Cytokine Profiles of Severe Influenza Virus-Related Complications in Children

Andrew Fiore-Gartland; Angela Panoskaltsis-Mortari; Anna A Agan; Anushay J Mistry; Paul G Thomas; Michael A Matthay; PALISI PICFlu Investigators; Tomer Hertz; Adrienne G Randolph

doi:10.3389/fimmu.2017.01423

Cytokine Profiles of Severe Influenza Virus-Related Complications in Children

Front Immunol. 2017 Nov 6:8:1423. doi: 10.3389/fimmu.2017.01423. eCollection 2017.

Authors

Collaborators

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

Affiliations

¹ Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States.
² Department of Pediatrics, Bone Marrow Transplantation, Pulmonary and Critical Care Medicine, University of Minnesota, Minneapolis, MN, United States.
³ Department of Anesthesiology, Perioperative, and Pain Medicine, Boston Children's Hospital, Boston, MA, United States.
⁴ Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States.
⁵ Department of Medicine, University of California, San Francisco, San Francisco, CA, United States.
⁶ Department of Anesthesia, University of California, San Francisco, San Francisco, CA, United States.
⁷ The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
⁸ National Institute for Biotechnology in the Negev, Ben-Gurion University of the Negev, Be'er-Sheva, Israel.
⁹ Department of Anaesthesia, Harvard Medical School, Boston, MA, United States.
¹⁰ Department of Pediatrics, Harvard Medical School, Boston, MA, United States.

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.

Keywords: acute lung injury; cytokine; inflammation; influenza; septic shock.

Abstract

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