TY - JOUR AU - Fiore-Gartland, Andrew AU - Panoskaltsis-Mortari, Angela AU - Agan, Anna A. AU - Mistry, Anushay J. AU - Thomas, Paul G. AU - Matthay, Michael A. AU - , PALISI PICFlu Investigators AU - Hertz, Tomer AU - Randolph, Adrienne G. AU - Sanders, Ronald C. AU - Hefley, Glenda AU - Tellez, David AU - Bliss, Courtney AU - Labell, Aimee AU - Liss, Danielle AU - Ortiz, Ashley L. AU - Typpo, Katri AU - Deschenes, Jen AU - Markovitz, Barry AU - Terry, Jeff AU - Morzov, Rica Sharon P. AU - Graciano, Ana Lia AU - Baldwin, Melita AU - Anas, Nick AU - Schwarz, Adam AU - Onwunyi, Chisom AU - Osborne, Stephanie AU - Patterson, Tiffany AU - Vargas-Shiraishi, Ofelia AU - Sapru, Anil AU - Convery, Maureen AU - Lo, Victoria AU - Flori, Heidi AU - Brumfield, Becky AU - Simon, Julie AU - Czaja, Angela AU - Mourani, Peter AU - Aymami, Valeri Batara AU - Burr, Susanna AU - Brocato, Megan AU - Huston, Stephanie AU - Jewett, Emily AU - Loyola, Danielle AU - Carroll, Christopher AU - Sala, Kathleen AU - Thornton-Thompson, Sherell AU - Giuliano, John S. AU - Tala, Joana AU - McLaughlin, Gwenn AU - Paden, Matthew AU - Manghram, Chee-Chee AU - Meisner, Stephanie AU - Stone, Cheryl L. AU - Wardenburg, Juliane Bubeck AU - DeDent, Andrea AU - Montgomery, Vicki AU - Sullivan, Janice AU - Evans, Tracy AU - Richardson, Kara AU - Thomas, Melissa AU - Randolph, Adrienne AU - Agan, Anna A. AU - Mistry, Anushay J. AU - Sullivan, Ryan M. AU - Cobb, Stephanie AU - Bembea, Melania AU - White, Elizabeth D. AU - Kurachek, Stephen AU - Doucette, Angela A. AU - Olson, Erin AU - Hartman, Mary AU - Jacobs, Rachel AU - Truemper, Edward AU - Dawson, Machelle AU - Levin, Daniel L. AU - Jarvis, J. Dean AU - Katyal, Chhavi AU - Ackerman, Kate AU - Daugherty, L. Eugene AU - Baglia, Laurel AU - Hall, Mark W. AU - Greathouse, Kristin AU - Steele, Lisa AU - Thomas, Neal AU - Raymond, Jill AU - Spear, Debra AU - Fitzgerald, Julie AU - Helfaer, Mark AU - Weiss, Scott AU - Bush, Jenny L. AU - Diliberto, Mary Ann AU - Park, Brooke B. AU - Sisko, Martha AU - Barr, Frederick E. AU - Higgerson, Renee AU - Christie, LeeAnn AU - Darnell, Cindy AU - Johnson, Shanda AU - Loftis, Laura L. AU - Jaimon, Nancy AU - Kyle, Ursula AU - Gedeit, Rainer AU - Horn, Briana E. AU - Luther, Kate AU - Murkowski, Kathy AU - Willson, Douglas F. AU - Kelly, Robin L. AU - Jouvet, Philippe A. AU - Fontaine, Anne-Marie AU - Dugas, Marc-André PY - 2017 M3 - Original Research TI - Cytokine Profiles of Severe Influenza Virus-Related Complications in Children JO - Frontiers in Immunology UR - https://www.frontiersin.org/articles/10.3389/fimmu.2017.01423 VL - 8 SN - 1664-3224 N2 - RationaleEffective 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.ObjectivesTo compare the endotracheal and serum cytokine profiles of children with influenza-related critical illness and to identify their associations with severe influenza-associated complications.MethodsChildren 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 resultsModules 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.ConclusionWe 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. ER -