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1. Association of a Network of Immunologic Response and Clinical Features With the Functional Recovery From Crotalinae Snakebite Envenoming

Author

Charles J. Gerardo, Elizabeth Silvius, Seth Schobel, John C. Eppensteiner, Lauren M. McGowan, Eric A. Elster, Allan D. Kirk, and Alexander T. Limkakeng

Subjects
snake bite, antivenin, cytokine, prognostic model, predictive modeling, chemokine, Immunologic diseases. Allergy, RC581-607
Abstract

BackgroundThe immunologic pathways activated during snakebite envenoming (SBE) are poorly described, and their association with recovery is unclear. The immunologic response in SBE could inform a prognostic model to predict recovery. The purpose of this study was to develop pre- and post-antivenom prognostic models comprised of clinical features and immunologic cytokine data that are associated with recovery from SBE. Materials and MethodsWe performed a prospective cohort study in an academic medical center emergency department. We enrolled consecutive patients with Crotalinae SBE and obtained serum samples based on previously described criteria for the Surgical Critical Care Initiative (SC2i)(ClinicalTrials.gov Identifier: NCT02182180). We assessed a standard set of clinical variables and measured 35 unique cytokines using Luminex Cytokine 35-Plex Human Panel pre- and post-antivenom administration. The Patient-Specific Functional Scale (PSFS), a well-validated patient-reported outcome of functional recovery, was assessed at 0, 7, 14, 21 and 28 days and the area under the patient curve (PSFS AUPC) determined. We performed Bayesian Belief Network (BBN) modeling to represent relationships with a diagram composed of nodes and arcs. Each node represents a cytokine or clinical feature and each arc represents a joint-probability distribution (JPD).ResultsTwenty-eight SBE patients were enrolled. Preliminary results from 24 patients with clinical data, 9 patients with pre-antivenom and 11 patients with post-antivenom cytokine data are presented. The group was mostly female (82%) with a mean age of 38.1 (SD ± 9.8) years. In the pre-antivenom model, the variables most closely associated with the PSFS AUPC are predominantly clinical features. In the post-antivenom model, cytokines are more fully incorporated into the model. The variables most closely associated with the PSFS AUPC are age, antihistamines, white blood cell count (WBC), HGF, CCL5 and VEGF. The most influential variables are age, antihistamines and EGF. Both the pre- and post-antivenom models perform well with AUCs of 0.87 and 0.90 respectively.DiscussionPre- and post-antivenom networks of cytokines and clinical features were associated with functional recovery measured by the PSFS AUPC over 28 days. With additional data, we can identify prognostic models using immunologic and clinical variables to predict recovery from SBE.

Published
2021
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2. Immune response profiling in patients with traumatic injuries associated with alcohol ingestion

Author

Mary-Beth Joshi, Lauren M McGowan, Bartley Adams, Adam W. Breslin, Elizabeth Silvius, Eric A. Elster, Bria E Johnston, Chandra A. Almond, Alexander T. Limkakeng, Allan D. Kirk, and Catherine A. Staton

Subjects
Adult, Male, medicine.medical_specialty, Future studies, Inflammatory stress, Alcohol Drinking, Alcohol, RM1-950, General Biochemistry, Genetics and Molecular Biology, Article, law.invention, chemistry.chemical_compound, Immune system, law, Internal medicine, Medicine, Humans, In patient, Prospective Studies, General Pharmacology, Toxicology and Pharmaceutics, ALCOHOL INGESTION, Ethanol, business.industry, Interleukin-6, General Neuroscience, Research, Bayes Theorem, General Medicine, Articles, Length of Stay, Middle Aged, Intensive care unit, Interleukin-12, Interleukin-10, chemistry, Wounds and Injuries, Blood alcohol content, Female, Therapeutics. Pharmacology, Public aspects of medicine, RA1-1270, business, Signal Transduction
Abstract

