Neutrophil FCγ Receptor 1 (CD64) Index As a Non-Invasive Biomarker for Clinical and Mucosal Disease Activity in Pediatric Inflammatory Bowel Disease

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Background: Neutrophil expression of the high affinity Fc γ receptor 1(CD64) is up-regulated in adult patients with active inflammatory bowel disease (IBD). Infliximab non-response has been associated with an increased mucosal CD64 mRNA expression. We assessed the clinical utility of whole blood analysis of CD64 in the pediatric IBD population as a reflection of disease activity and severity. We hypothesized that the polymorphonuclear neutrophil (PMN) CD64 index would correlate with fecal calprotectin (FC) and serve as a surrogate biomarker for mucosal activity. Methods: We enrolled children having colonoscopy for suspicion of IBD (18 Crohn's disease [CD], 2 Ulcerative Colitis [UC], 10 healthy controls) and children during routine clinic visits or undergoing colonoscopy with known IBD (82 CD, 14 UC, 2 IBD-U). The polymorphonuclear neutrophil (PMN) CD64 index was determined from each subject's whole blood by flow cytometry using Leuko64 (Trillium Diagnostics, LLC). RNA sequence analysis of CD64 and S100A9 (calprotectin) was performed on ileal tissue obtained at diagnosis from 32 CD patients and 18 healthy controls and provided by the PRO-KIIDS consortium. Results: Mean(SD) PMN CD64 index for new diagnosis IBD was 2.79(0.36) compared with 0.78(0.04) for healthy controls (p=0.0005). For those with known IBD (41 active, 57 quiescent), the mean(SD) PMN CD64 index for active IBD was 2.38(0.26)) compared with 1.048(0.05) for quiescent IBD (p ,0.0001). ROC curve analysis from the two groups demonstrated an AUC of 0.89 (95% CI 0.83-0.95). At a cut off of 1.2, the CD64 index was 85% sensitive and 84% specific for active IBD. In the patients with active disease, the CD64 index was elevated in 35/41 (85%) subjects compared with elevations in FC (81%), CRP (72%), and ESR (57%). The PMN CD64 index did not differ by disease location (ileum only, colon only, ileocolonic) in those with active IBD, but CD64 index was highly correlated with the pediatric CD activity index (PCDAI, Spearman r = 0.68; p , 0.0001) and the pediatric UC activity index (r = 0.88; p , 0.0001). In patients with mild disease activity (PCDAI score 10-27.5), the mean PMN CD64 index was 1.84 compared with 3.03 in those with moderate-severe disease activity (PCDAI 30-100, p=0.014). Importantly, the PMN CD64 index significantly correlated with the simplified endoscopic score-CD (SESCD) in 32 CD patients (r = 0.68, p , 0.0001), while no correlation was found with CRP or ESR and SES-CD. RNA sequencing from ileal tissue revealed Fc γR1A (CD64) correlated significantly with S100A9 (r = 0.879; p , 0.0001). The PMN CD64 index also correlated with FC (r = 0.485; p = 0.002). Conclusions: The PMN CD64 index is a useful biomarker in determining disease activity in pediatric IBD and correlates significantly with FC, disease activity indices, and the SES-CD.

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