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Results
Prevalence of siblings with IBD there were 16 families identified with more than one offspring with IBD. This is a prevalence of 2.5%. Of the 16 families, there were 4 families with three offspring (25%). There was 1 family in which all three siblings had IBD. Amongst the remaining 3 families with three offspring, the third sibling was free of IBD thus far. All of our sibling pairs with IBD were consecutive in birth order.
Birth order of presentation
The second born (youngest) sibling was the first to present with IBD in 11 of the 16 families (69%). In the remaining 5 families, the firstborn (older) sibling presented first (31%) (Table 1).
First to present(%) Second to present (%)
Youngest 11 (69) 5 (31%)
Oldest 5 (31) 11 (69)
Total (33)* 16 16
Table 1: Distribution of sibling’s presentation by birth order. *One family with three effected.
Incidence of parental IBD
In 3 of the 16 families, one parent had IBD (19%). One parent had Ulcerative Colitis (UC) and two had Crohn’s disease (CD).
Gender
Of the total group of siblings with IBD, there were 12 females and 21 males. Seven of the females presented first (58%), whereas 9 males presented first (43%). This difference was not statistically significant (p = 0.39, by the Chi-square test).
Time to presentation between siblings
Overall median time from presentation of the first sibling to the second sibling was 3.9 years (10–19 years of age). Median time of presentation from youngest to oldest was 3.3 years (10–17). Median time of presentation from oldest to youngest was 4.4 years (13–19) (NS).
Concordance
In 6 of the families there were seven siblings with mixed phenotype. Amongst these families, UC presented first in six patients (86%) and CD in 1 (14%). In 10 families there was concordance of phenotype amongst the siblings. Six families were concordant for CD (60%) and four with UC (40%). In the remaining six families the siblings had discordant phenotypes (Table 2).
Phenotype No. Families No. Sibs Sibs with CD Sibs with UC
Concordance 10 20 16 4
Discordance 6 13 6 7
Total 16 33 22 11
Table 2: Distribution of IBD phenotype among siblings.
Discussion
The major finding in this study was that, in the vast majority of cases of pediatric siblings with IBD, the second-born (youngest) sibling presented before the first-born (oldest) sibling. This is not what one would expect if the disease distribution of birth order were random. Hugot et al. studied 10 sibling pairs with IBD using the CAST statistical model and found that the distribution of disease onset was not random and that birth order had an influence on disease. They concluded that environmental factors contribute to the observed familial aggregation of disease [14]. Hampe et al. found that higher birth rank was associated with a lower risk of IBD [15]. Our findings support the existence of environmental factor(s) resulting in the distribution of the birth order of presentation of IBD that we observed. What could be responsible for the distribution we observed in patients who were raised in a very similar milieu? One factor may be an alteration in the gut microbiome. For this to explain our findings, the youngest sibling would have to be affected by factors that would alter the microbiome more frequently than the older sibling. Recently, there has been great interest in the gut microbiome and the role it may play in IBD. It is felt that perturbation of the gut microbiome may, in turn, alter host immunity. When this occurs in the presence of an at-risk genetic host, IBD may follow.
In fact, this dysbiosis in IBD has been described in detail in patients with IBD [16,17]. Ponsonby et al. examined perinatal risk factors and their relationship to the development of IBD and found that delivery by Cesarean (elective or emergent) was associated with a higher risk of developing IBD. The microbiome in newborns differs markedly between those delivered vaginally versus by Cesarean section [18]. Furthermore, the resultant dysbiosis associated with antibiotic treatment may last long after the antibiotics have been discontinued. There is also evidence to support that there may be a slow and incomplete recovery of the microbiome in infants treated with antibiotics [19]. Shaw et al. showed that there is an association between the risk of IBD in children and the occurrence of otitis media prior to age 5 years [20]. Otitis media may indeed represent a proxy for antibiotic use. More specifically, it has been shown that antibiotic use in early childhood is a risk factor for the development of IBD [21-23]. The use of broad-spectrum antibiotics has significantly increased during the last four to five decades. The increased incidence of IBD and other disorders of immune dysregulation has paralleled the increasing use of antibiotics since the first introduction of amoxicillin in the UK in 1972 [24,25]. This trend in aggressive, non-specific antibiotic use has likely caused a perturbation of the intestinal microbiome and hence changes in both the mucosal and systemic immune systems.
Another trend that has become widespread during the past several decades is attendance in some form of “school” at a very early age. The resultant risk of acute illness in daycare attendees is greatest during the first three years of life and decreases with advancing age. In a large Danish cohort, it was shown that the second-born sibling had a greater number of acute illnesses and received a greater number of courses of antibiotics when compared to the first-born sibling [26]. Furthermore, there is a significant increase of antibiotic use among second-born siblings versus first -born siblings that has been confirmed by Koppleman et al. [27]. Our study is notable for describing certain trends. The prevalence of IBD of 2.5% in siblings with IBD in pediatrics is roughly half of that shown in siblings with IBD over a lifetime, which is 4.8% [28,29]. We also found that the onset of IBD in the second-born sibling preceded that of the older siblings in about 70% of the sibling pairs. Our findings are consistent with studies showing that exposure to antibiotics in early childhood is a risk factor for IBD. Furthermore, the younger sibling is more likely to contact common illnesses and receive a course of antibiotics as compared to the older sibling. This may indeed account for our findings. The primary limitations of this study include a relatively small number of pediatric sibling pairs with IBD to power this analysis. This is unavoidable in any one institution given the low prevalence of pediatric siblings with IBD. Furthermore, we did not have access to specific antibiotic regimen(s) amongst our patients. This study is, however, a first step and should be confirmed by other studies.
Conclusion
The more we know about the epidemiology of a disease, the closer we get to elucidating the etiology. The ultimate goal is to find ways to prevent the disease from occurring. This study is the first to examine certain trends in children and adolescents who are siblings and have been diagnosed with IBD. Our most striking finding was that in the majority of cases, the onset of IBD in pediatric sibships occurred in the second-born sibling first. The age of onset for the next sibling to present was approximately four years no matter what combinations of phenotype we examined. Our findings lend support to the potential role of antibiotic use and the potential role in the increasing incidence of disorders of immune dysregulation. Finally, it should add further support to the judicious use of antibiotics in the pediatric age group. This study was approved by the institution’s IRB.
From
https://www.omicsonline.org/open-ac...sease-jibdd-1000103.php?aid=73369&view=mobile
