AUTHOR=Novak Tanya , Crawford Jeremy Chase , Hahn Georg , Hall Mark W. , Thair Simone A. , Newhams Margaret M. , Chou Janet , Mourani Peter M. , Tarquinio Keiko M. , Markovitz Barry , Loftis Laura L. , Weiss Scott L. , Higgerson Renee , Schwarz Adam J. , Pinto Neethi P. , Thomas Neal J. , Gedeit Rainer G. , Sanders Ronald C. , Mahapatra Sidharth , Coates Bria M. , Cvijanovich Natalie Z. , Ackerman Kate G. , Tellez David W. , McQuillen Patrick , Kurachek Stephen C. , Shein Steven L. , Lange Christoph , Thomas Paul G. , Randolph Adrienne G. TITLE=Transcriptomic profiles of multiple organ dysfunction syndrome phenotypes in pediatric critical influenza JOURNAL=Frontiers in Immunology VOLUME=14 YEAR=2023 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.1220028 DOI=10.3389/fimmu.2023.1220028 ISSN=1664-3224 ABSTRACT=Background

Influenza virus is responsible for a large global burden of disease, especially in children. Multiple Organ Dysfunction Syndrome (MODS) is a life-threatening and fatal complication of severe influenza infection.

Methods

We measured RNA expression of 469 biologically plausible candidate genes in children admitted to North American pediatric intensive care units with severe influenza virus infection with and without MODS. Whole blood samples from 191 influenza-infected children (median age 6.4 years, IQR: 2.2, 11) were collected a median of 27 hours following admission; for 45 children a second blood sample was collected approximately seven days later. Extracted RNA was hybridized to NanoString mRNA probes, counts normalized, and analyzed using linear models controlling for age and bacterial co-infections (FDR q<0.05).

Results

Comparing pediatric samples collected near admission, children with Prolonged MODS for ≥7 days (n=38; 9 deaths) had significant upregulation of nine mRNA transcripts associated with neutrophil degranulation (RETN, TCN1, OLFM4, MMP8, LCN2, BPI, LTF, S100A12, GUSB) compared to those who recovered more rapidly from MODS (n=27). These neutrophil transcripts present in early samples predicted Prolonged MODS or death when compared to patients who recovered, however in paired longitudinal samples, they were not differentially expressed over time. Instead, five genes involved in protein metabolism and/or adaptive immunity signaling pathways (RPL3, MRPL3, HLA-DMB, EEF1G, CD8A) were associated with MODS recovery within a week.

Conclusion

Thus, early increased expression of neutrophil degranulation genes indicated worse clinical outcomes in children with influenza infection, consistent with reports in adult cohorts with influenza, sepsis, and acute respiratory distress syndrome.