Traumatic injuries afflict more than 5 million people globally every year. Current and past animal research has demonstrated association among alcohol, trauma, and impaired immune function, whereas human registries have shown association between alcohol and morbidity as well as mortality. The purpose of this study is to elucidate the immune interactions with alcohol in traumatically injured patients. We prospectively enrolled 379 patients after trauma at three medical centers in the Surgical Critical Care Initiative. Plasma was analyzed using Luminex for up to 35 different cytokines. Collected samples were grouped by patients with detectable plasma alcohol levels versus those without. Univariate testing determined differences in analytes between groups. We built Bayesian belief networks with multiple minimum descriptive lengths to compare the two groups. All 379 patient samples were analyzed. Two hundred eighty‐two (74.4%) patients were men, and 143 (37.7%) were White. Patients had a median intensive care unit length of stay (LOS) of 5.8 days and hospital LOS of 12 days. Using single variate analyses, eight different cytokines were differentially associated with alcohol. Cytokines IL‐12 and IL‐6 were important nodes in both models and IL‐10 was a prominent node in the nonalcohol model. This study found select immune function differed between traumatically injured patients with measurable serum alcohol levels as compared with those without. Traumatically injured patients with positive blood alcohol content appear less able to inhibit inflammatory stress. Alcohol appears to suppress pro‐inflammatory IL‐12 and IL‐6, whereas patients without alcohol have greater levels of anti‐inflammatory IL‐10 expressed at injury and may better regulate anti‐inflammatory pathways. Future studies should determine the relationship with these markers with clinically oriented outcomes.

Published
2021

3. Efficacy and safety of two neutralising monoclonal antibody therapies, sotrovimab and BRII-196 plus BRII-198, for adults hospitalised with COVID-19 (TICO):a randomised controlled trial

