) nasopharyngeal (NP) samples to measure preF and postF specific IgG and IgA Abs by ELISA. Demographic and clinical data were collected and analyzed according to Abs responses. Results We enrolled 77 children (median [IQR] age: 2.8 [1.5-5.2] months; 49 % females) within the first 24 hours of hospitalization. Of those 25 (33%) patients required PICU care. A significant increase in convalescent IgG preF Abs titers was detected in 62 (81%) children, while IgA preF titers significantly increased in all but one child on D30. The magnitude of the increase was 56-fold higher for preF IgA versus preF IgG (p< 0.0001). PostF IgG and IgA titers were also increased on D30 but at significant lower levels. Infants < 3 months of age compared with those >3-24 months had significantly higher baseline preF and postF IgG Abs titers (p < 0.001) but not IgA antibodies. D30 preF and post F IgG titers were higher in children > 6 months of age (p < 0.0001) but only preF titers fold change significantly correlated with age (r=0.4, p< 0.0001). These correlations were not identified with IgA preF antibodies. There were no statistical differences in antibody titers at baseline and on D30 according to breastfeeding, and disease severity as defined by the need for PICU care. Conclusion Children hospitalized with RSV infection demonstrated significantly increased titers of mucosal preF and post F IgG and IgA specific Abs in convalescent samples. Baseline IgG Abs where higher in younger infants, which likely reflects maternally acquired antibodies. Age significantly correlated with Abs production, suggesting a more robust immune response in older children. Disclosures Mark E. Peeples, PhD, Janssen (Research Grant or Support)Pfizer (Research Grant or Support) Octavio Ramilo, MD, Adagio (Consultant)Bill & Melinda Gates Foundation (Grant/Research Support)Janssen (Grant/Research Support)Lilly (Consultant)Merck (Consultant, Grant/Research Support)NIH (Grant/Research Support)Pfizer (Consultant)SANOFI (Board Member) Asuncion Mejias, MD, PhD, MsCS, Janssen (Grant/Research Support, Advisor or Review Panel member)Merck (Grant/Research Support, Advisor or Review Panel member)Roche (Advisor or Review Panel member)Sanofi (Advisor or Review Panel member)

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Airway gene expression correlates of RSV disease severity and microbiome composition in infants

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa576 ◽

2020 ◽

Author(s):

Chin-Yi Chu ◽

Xing Qiu ◽

Matthew N McCall ◽

Lu Wang ◽

Anthony Corbett ◽

...

Keyword(s):

Gene Expression ◽

Disease Severity ◽

Clinical Symptoms ◽

Expression Patterns ◽

Gene Expression Signature ◽

Illness Severity ◽

Severe Illness ◽

Gene Expression Patterns ◽

Rsv Infection ◽

Syncytial Virus

Abstract Rationale Respiratory syncytial virus (RSV) is the leading cause of severe respiratory disease in infants. The causes and correlates of severe illness in the majority of infants are poorly defined. Objectives We identified molecular correlates of illness severity from the airways of infants infected with RSV. Methods We recruited a cohort of RSV-infected infants and simultaneously assayed the molecular status of their airways and the presence of airway microbiota. Rigorous statistical approaches identified gene expression patterns associated with disease severity and microbiota composition, separately and in combination. Measurements and Main Results We measured comprehensive airway gene expression patterns in 106 infants with primary RSV infection. We identified an airway gene expression signature of severe illness dominated by excessive chemokine expression. We also found an association between H. influenzae, disease severity and airway lymphocyte accumulation. Exploring the time of onset of clinical symptoms revealed acute activation of interferon (IFN) signaling following RSV infection in infants with mild or moderate illness, which was absent in subjects with severe illness. Conclusion Our data reveal that airway gene expression patterns distinguish mild/moderate from severe illness severity. Furthermore, our data identify biomarkers that may be therapeutic targets or useful for measuring efficacy of intervention responses.

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