AUTHOR=Fiore-Gartland Andrew , Panoskaltsis-Mortari Angela , Agan Anna A. , Mistry Anushay J. , Thomas Paul G. , Matthay Michael A. , PALISI PICFlu Investigators , Hertz Tomer , Randolph Adrienne G. , Sanders Ronald C. , Hefley Glenda , Tellez David , Bliss Courtney , Labell Aimee , Liss Danielle , Ortiz Ashley L. , Typpo Katri , Deschenes Jen , Markovitz Barry , Terry Jeff , Morzov Rica Sharon P. , Graciano Ana Lia , Baldwin Melita , Anas Nick , Schwarz Adam , Onwunyi Chisom , Osborne Stephanie , Patterson Tiffany , Vargas-Shiraishi Ofelia , Sapru Anil , Convery Maureen , Lo Victoria , Flori Heidi , Brumfield Becky , Simon Julie , Czaja Angela , Mourani Peter , Aymami Valeri Batara , Burr Susanna , Brocato Megan , Huston Stephanie , Jewett Emily , Loyola Danielle , Carroll Christopher , Sala Kathleen , Thornton-Thompson Sherell , Giuliano John S. , Tala Joana , McLaughlin Gwenn , Paden Matthew , Manghram Chee-Chee , Meisner Stephanie , Stone Cheryl L. , Wardenburg Juliane Bubeck , DeDent Andrea , Montgomery Vicki , Sullivan Janice , Evans Tracy , Richardson Kara , Thomas Melissa , Randolph Adrienne , Agan Anna A. , Mistry Anushay J. , Sullivan Ryan M. , Cobb Stephanie , Bembea Melania , White Elizabeth D. , Kurachek Stephen , Doucette Angela A. , Olson Erin , Hartman Mary , Jacobs Rachel , Truemper Edward , Dawson Machelle , Levin Daniel L. , Jarvis J. Dean , Katyal Chhavi , Ackerman Kate , Daugherty L. Eugene , Baglia Laurel , Hall Mark W. , Greathouse Kristin , Steele Lisa , Thomas Neal , Raymond Jill , Spear Debra , Fitzgerald Julie , Helfaer Mark , Weiss Scott , Bush Jenny L. , Diliberto Mary Ann , Park Brooke B. , Sisko Martha , Barr Frederick E. , Higgerson Renee , Christie LeeAnn , Darnell Cindy , Johnson Shanda , Loftis Laura L. , Jaimon Nancy , Kyle Ursula , Gedeit Rainer , Horn Briana E. , Luther Kate , Murkowski Kathy , Willson Douglas F. , Kelly Robin L. , Jouvet Philippe A. , Fontaine Anne-Marie , Dugas Marc-André TITLE=Cytokine Profiles of Severe Influenza Virus-Related Complications in Children JOURNAL=Frontiers in Immunology VOLUME=8 YEAR=2017 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2017.01423 DOI=10.3389/fimmu.2017.01423 ISSN=1664-3224 ABSTRACT=Rationale

Effective immunomodulatory therapies for children with life-threatening “cytokine storm” triggered by acute influenza infection are lacking. Understanding the immune profiles of children progressing to severe lung injury and/or septic shock could provide insight into pathogenesis.

Objectives

To compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications.

Methods

Children with influenza-related critical illness were enrolled across 32 hospitals in development (N = 171) and validation (N = 73) cohorts (December 2008 through May 2016). Concentrations of 42 cytokines were measured in serum and endotracheal samples and clustered into modules of covarying cytokines. Relative concentrations of cytokines and cytokine modules were tested for associations with acute lung injury (ALI), shock requiring vasopressors, and death/ECMO.

Measurements and main results

Modules of covarying cytokines were more significantly associated with disease severity than individual cytokines. In the development cohort, increased levels of a serum module containing IL6, IL8, IL10, IP10, GCSF, MCP1, and MIP1α [shock odds ratio (OR) = 3.37, family-wise error rate (FWER) p < 10−4], and decreased levels of a module containing EGF, FGF2, SCD40L, and PAI-1 (shock OR = 0.43, FWER p = 0.002), were both associated with ALI, shock, and death-ECMO independent of age and bacterial coinfection. Both of these associations were confirmed in the validation cohort. Endotracheal and serum cytokine associations differed markedly and were differentially associated with clinical outcomes.

Conclusion

We identified strong positive and negative associations of cytokine modules with the most severe influenza-related complications in children, providing new insights into the pathogenesis of influenza-related critical illness in children. Effective therapies may need to target mediators of both inflammation and repair.