Author

Wesley H. Self, Uriel Sandkovsky, Cavan S. Reilly, David M. Vock, Robert L. Gottlieb, Michael Mack, Kevin Golden, Emma Dishner, Andrew Vekstein, Emily R. Ko, Tatyana Der, John Franzone, Eyad Almasri, Mohamed Fayed, Michael R. Filbin, Kathryn A. Hibbert, Todd W. Rice, Jonathan D. Casey, J. Awori Hayanga, Vinay Badhwar, Bradley G. Leshnower, Milad Sharifpour, Kirk U. Knowlton, Ithan D. Peltan, Elizieta Bakowska, Justyna Kowalska, Michael E. Bowdish, Jeffrey M. Sturek, Angela J. Rogers, D. Clark Files, Jarrod M. Mosier, Michelle N. Gong, David J. Douin, R. Duncan Hite, Barbara W. Trautner, Mamta K. Jain, Edward M. Gardner, Akram Khan, Jens-Ulrik Jensen, Michael A. Matthay, Adit A. Ginde, Samuel M. Brown, Elizabeth S. Higgs, Sarah Pett, Amy C. Weintrob, Christina C. Chang, Daniel D. Murrary, Huldrych F. Günthard, Ellen Moquete, Greg Grandits, Nicole Engen, Birgit Grund, Shweta Sharma, Huyen Cao, Rajesh Gupta, Suzette Osei, David Margolis, Qing Zhu, Mark N. Polizzotto, Abdel G. Babiker, Victoria J. Davey, Virginia Kan, B. Taylor Thompson, Annetine C. Gelijns, James D. Neaton, H. Clifford Lane, Jens D. Jundgren, John Tierney, Kevin Barrett, Betsey R. Herpin, Mary C. Smolskis, Susan E. Voge, Laura A. McNay, Kelly Cahill, Page Crew, Matthew Kirchoff, Ratna Sardana, Sharon Segal Raim, Joseph Chiu, Lisa Hensley, Josua Lorenzo, Rebecca Mock, Katy Shaw-Saliba, Judith Zuckerman, Stacey J. Adam, Judy Currier, Sarah Read, Eric Hughes, Laura Amos, Amy Carlsen, Anita Carter, Bionca Davis, Eileen Denning, Alain DuChene, Merrie Harrison, Payton Kaiser, Joseph Koopmeiners, Sue Meger, Thomas Murray, Kien Quan, Siu Fun Quan, Greg Thompson, Jamie Walski, Deborah Wentworth, Alan J. Moskowitz, Emilia Bagiella, Karen O'Sullivan, Mary E. Marks, Evan Accardi, Emily Kinzel, Gabriela Bedoya, Lopa Gupta, Jessica R. Overbey, Maria L. Padillia, Milerva Santos, Marc A. Gillinov, Marissa A. Miller, Wendy C. Taddei-Peters, Kathleen Fenton, Mezgebe Berhe, Clinton Haley, Christopher Bettacchi, Erin Duhaime, Madison Ryan, Sarah Burris, Felecia Jones, Samantha Villa, Samantha Want, Raven Robert, Tanquinisha Coleman, Laura Clariday, Rebecca Baker, Marian Hurutado-Rodriguez, Nazia Iram, Michelle Fresnedo, Allyson Davis, Kiara Leonard, Noelia Ramierez, Jon Thammavong, Krizia Duque, Emma Turner, Tammy Fisher, Dianna Robinson, Desirae Ransom, Erica Lusk, Aaron Killian, Adriana Palacious, Edilia Solis, Janet Jerrow, Matthew Watts, Heather Whitacre, Elizabeth Cothran, Peter K. Smith, Christina E. Barkauskas, Grace R. Dreyer, Marie Witte, Nilima Mosaly, Ahmad Mourad, Thomas L. Holland, Kathleen Lane, Andrew Bouffler, Lauren M. McGowan, Marry Motta, Gregory Tipton, Ben Stallings, Gennifer Stout, Beth McLendon-Arvik, Beth A. Hollister, Dana M. Giangiacomo, Sunil Sharma, Brian Pappers, Paul McCarthy, Troy Krupica, Arif Sarwari, Rebecca Reece, Lisa Fornaresio, Chad Glaze, Raquel Evans, Katarina Preamble, Lisa Giblin Sutton, Sabrina Buterbaugh, Elizabeth Berry Bartolo, Roger Williams, Robin Bunner, William Bender, Jeffrey Miller, Kim T. Baio, Mary K. McBride, Michele Fielding, Sonya Mathewson, Kristina Porte, Missy Maton, Chari Ponder, Elizabeth Haley, Christine Spainhour, Susan Rogers, Derrick Tyler, Noah Wald-Dickler, Douglass Hutcheon, Amytis Towfighi, May M. Lee, Meghan R. Lewis, Brad Spellberg, Linda Sher, Aniket Sharma, Anna P. Olds, Chris Justino, Edward Lozano, Chris Romero, Janet Leong, Valentina Rodina, Tammie Possemato, Jose Escobar, Charlene Chiu, Kevin Weissman, Andrew Barros, Kyle B. Enfield, Alexandra Kadl, China J. Green, Rachel