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

Abstract

Background: The 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 methods: We 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).

Results: Twenty-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.

Discussion: Pre- 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.

Keywords: Patient Specific Functional Scale; antivenin; chemokine; cytokine; predictive modeling; prognostic model; snake bite.

Conflict of interest statement

ES was employed by DecisionQ. CG receives grant funding from BTG Specialty Pharmaceuticals. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2021 Gerardo, Silvius, Schobel, Eppensteiner, McGowan, Elster, Kirk and Limkakeng.

Figures

Figure 1

The range of the Patient-Specific Functional Scale Area Under the Patient Curves at 28 days for 24 patients with available preliminary data. (examples lowest, median, highest). PSFS AUPC, Patient-Specific Functional Scale Area Under the Patient Curve.

Figure 2

Individual cytokine and chemokine values pre- and post-antivenom treatment. EGF: endothelial growth factor, EOTAXIN: eosinophil chemotactic proteins, *FGFBASIC: fibroblastic growth factor, basic, GCSF: granulocyte colony stimulating factor, GMCSF: ganulocyte-macrophage colony stimulating factor, *HGF: hepatocyte growth factor, IFNA: interferon alpha, IFNG: interferon gamma, IL01interleukin 1a, IL01b: interleukin 1b, IL01Ra: Interleukin 1 receptor antagonist, IL02: interleukin 2,* IL02R: interleukin 2 receptor, IL03: interleukin 3, IL04: interleukin 4, IL05: interleukin 5, IL06: interleukin 6, IL08: interleukin 8, IL09: interleukin 9, IL10: interleukin 10, IL12: interleukin 12, IL13: interleukin 13, IL15: interleukin 15, IL17A: interleukin 17A, IL17F: interleukin 17F, IL22: interleukin 22, CXCL10: C-X-C motif ligand 10, CCL2: C-C motif ligand 2, CXCL9: C-X-C motif ligand 9, CCL3: C-C motif ligand 3, CCL4: C-C motif ligand 4, *CCL5: C-C motif ligand 5, VEGF: vascular endothelial growth factor. *Difference in populations based on box plots.

Figure 3

Pre-antivenom cytokines and chemokines values of patients with good and poor recovery. EGF: endothelial growth factor, *EOTAXIN: eosinophil chemotactic proteins, *HGF: hepatocyte growth factor, IFNA: interferon alpha, IL01a: interleukin 1a, IL01Ra: Interleukin 1 receptor antagonist, IL08: interleukin 8, *IL10: interleukin 10, *IL12: interleukin 12, IL13: interleukin 13, *CXCL10: C-X-C motif ligand 10, *CCL2: C-C motif ligand 2, *CCL4: C-C motif ligand 4, *CCL5: C-C motif ligand 5, *VEGF: vascular endothelial growth factor. *Difference in populations based on box plots.

Figure 4

Post-antivenom cytokine and chemokine values of patients with good and poor recovery. *EGF: endothelial growth factor, EOTAXIN: eosinophil chemotactic proteins, *HGF: hepatocyte growth factor, IFNA: interferon alpha, *IL01RA: Interleukin 1 receptor antagonist, IL10: interleukin 10, *IL12: interleukin 12, IL13: interleukin 13, *CXCL10: C-X-C motif ligand 10, *CCL2: C-C motif ligand 2, *CCL4: C-C motif ligand 4, CCL5: C-C motif ligand 5, VEGF: vascular endothelial growth factor. *Difference in populations based on box plots.

Figure 5

Pre-antivenom prognostic model predictive of recovery. PSFS AUPC: Patient-Specific Functional Scale Area Under the Patient Curve, CCL4: C-C motif ligand 4, GI: gastro-intestinal, CO2: carbon dioxide, Resp Rate: respiratory rate.

Figure 6

Post-antivenom prognostic model predictive of recovery. PSFS AUPC: Patient-Specific Functional Scale Area Under the Patient Curve, CCL4: C-C motif ligand 4, CCL5: C-C motif ligand 5, ECG: endothelial growth factor, HGF: hepatocyte growth factor, VEGF: vascular endothelial growth factor, WBC: white blood cell count.