Pediatric inflammatory bowel disease (PIBD; age < 17 years) constitutes up to 10%-25% of all IBD patients [1]. Of these, a small proportion are very early onset IBD (VEOIBD; < 6 years). VEOIBD appears to be a distinct subset of pediatric IBD with unique epidemiological and phenotypic characteristics including a severe and aggressive course of disease, predominant colonic involvement and a higher incidence of familial IBD compared to PIBD other than VEOIBD (6-17 years) [1].

The incidence of PIBD is on the rise globally [2]. A complex interplay of genetic and changing environmental factors has been implicated for the rising incidence although specific factors are yet to be completely understood [2-6].

Most of the epidemiological data however are from the West including North America, Canada, and Europe [3]. A few recent studies from Asia also suggest a rising trend of PIBD. Interestingly the phenotype appears to be distinct from that of the West including a milder ulcerative colitis (UC) and a higher perianal involvement in Crohn’s disease (CD) [4-10]. India is a large country with a large population where IBD is a new but emerging disease. Though the incidence of IBD is lower than that of the West expectedly, the burden of disease is high. The diagnosis of IBD itself poses significant challenges in a country where infectious diseases predominate, and tuberculosis (TB) is endemic [11,12].

Data on PIBD behavior and outcomes from India is limited. There are no published reports or separate analysis of VEOIBD and its differences from later onset disease. Similarities to adult IBD and distinctive features have been described in small and questionnaire-based studies [5,13-20].

The primary aim of this study was to evaluate the disease characteristics and treatment patterns in VEOIBD and compare that to later onset PIBD (LO-PIBD; 6-17 years). We also compared our data with other PIBD or VEOIBD studies from Asia and the West.

This is a retrospective analysis of prospectively maintained database of a large number of PIBD patients. This is the first study from India that has highlighted the disease characteristics and treatment patterns of PIBD particularly VEOIBD and IOIBD and compared the differences with later onset disease (6-17 years). Severity of disease was significantly higher in VEOIBD (in both UC and CD subgroups) compared to later onset disease (P=0.003 and P<0.001, respectively) consistent with earlier studies [27,28].

A family history of IBD was found in 14% patients with VEOIBD compared to 9% in later onset disease. The entire cohort from our registry has a positive family history in only 4% (CD of 4.13% and UC of 4.34%) which we have published recently [29]. This has been reported in many other studies that familial IBD is less common in Asia than the West [30,31]. This clearly demonstrates that a genetic predisposition to IBD correlates with the onset of disease being highest in the IOIBD and VEOIBD.

We compared our data with that of other studies both in Asia and the West (Supplementary Tables 2, 3). The large Western population-based Epidemiology of inflammatory bowel diseases: new insights from a French population-based registry (EPIMAD) (1,412 PIBD patients) was used for comparison (Supplementary Table 2) [32]. Male preponderance was more evident (82% vs. 52%, P=0.02). The VEOIBD disease character otherwise was similar to our study. Interestingly the LO-PIBD group in our study had significant differences compared to EPIMAD study. A higher number of patients had a diagnostic delay > 6 months (78.8% vs. 30%, P=0.004) and the incidence of familial IBD (9.2% vs. 15%, P=0.009) was significantly lower. The Indian PIBD appears to be more severe with a higher incidence of stricturing and penetrating disease (B2 and B3) in CD and pan colitis (E4) in UC compared to EPIMAD cohort [31].

We also compared our data with other PIBD cohorts from Asia and Europe (Supplementary Table 3) [6,7,16,17,32]. We noted a high incidence of ileal CD (31.4%) though colonic disease was most common (37.1%) [10]. Another Indian study by Sonavane et al. [17] similarly showed that the most common phenotype was ileal (37.5%). Perianal disease and upper gastrointestinal (L4) was less common. A recent study on PIBD from East Asia (Japan) showed higher incidence of upper gastrointestinal and perianal disease compared to European Cohort (EUROKIDS) [32,33]. The incidence of structuring and fistulizing disease was significantly higher than other studies. The rates of surgery in CD (16.5%) comparable to other Asian study (South Korea, 22.7%) [34,35]. In UC, although pan colitis was the most common phenotype, colectomy rates were lower (2.7%) supporting the notion that UC is a milder disease in Asian countries with less incidence of acute severe colitis and colectomy (Supplementary Table 3) [13,16,36,37]. Compared to another questionnaire-based survey from India by Sathiyasekaran et al. [16], the proportion of VEOIBD, disease location and proportion of perianal CD were different. Such differences could be due to variation in methods of data collection and study settings [22]. However, results appear more consistent with a recent study from India by Sonavane et al. [17].