M. Simon, Ashley Fox, Kara Thornton, Patrick E. Parrino, Stephen Spindel, Aditya Bansal, Katherine Baumgarten, Jonathan Hand, Derek Vonderhaar, Bobby Nossaman, Sylvia Laudun, DeAnna Ames, Shane Broussard, Nilmo Hernandez, Geralyn Isaac, Huan Dinh, Yiling Zheng, Sonny Tran, Hunter McDaniel, Nicolle Crovetto, Leslie Miller, Beth Schelle, Sherry McLean, Howard R. Rothbaum, Michael S. Alvarez, Shivam P. Kalan, Heather H. Germann, Jennifer Hendershot, Karen Maroney, Karen Herring, Sharri Cook, Pam Paul, Ronson J. Madathil, Joseph Rabin, Andrea Levine, Kapil Saharia, Ali Tabatabai, Christine Lau, James S. Gammie, Maya-Loren Peguero, Kimberley McKernan, Matthew Audette, Emily Fleischmann, Freshta Akbari, Maia Lee, Myounghee Lee, Andrew Chi, Hanna Salehi, Alan Pariser, Phuong Tran Nguyen, Jessica Moore, Adrienne Gee, Shelika Vincent, Richard A. Zuckerman, Alexander Iribarne, Sara Metzler, Samantha Shipman, Taylor Caccia, Haley Johnson, Crystallee Newton, Doug Parr, Vicente Rodriguez, Gordon Bokhart, Sharon M. Eichman, Crystal North, Cathryn Oldmixon, Nancy Ringwood, Laura Fitzgerald, Haley D. Morin, Ariela Muzikansky, Richard Morse, Roy G. Brower, Lora A. Reineck, Neil R. Aggarwal, Karen Bienstock, Peter Hou, Jay Steingrub, Mark A. Tidswell, Lori-Ann Kozikowski, Cynthia Kardos, Leslie DeSouza, Sherell Thornton-Thompson, Daniel Talmor, Nathan Shapiro, Valerie Banner-Goodspeed, Katherine L. Boyle, Sharon Hayes, Alan E. Jones, James Galbraith, Utsav Nandi, Rebekah K. Peacock, Blair Alden Parry, Justin D. Margolin, Kelsey Brait, Caroline Beakes, Kirsten N. Kangelaris, Kimberly J. Yee, Kimia Ashktorab, Alejandra E. Jauregui, Hanjing Zhuo, Gregory Hendey, Kinsley A. Hubel, Alyssa R. Hughes, Rebekah L. Garcia, Jennifer G. Wilson, Rosemary Vojnik, Jonasel Roque, Cynthia Perez, George W. Lim, Steven Y. Chang, Rebecca Beutler, Trisha Agarwal, Julia Vargas, Marc Moss, Amiran Baduashvili, Lakshmi Chauhan, Lani L. Finck, Michelle Howell, Robert C. Hyzy, Pauline K. Park, Kristine Nelson, Jake I. McSparron, Ivan N. Co, Bonnie R. Wang, Shijing Jia, Barbara Sullins, Sinan Hanna, Norman Olbrich, Lynne D. Richardson, Rahul Nair, Obiageli Offor, Brenda Lopez, Omowunmi Amosu, Hiwet Tzehaie, Thomas E. Terndrup, Herbert P. Wiedemann, Abhijit Duggal, Nirosshan Thiruchelvam, Kiran Ashok, Alexander H. King, Omar Mehkri, Kristin Hudock, Simra Kiran, Harshada More, Tammy Roads, Jamie Martinkovic, Sarah Kennedy, Bryce H. Robinson, Catherine L. Hough, Olivia F. Krol, Mistry Kinjal, Emmanuel Mills, Madeline McDougal, Rupali Deshmukh, Peter Chen, Sam S. Torbati, Yuri Matusov, June Choe, Niree A. Hindoyan, Susan E. Jackman, Emad Bayoumi, Timothy Wynter, Antonina Caudill, Ethan Pascual, Gregg J. Clapham, Lisa Herrera, Cristabelle Ojukwu, Shaunt Mehdikhani, D. Shane O'Mahony, Sonam T. Nyatsatsang, David M. Wilson, Julie A. Wallick, Chadwick Miller, Keven W. Gibbs, Lori S. Flores, Mary E. LaRose, Leigha D. Landreth, Peter E. Morris, Jamie L. Sturgill, Evan P. Cassity, Sanjay Dhar, Ashley A. Montgomery-Yates, Sara N. Pasha, Kirby P. Mayer, Brittany Bissel, Joseph Bledsoe, Samuel Brown, Michael Lanspa, Lindsey Leither, Brent P. Armbruster, Quinn Montgomery, Darrin Applegate, Naresh Kumar, Melissa Fergus, Erna Serezlic, Karah Imel, Ghazal Palmer, Brandon Webb, Valerie T. Aston, Jakea Johnson, Christopher Gray, Margaret Hays, Megan Roth, Adriana Sánchez, Laura Popielski, Heather Rivasplata, Melissa Turner, Michael Vjecha, Tianna Petersen, Dena Kamel, Laura Hansen, Claudia Sanchez Lucas, Natalie DellaValle, Sonia Gonzales, James