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. 2015 Jul 10;10(7):e0131927.
doi: 10.1371/journal.pone.0131927. eCollection 2015.

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

H K Brand  1 , I M L Ahout  1 , D de Ridder  2 , A van Diepen  1 , Y Li  3 , M Zaalberg  4 , A Andeweg  5 , N Roeleveld  6 , R de Groot  1 , A Warris  1 , P W M Hermans  1 , G Ferwerda  1 , F J T Staal  7
Affiliations

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

H K Brand et al. PLoS One. .

Abstract

Background: Respiratory viral infections follow an unpredictable clinical course in young children ranging from a common cold to respiratory failure. The transition from mild to severe disease occurs rapidly and is difficult to predict. The pathophysiology underlying disease severity has remained elusive. There is an urgent need to better understand the immune response in this disease to come up with biomarkers that may aid clinical decision making.

Methods: In a prospective study, flow cytometric and genome-wide gene expression analyses were performed on blood samples of 26 children with a diagnosis of severe, moderate or mild Respiratory Syncytial Virus (RSV) infection. Differentially expressed genes were validated using Q-PCR in a second cohort of 80 children during three consecutive winter seasons. FACS analyses were also performed in the second cohort and on recovery samples of severe cases in the first cohort.

Results: Severe RSV infection was associated with a transient but marked decrease in CD4+ T, CD8+ T, and NK cells in peripheral blood. Gene expression analyses in both cohorts identified Olfactomedin4 (OLFM4) as a fully discriminative marker between children with mild and severe RSV infection, giving a PAM cross-validation error of 0%. Patients with an OLFM4 gene expression level above -7.5 were 6 times more likely to develop severe disease, after correction for age at hospitalization and gestational age.

Conclusion: By combining genome-wide expression profiling of blood cell subsets with clinically well-annotated samples, OLFM4 was identified as a biomarker for severity of pediatric RSV infection.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Fig 1
Fig 1. Venn diagram with differentially expressed genes between groups.
Differentially expressed genes (q <0.05; >2 fold difference; absolute expression value >200) in patients with RSV infections comparing patients with mild vs severe disease and during acute infection vs recovery in patients with moderate and severe disease.
Fig 2
Fig 2. OLFM4 gene expression values of patients from the micro-array and validation cohort.
OLFM4 gene expression levels were significantly higher in patients with severe disease compared to those with mild and moderate disease in the micro-array cohort (Panel A) and an independent validation cohort (Panel B). Expression levels are presented as ΔCt and median with inter quartile range (IQR). Statistics were performed by Kruskall Wallis tests, followed by Mann Whitney U tests for individual comparisons.
Fig 3
Fig 3. Plasma levels of OLFM4 in patients with viral RTI.
OLFM4 plasma levels are statistically significantly higher during acute (n = 41) infections compared to recovery samples (n = 25) (Panel A). However, there are no statistically significant differences among the three severity groups (Panel B). Plasma levels (ng/ml) are presented as median with inter quartile range (IQR). Statistics were performed by Mann Whitney U tests for comparison acute vs recovery (p<0.05), and Kruskall Wallis tests for comparison mild vs moderate vs severe (p = 0.29).
See this image and copyright information in PMC

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