We found that a diagnostic delay > 6 months was lesser in VEOIBD compared to later onset disease (40.9% vs. 78.8%, P<0.001) disease perhaps because of more severe disease at presentation prompting early referral in VEOIBD. Another plausible explanation could be the use of diapers in infants and hence easier observation of their stools. Ileal disease (L1) was predictive of longer diagnostic delay ( > 50th percentile) in CD [38]. This is in sharp contrast to the EPIMAD study where diagnostic delay > 6 months were seen in only 27% and 30% patients respectively in VEOIBD and LO-PIBD [32]. The disproportionately longer delay in diagnosis could be attributable to poor physician awareness of pediatric IBD in India and high percentage of ileal (31.4%) disease in our study which is a known risk factor for diagnostic delay in pediatric CD [39].

The other contributory factors for diagnostic delay include the infectious mimics of IBD and over the counter antibiotics (like fluoroquinolone and metronidazole) are easily available and is often the first line of treatment. The high prevalence of TB which is often symptomatically, endoscopically and histopathologically difficult to differentiate from ileo-colonic CD is another diagnostic dilemma which results in empirical use of ATT [39-42]. Almost one-fifth of children with CD in our cohort had received ATT prior to diagnosis adding to diagnostic delay. We have earlier reported that empirical use of ATT was the single largest contributor for diagnostic delay in an adult CD cohort of more than 700 patients which resulted in higher long term stenotic complications and need for surgery [43]. India is endemic for TB and there is limited awareness about CD. Hence at the community level, patients are initiated on ATT and CD is diagnosed only if there is no response leading to inordinate delays in diagnosis.

We also compared data between the adult and PIBD cohort in our registry (Supplementary Table 4). Familial IBD was more common in PIBD cohort. Higher incidence of ileal disease (L1), stricturing phenotype (B2) and perianal disease was found in pediatric CD cohort. UC in PIBD cohort was more extensive. Steroid, immunomodulator, and biologic usage was also higher in PIBD group. However, the diagnostic delay was significantly higher (P<0.001) in adults with CD (mean ± standard deviation [SD], 42.2 ± 46.1 months) compared to pediatric CD (mean ± SD, 23.56 ± 27.76 months) [22]. This could be attributable to the higher usage of empirical ATT in the adult cohort.

IOIBD was seen in 8 children (2.7% of PIBD). Three had refractory disease requiring surgery. IL-10 receptor mutation was detected in 1 child who later underwent allogenic hematopoietic stem cell transplantation. This is very much in concordance with other studies from across the globe suggesting that IOIBD is a distinct and the most difficult to treat subset of pediatric IBD [44]. Monogenic defects like IL-10/IL-10R mutations are not uncommon in this subgroup [45,46]. However, mutational defects often go undetected due to unavailability of required facilities and financial constraints in emerging economies like India. Only 1 of our VEOIBD patients was tested for receptor mutations.

The rate of steroid and biologic usage did not differ between the VEOIBD and LO-PIBD group. Although the disease severity was high and complicated and extensive disease phenotypes were common in our study, biologic usage was limited in our study. The risk of opportunistic infections, high prevalence of latent TB and of course the high cost with limited or no insurance coverage precludes biological therapy in the resource limited country settings like India [47]. Exclusive enteral nutrition was not used due to poor acceptability and compliance in addition to cost concerns. However, PEN was used as an adjunct to other therapies. PEN in CD is known to be associated with an extended period of disease remission [48].

We acknowledge certain limitations including, the relatively small number of children in VEOIBD group and inability to perform mutation analysis in a large fraction of children. We did not assess all the PIBD patients routinely for growth failure- so we could not assess the extent of growth failure in various groups which is important aspect of PIBD specially in CD [49]. It was also a single tertiary care center analysis with the possibility of overrepresentation of severe disease. Comparisons with the Western and other Asian data are at best tentative.

This is the first PIBD cohort from India highlighting the differences between VEOIBD and LO-PIBD in children. VEOIBD though uncommon was associated with more severe disease and poorer outcomes compared to later onset disease. VEOIBD in India was phenotypically similar to the West although later onset (6-17 years) disease phenotype differed. Large multicenter studies based on prospective databases are required to confirm whether PIBD in India is phenotypically different. We found that diagnostic delays were common and most children received multiple courses of antibiotics before confirmation of diagnosis. This would have significant long term prognostic implications. This study highlights the urgent need for increasing the awareness on the prevalence of IBD in the pediatric population amongst primary care physicians to ensure early diagnosis and timely treatment of this chronic disease.