Scott, David Wyles, Ivor Douglas, Jason Haukoos, Kevin Kamis, Caitlin Robinson, Jason V. Baker, Anne Frosch, Rachael Goldsmith, Hodan Jibrell, Melanie Lo, Jonathan Klaphake, Shari Mackedanz, Linh Ngo, Kelly Garcia-Myers, Norman Markowitz, Erika Pastor, Mayur Ramesh, Indira Brar, Emanuel Rivers, Princy Kumar, Maximiliano Menna, Kousick Biswas, Cristin Harrington, Alex Delp, Lavannya Pandit, Casey Hines-Munson, John Van, Laura Dillon, Yiqun Want, Paola Lichtenberger, Gio Baracco, Carol Ramos, Lauren Bjork, Melyssa Sueiro, Phyllis Tien, Heather Freasier, Theresa Buck, Hafida Nekach, Stephanie Nagy-Agren, Shikha Vasudeva, Tracy Ochalek, Brentin Roller, Chinh Nguyen, Amani Mikail, Dorthe Raben, Tomas O. Jensen, Bitten Aagaard, Charlotte B. Nielsen, Katharina Krapp, Bente Rosdahl Nykjær, Katja Lisa Kanne, Anne Louise Grevsen, Zillah Maria Joensen, Tina Bruun, Ane Bojesen, Frederik Woldbye, Nick E. Normand, Frederik V.L. Esmann, Clara Lundetoft Clausen, Nichlas Hovmand, Karen Brorup Pedersen, Louise Thorlacius-Ussing, Michaela Tinggaard, Dorthe S. Høgsberg, Ema Rastoder, Thobias Kamstrup, Christina Marisa Bergsøe, Lars Østergaard, Nina Breinholt Stærke, Isik S. Johansen, Fredrikke C. Knudtzen, Lykke Larsen, Mathias A. Hertz, Thilde Fabricius, Marie Helleberg, Jan Gerstoft, Tomas Østergaard Jensen, Birgitte Lindegaard, Thomas Ingemann Pedersen, Birgit Thorup Røge, Sandra Valborg Løfberg, Thomas Michael Hansen, Ariella Denize Nielsen, Sebastian Leicht von Huth, Henrik Nielsen, Rikke Krog Thisted, Daria Podlekareva, Stine Johnsen, Helle Frost Andreassen, Lars Pedersen, Cecilia Ebba Clara Ellinor Lindnér, Lothar Wiese, Lene Surland Knudsen, Nikolaj Julian Skrøder Nytofte, Signe Ravn Havmøller, Roger Paredes, Maria Exposito, Eduardo Fernández-Cruz, José Muñoz, Jose R. Arribas, Vicente Estrada, Juan P. Horcajada, Joaquin Burgos, Jose Luis Morales-Rull, Dominique L. Braun, Emily West, Khadija M'Rabeth-Bensalah, Mareile L. Eichinger, Manuela Grüttner-Durmaz, Christina Grube, Veronika Zink, Andrzej Horban, Agnieszka Bednarska, Natalia Jurek, Gerd Fätkenheuer, Jakob J. Malinm, Gail Matthews, Anthony Kelleher, Gesalit Cabrera, Catherine Carey, Sally Hough, Sophie Virachit, Amy Zhong, Barnaby E. Young, Po Ying Chia, Tau Hong Lee, Ray J. Lin, David Lye, Sean Ong, Ser Hon Puah, Tsin Wen Yeo, Shiau Hui Diong, Juwinda Ongko, Fleur Hudson, Mahesh KB Parmar, Anna Goodman, Jonathan Badrock, Adam Gregory, Nicola Harris, Giota Touloumi, Nikos Pantaz, Vicky Gioukari, Joseph Lutaakome, Cissy M. Kityo, Henry Mugerwa, Francis Kiweewa, Anu Osinusi, Craig Tipple, Angela Willis, Amanda Peppercorn, Helen Watson, Elizabeth Alexander, Erik Mogalian, Leo Lin, Xiao Ding, Li Yan, Jean-Luc Girardet, Ji Ma, Zhi Hong, Amy Adams, Sara Albert, Abby Balde, Michelle Baracz, Beth Baseler, Nancy Becker, Mona Bielica, Shere Billouin-Frazier, Jennifer Cash, Jay Choudhary, Suzanne Dolney, Mary Dixon, Carolyn Eyler, Leanna Frye, Michael Galcik, Jensen Gertz, Lisa Giebeig, Neelam Gulati, Liz Hankinson, Debbie Hissey, Debi Hogarty, Matt Hohn, H Preston Holley, Lisa Hoopengardner, Lynda Huber, Shirley Jankelevich, Gary Krauss, Eileen Lake, Jessica Linton, Leah MacDonald, Meryan Manandhar, Mary Spinelli-Nadzam, Charles Oluremi, Calvin Proffitt, Erin Rudzinski, Jen Sandrus, Marylu Schaffhauser, Adam Schechner, Connie Suders, Norman P. Gerry, Kenneth Smith, Courtney Solomon, Amanda Kubernac, Marium Rashid, Bhakti Patel, Robert Kubernac, Joseph Murphy, Marie L. Hoover, Craig Brown, Nadine DuChateau, Adam Flosi, Les Johnson, Amy Treagus, and Christine Wenner

