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Study Unearths Blood Expression Signatures for Infants Infected with Respiratory Virus

NEW YORK (GenomeWeb News) – The molecular signatures associated with a child's immune response to respiratory syncytial virus may provide hints to the severity of lower respiratory tract infections the virus causes, according to a new study in PLOS Medicine.

Starting with blood samples from hundreds of infants infected with RSV, human rhinovirus, or influenza over half a dozen cold and flu seasons, the Ohio State University College of Medicine's Octavio Ramilo and colleagues from the US and Finland used array-based gene expression profiling to track down a transcriptional signature coinciding with RSV infection.

The team validated that signature in three more groups of American or Finnish infants with lower respiratory infections, before narrowing in on expression patterns that proved useful for distinguishing the most serious RSV cases — in particular, those that involved extensive hospital stays or supplemental oxygen treatments.

In addition to providing a potential avenue for future RSV diagnostic and/or prognostic tests, study authors noted that the transcripts involved in the RSV infection and severity signatures are expected to help in understanding the immune system peculiarities associated with RSV infection.

"[T]his study provides evidence of the profound systemic dysregulation of both the innate and adaptive immune response induced by RSV infection in children," Ramilo and his co-authors wrote, "and confirms the value of gene expression profiling as a practical and powerful strategy to objectively stratify children with acute RSV [lower respiratory tract infections]."

Although lower respiratory tract infections involving RSV can become quite severe in infants and children, the researchers noted, there is currently no accurate way of predicting which cases will lead to hospitalization and other forms of advanced care.

"[T]here is a clear need to understand the immune response to RSV and how it relates to disease pathogenesis, progression, and severity," they wrote.

To that end, the team turned to a set of blood samples prospectively collected from 156 infants with RSV infections, 16 infants with influenza, and 30 infants with human rhinovirus at hospitals in the US and Finland.

After dividing samples from the 135 cases with acute RSV infection into four different cohorts, they used Illumina arrays to assess expression patterns in the 45 samples from RSV-infected infants in one of the cohorts, designated the training cohort.

Compared to samples from 14 unaffected controls, the RSV-positive samples in the training group showed differential expression for more than 2,300 transcripts, the study's authors reported.

Researchers verified that transcript signature using samples from dozens more RSV cases and controls before taking a crack at using it to classify individuals in another validation group comprised of 16 infants with RSV infections and four without. There, they found that expression profiles at the 2,317 transcripts could correctly identify all but one of the samples from children with RSV infection.

In a final validation cohort that included 28 RSV-infected infants and eight uninfected infants, the team saw that the same transcript signature, used in conjunction with a different expression array, could correctly classify 27 of the infected infants.

The signature also distinguished between samples from infants with RSV and those with other types of respiratory tract infections — including those caused by the influenza virus or human rhinovirus — with around 94 percent sensitivity and 98 percent specificity.

When they looked at the nature of the genes behind the expression signature, the investigators saw that inflammation and innate immune genes were among those showing a jump in expression in those with RSV infections, while levels of genes contributing to adaptive immune functions often waned.

And based on the extent of the expression shift for 1,536 transcripts in the RSV-related signature, the group reported, it was possible to begin making predictions about which cases would progress to the point of requiring lengthy hospital stays and/or treatments such as supplemental oxygen.

In particular, results of the study suggest that infants with especially low expression of genes coding for adaptive immune contributors and high expression of inflammation-related transcripts tended to have more severe RSV infections, while those with milder infections showed an extra boost in innate immune gene expression.

Although the transcript signatures unearthed in the analysis "were derived only from infants requiring hospitalization, which represents the tips of the iceberg of the disease spectrum caused by RSV," study authors noted, "it serves as a reference, and warrants future research including studies with earlier, sequential samples as well as samples from infants with milder RSV infection who are managed as outpatients."

In a perspectives article appearing alongside the study in PLOS Medicine, the Imperial College, London's Peter Openshaw opined on the work as well as the broader impact of potential expression-based tests for assessing RSV and other respiratory viral infections affecting children.

"With multiplex testing for combinations of disease subtypes (or "endophenotypes") becoming ever more feasible as a near-patient diagnostic aid," Openshaw wrote, such studies "may give rise to new and informative tests that help to define the pathogenesis of disease on an individual basis and thus dictate clinical management."