Clinical Features and Outcomes of Very-Early-Onset Inflammatory Bowel Disease in Brazilian Children

**Background:** Very-early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed before 6 years of age, is a distinct and often more severe phenotype compared to IBD in older children and adults. Monogenic defects are increasingly recognized in this group. Data on VEO-IBD from developing countries are limited. This study aimed to describe the clinical, laboratory, and histopathologic features and outcomes of VEO-IBD in Brazilian children.

**Methods:** A retrospective, single-center, descriptive study was conducted by chart review of children under 6 years diagnosed with IBD (UC or CD) at the University Hospital Botucatu Medical School (Unesp), São Paulo, Brazil, from January 2000 to February 2020. Diagnosis was based on endoscopic and histologic findings. Clinical data were collected at diagnosis and every 3 months. Patients were categorized by Paris classification into neonatal (<28 d), infantile (<2 yr), and very early onset (<6 yr). Statistical analysis used GraphPad Prism 7.00; continuous data reported as medians with IQR, categorical as proportions. Fisher exact test and Mann-Whitney U test were used; P<0.05 was significant.

**Key Results:** Twenty children were included: 13 UC (65%) and 7 CD (35%). Mean follow-up was 8.3 years (SD 3.4). Of these, 4 had neonatal-onset (1 UC, 3 CD), 8 infantile (4 UC, 4 CD), and 8 UC beyond infantile but <6 years. Seventeen were female (12 UC, 5 CD). Patients with CD were significantly younger at symptom onset (median 2.5 vs 36 months; P=0.006) and at first visit (median 14 vs 48 months; P=0.001). At presentation, CD patients had significantly lower weight z-score (median -1.72 vs 0.13; P=0.003) and height z-score (median -2.44 vs 0.09; P=0.03). Weight z-score remained lower in CD at 12 months (median -0.96 vs 0.77; P=0.03) but not at 48 months. All children had diarrhea and bloody stools. Weight loss was more common in CD (85% vs 30%; P=0.04). Laboratory findings: CD patients had lower hemoglobin (median 9.2 vs 12.2 g/dL; P=0.009), all had hemoglobin <11 g/dL (100% vs 30%; P=0.004), higher CRP (median 7.4 vs 0.9; P=0.04), lower total protein (median 6.4 vs 7.4 g/dL; P=0.05), and more hypoalbuminemia <3.5 g/dL (71% vs 15%; P=0.02). Fecal calprotectin was higher in CD (median 957 vs 607 μg/g) but not significant (P=0.7). All CD and 92% of UC had moderate/severe PUCAI/PCDAI scores at diagnosis. Colon was affected in all; pancolitis in 12 UC and 5 CD. Perianal lesions occurred in 6 CD patients (85%), including fistulae in 5. Histology: diffuse inflammation with cryptitis in all UC vs 1 CD; crypt microabscesses in 10 UC vs 1 CD; crypt distortion in 11 UC vs 1 CD; plasmacytosis in 12 UC vs 1 CD; epithelioid microgranulomas in 3 CD vs 0 UC. All children initially received mesalamine and corticosteroids; 85% CD and 76% UC started azathioprine; infliximab was given to 42% CD and 15% UC. Two children with CD developed non-Hodgkin diffuse large B-cell lymphoma while on azathioprine and infliximab; one died post-colectomy, one was cured at 3 years. Another CD patient with neonatal-onset and severe perianal disease died of septicemia. No other surgeries were needed.

**Clinical Implications:** This study confirms that VEO-IBD in Brazilian children presents with an aggressive phenotype, similar to reports from other countries. CD presents at a younger age with more severe nutritional impairment, anemia, and inflammation compared to UC. The high rate of perianal disease in CD and the occurrence of lymphoma in two children on combination immunosuppression underscore the need for careful monitoring and consideration of genetic testing for monogenic defects, which was a limitation of this study. The predominance of colonic involvement and the difficulty in distinguishing UC from CD highlight the importance of histopathology. These findings support the need for specialized multidisciplinary care for VEO-IBD patients.