Subjects
Adult, Male, Adolescent, SARS-CoV-2, Comment, COVID-19, Antibodies, Monoclonal, Articles, Middle Aged, Antibodies, Monoclonal, Humanized, Antibodies, Neutralizing, COVID-19/drug therapy, COVID-19 Drug Treatment, Hospitalization, Infectious Diseases, Antineoplastic Agents, Immunological, Treatment Outcome, Antibodies, Monoclonal, Humanized/therapeutic use, Double-Blind Method, Humans, Female, Aged
Abstract

BACKGROUND: We aimed to assess the efficacy and safety of two neutralising monoclonal antibody therapies (sotrovimab [Vir Biotechnology and GlaxoSmithKline] and BRII-196 plus BRII-198 [Brii Biosciences]) for adults admitted to hospital for COVID-19 (hereafter referred to as hospitalised) with COVID-19.METHODS: In this multinational, double-blind, randomised, placebo-controlled, clinical trial (Therapeutics for Inpatients with COVID-19 [TICO]), adults (aged ≥18 years) hospitalised with COVID-19 at 43 hospitals in the USA, Denmark, Switzerland, and Poland were recruited. Patients were eligible if they had laboratory-confirmed SARS-CoV-2 infection and COVID-19 symptoms for up to 12 days. Using a web-based application, participants were randomly assigned (2:1:2:1), stratified by trial site pharmacy, to sotrovimab 500 mg, matching placebo for sotrovimab, BRII-196 1000 mg plus BRII-198 1000 mg, or matching placebo for BRII-196 plus BRII-198, in addition to standard of care. Each study product was administered as a single dose given intravenously over 60 min. The concurrent placebo groups were pooled for analyses. The primary outcome was time to sustained clinical recovery, defined as discharge from the hospital to home and remaining at home for 14 consecutive days, up to day 90 after randomisation. Interim futility analyses were based on two seven-category ordinal outcome scales on day 5 that measured pulmonary status and extrapulmonary complications of COVID-19. The safety outcome was a composite of death, serious adverse events, incident organ failure, and serious coinfection up to day 90 after randomisation. Efficacy and safety outcomes were assessed in the modified intention-to-treat population, defined as all patients randomly assigned to treatment who started the study infusion. This study is registered with ClinicalTrials.gov, NCT04501978.FINDINGS: Between Dec 16, 2020, and March 1, 2021, 546 patients were enrolled and randomly assigned to sotrovimab (n=184), BRII-196 plus BRII-198 (n=183), or placebo (n=179), of whom 536 received part or all of their assigned study drug (sotrovimab n=182, BRII-196 plus BRII-198 n=176, or placebo n=178; median age of 60 years [IQR 50-72], 228 [43%] patients were female and 308 [57%] were male). At this point, enrolment was halted on the basis of the interim futility analysis. At day 5, neither the sotrovimab group nor the BRII-196 plus BRII-198 group had significantly higher odds of more favourable outcomes than the placebo group on either the pulmonary scale (adjusted odds ratio sotrovimab 1·07 [95% CI 0·74-1·56]; BRII-196 plus BRII-198 0·98 [95% CI 0·67-1·43]) or the pulmonary-plus complications scale (sotrovimab 1·08 [0·74-1·58]; BRII-196 plus BRII-198 1·00 [0·68-1·46]). By day 90, sustained clinical recovery was seen in 151 (85%) patients in the placebo group compared with 160 (88%) in the sotrovimab group (adjusted rate ratio 1·12 [95% CI 0·91-1·37]) and 155 (88%) in the BRII-196 plus BRII-198 group (1·08 [0·88-1·32]). The composite safety outcome up to day 90 was met by 48 (27%) patients in the placebo group, 42 (23%) in the sotrovimab group, and 45 (26%) in the BRII-196 plus BRII-198 group. 13 (7%) patients in the placebo group, 14 (8%) in the sotrovimab group, and 15 (9%) in the BRII-196 plus BRII-198 group died up to day 90.INTERPRETATION: Neither sotrovimab nor BRII-196 plus BRII-198 showed efficacy for improving clinical outcomes among adults hospitalised with COVID-19.FUNDING: US National Institutes of Health and Operation Warp Speed.

