Dataset Information

Airway gene-expression classifiers for respiratory syncytial virus (RSV) disease severity in infants.

ABSTRACT:

Background

A substantial number of infants infected with RSV develop severe symptoms requiring hospitalization. We currently lack accurate biomarkers that are associated with severe illness.

Method

We defined airway gene expression profiles based on RNA sequencing from nasal brush samples from 106 full-tem previously healthy RSV infected subjects during acute infection (day 1-10 of illness) and convalescence stage (day 28 of illness). All subjects were assigned a clinical illness severity score (GRSS). Using AIC-based model selection, we built a sparse linear correlate of GRSS based on 41 genes (NGSS1). We also built an alternate model based upon 13 genes associated with severe infection acutely but displaying stable expression over time (NGSS2).

Results

NGSS1 is strongly correlated with the disease severity, demonstrating a naïve correlation (?) of ??=?0.935 and cross-validated correlation of 0.813. As a binary classifier (mild versus severe), NGSS1 correctly classifies disease severity in 89.6% of the subjects following cross-validation. NGSS2 has slightly less, but comparable, accuracy with a cross-validated correlation of 0.741 and classification accuracy of 84.0%.

Conclusion

Airway gene expression patterns, obtained following a minimally-invasive procedure, have potential utility for development of clinically useful biomarkers that correlate with disease severity in primary RSV infection.

SUBMITTER: Wang L

PROVIDER: S-EPMC7908785 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Publications

Airway gene-expression classifiers for respiratory syncytial virus (RSV) disease severity in infants.

Wang Lu L Chu Chin-Yi CY McCall Matthew N MN Slaunwhite Christopher C Holden-Wiltse Jeanne J Corbett Anthony A Falsey Ann R AR Topham David J DJ Caserta Mary T MT Mariani Thomas J TJ Walsh Edward E EE Qiu Xing X

BMC medical genomics 20210225 1

<h4>Background</h4>A substantial number of infants infected with RSV develop severe symptoms requiring hospitalization. We currently lack accurate biomarkers that are associated with severe illness.<h4>Method</h4>We defined airway gene expression profiles based on RNA sequencing from nasal brush samples from 106 full-tem previously healthy RSV infected subjects during acute infection (day 1-10 of illness) and convalescence stage (day 28 of illness). All subjects were assigned a clinical illness ...[more]

PMID: 33632195

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Project description:PurposePRESORS ClinRO completed by clinicians and ObsRO completed by caregivers were developed to characterize the clinical course of respiratory syncytial virus (RSV) infection. This study describes preliminary analysis of PRESORS' measurement properties using clinical trial data.Patients and methodsPRESORS ClinRO and ObsRO data were collected in a 28-day randomized, double-blind, Phase 1b trial of JNJ-53718678 or placebo in infants and children ≤24 months of age treated for RSV infection in hospitals. PRESORS data were scored and key psychometric properties of scores were evaluated, including ability to discriminate between known groups and to detect change over time. Time to resolution of RSV signs was explored using two responder definitions.ResultsDaily completion rates for PRESORS ClinRO and ObsRO were high for the 44 children in the study (median: 100% and 93%, respectively). Large floor effects were observed at baseline for signs of severe RSV infection that were either absent (cyanosis, fever, apnea) or rarely reported (reduced urination/dehydration, vomiting). Implausible ObsRO ratings suggested some caregivers could not accurately measure heart rate. Known-group validity was confirmed: children in poor health based on baseline ClinRO had mean baseline composite scores that were significantly worse for both ObsRO (p=0.001) and ClinRO (p<0.001) compared to those with better overall health. ObsRO (p=0.009) and ClinRO (p<0.001) composite scores were responsive to change in overall health status from baseline to Day 3. Mean scores for RSV sign dimensions decreased rapidly from baseline to Day 7 except for coughing and sleep ratings by caregivers. Time to recovery varied greatly depending on definitions used.ConclusionPRESORS ClinRO and ObsRO can inform endpoints and enable monitoring the clinical course of RSV in pediatric trials. Improved alignment between ClinRO and ObsRO and revisions ensuring caregivers can assess all signs will be addressed in revised PRESORS.

Project description:BackgroundRespiratory syncytial virus (RSV) is the leading cause of viral lower respiratory tract infection (LRTI) and hospitalization in infants. Mostly because of the incomplete understanding of the disease pathogenesis, there is no licensed vaccine, and treatment remains symptomatic. We analyzed whole blood transcriptional profiles to characterize the global host immune response to acute RSV LRTI in infants, to characterize its specificity compared with influenza and human rhinovirus (HRV) LRTI, and to identify biomarkers that can objectively assess RSV disease severity.Methods and findingsThis was a prospective observational study over six respiratory seasons including a cohort of infants hospitalized with RSV (n?=?135), HRV (n?=?30), and influenza (n?=?16) LRTI, and healthy age- and sex-matched controls (n?=?39). A specific RSV transcriptional profile was identified in whole blood (training cohort, n?=?45 infants; Dallas, Texas, US) and validated in three different cohorts (test cohort, n?=?46, Dallas, Texas, US; validation cohort A, n?=?16, Turku, Finland; validation cohort B, n?=?28, Columbus, Ohio, US) with high sensitivity (94% [95% CI 87%-98%]) and specificity (98% [95% CI 88%-99%]). It classified infants with RSV LRTI versus HRV or influenza LRTI with 95% accuracy. The immune dysregulation induced by RSV (overexpression of neutrophil, inflammation, and interferon genes, and suppression of T and B cell genes) persisted beyond the acute disease, and immune dysregulation was greatly impaired in younger infants (<6 mo). We identified a genomic score that significantly correlated with outcomes of care including a clinical disease severity score and, more importantly, length of hospitalization and duration of supplemental O2.ConclusionsBlood RNA profiles of infants with RSV LRTI allow specific diagnosis, better understanding of disease pathogenesis, and assessment of disease severity. This study opens new avenues for biomarker discovery and identification of potential therapeutic or preventive targets, and demonstrates that large microarray datasets can be translated into a biologically meaningful context and applied to the clinical setting. Please see later in the article for the Editors' Summary.

Dataset Information

Airway gene-expression classifiers for respiratory syncytial virus (RSV) disease severity in infants.

Background

Method

Results

Conclusion

Publications

Airway gene-expression classifiers for respiratory syncytial virus (RSV) disease severity in infants.

Similar Datasets

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