Published
2022

4. Association of a Network of Immunologic Response and Clinical Features With the Functional Recovery From Crotalinae Snakebite Envenoming

Author

John Eppensteiner, Lauren M McGowan, Alexander T. Limkakeng, Charles J. Gerardo, Eric A. Elster, Allan D. Kirk, Seth Schobel, and Elizabeth Silvius

Subjects
Male, Oncology, Time Factors, medicine.medical_treatment, Snake Bites, 0302 clinical medicine, cytokine, Immunology and Allergy, Medicine, prognostic model, Prospective Studies, 030212 general & internal medicine, Prospective cohort study, Original Research, Antivenins, antivenin, Middle Aged, Treatment Outcome, medicine.anatomical_structure, Cytokine, Predictive value of tests, Cytokines, Female, predictive modeling, Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Immunology, 03 medical and health sciences, Patient Specific Functional Scale, Predictive Value of Tests, Internal medicine, White blood cell, Crotalid Venoms, Animals, Humans, snake bite, Prognostic models, Aged, business.industry, chemokine, Models, Immunological, 030208 emergency & critical care medicine, Recovery of Function, Emergency department, Functional recovery, Prognostic model, business, lcsh:RC581-607, Crotalinae, Biomarkers
Abstract

BackgroundThe immunologic pathways activated during snakebite envenoming (SBE) are poorly described, and their association with recovery is unclear. The immunologic response in SBE could inform a prognostic model to predict recovery. The purpose of this study was to develop pre- and post-antivenom prognostic models comprised of clinical features and immunologic cytokine data that are associated with recovery from SBE. Materials and MethodsWe performed a prospective cohort study in an academic medical center emergency department. We enrolled consecutive patients with Crotalinae SBE and obtained serum samples based on previously described criteria for the Surgical Critical Care Initiative (SC2i)(ClinicalTrials.gov Identifier: NCT02182180). We assessed a standard set of clinical variables and measured 35 unique cytokines using Luminex Cytokine 35-Plex Human Panel pre- and post-antivenom administration. The Patient-Specific Functional Scale (PSFS), a well-validated patient-reported outcome of functional recovery, was assessed at 0, 7, 14, 21 and 28 days and the area under the patient curve (PSFS AUPC) determined. We performed Bayesian Belief Network (BBN) modeling to represent relationships with a diagram composed of nodes and arcs. Each node represents a cytokine or clinical feature and each arc represents a joint-probability distribution (JPD).ResultsTwenty-eight SBE patients were enrolled. Preliminary results from 24 patients with clinical data, 9 patients with pre-antivenom and 11 patients with post-antivenom cytokine data are presented. The group was mostly female (82%) with a mean age of 38.1 (SD ± 9.8) years. In the pre-antivenom model, the variables most closely associated with the PSFS AUPC are predominantly clinical features. In the post-antivenom model, cytokines are more fully incorporated into the model. The variables most closely associated with the PSFS AUPC are age, antihistamines, white blood cell count (WBC), HGF, CCL5 and VEGF. The most influential variables are age, antihistamines and EGF. Both the pre- and post-antivenom models perform well with AUCs of 0.87 and 0.90 respectively.DiscussionPre- and post-antivenom networks of cytokines and clinical features were associated with functional recovery measured by the PSFS AUPC over 28 days. With additional data, we can identify prognostic models using immunologic and clinical variables to predict recovery from SBE.

Published
2021

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