Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Characteristics of Inflammatory Bowel Disease With Onset During the First Year of Life
Ruemmele, Frank M*,†; El Khoury, Maurice G*; Talbotec, Cécile*; Maurage, Chantal*; Mougenot, Jean-François*; Schmitz, Jacques*,†; Goulet, Olivier*,†
*Paediatric Gastroenterology Unit, Department of Paediatrics, Hôpital Necker-Enfants Malades, Paris, National Center for Rare Digestive Diseases
†INSERM EMI U793, University René Descartes, Paris, France
Received 6 September, 2005
Accepted 2 March, 2006
Address correspondence and reprint requests to Dr F.M. Ruemmele, Paediatric Gastroenterology Unit, Hôpital Necker-Enfants Malades, INSERM U793, 149 Rue de Sèvres, F-75743 Paris, France (e-mail: firstname.lastname@example.org).
Background: Inflammatory bowel disease (IBD) is recognized in young children, however, only rare data on onset and evolution are available in children younger than 1 year. In the present clinical study, we aimed to analyze characteristics and clinical course of children with very early onset IBD. We were particularly interested in the relationship between bacterial infections and the use of antibiotics before the onset of IBD.
Patients and Methods: The IBD database of Necker-Enfants-Malades-Hospital was screened for patients with IBD with disease onset during the first year of life and a follow-up of at least 2.5 years. Ten patients were identified during the period 1996–2002.
Results: All patients presented with rectal bleeding and had colonic involvement. Four patients had definitive diagnosis of Crohn disease; ulcerative or indeterminate colitis was seen in 2 and 4 children, respectively. Five of the patients had a positive history of neonatal or early-onset bacterial infection with use of antibiotics before onset of IBD, 4 patients were still breastfed and 3 just weaned when GI symptoms started. Seven patients had a severe onset of disease requiring bowel rest, parenteral nutrition and steroid medication, followed by azathioprine or cyclosporine medication. Surgery was necessary in 3 of 10 patients. Disease relapses were frequent and observed in 8 of 10 children.
Discussion: Very early onset IBD may reflect a subgroup of patients characterized by a particular sensitivity to modifications of the intestinal flora. Neonatal IBD was most often severe in presentation and evolution.
The incidence and prevalence of inflammatory bowel disease (IBD) markedly increased over the second half of the 20th century, and at the beginning of the 21st century IBD is considered 1 of the most prevalent GI diseases in adults (1). Pediatric epidemiological data from the UK, northern France, Sweden and the US (2–6) indicate an increased incidence for pediatric Crohn disease (CD) with a stable incidence of pediatric ulcerative colitis (UC). Onset of symptoms peaks within the second decade of life, and approximately 10% of patients with IBD are diagnosed in the pediatric age group (4,7,8), however, precise epidemiological data are still rare. The etiology of IBD is unknown; recent research data point to an altered immune homeostasis within the intestinal mucosa in genetically predisposed individuals (9–11). This may result in an exaggerated and uncontrolled inflammatory response probably triggered by the intestinal flora and/or other environmental factors (11). Some experimental and in vivo animal data indicate regulatory defects within the innate immune system as causal in the development of IBD (11–13).
It is unclear why the incidence of IBD increased during the past several decades: changes in lifestyle and alimentary habits were discussed (14,15). Not only are the number of patients increasing but there are also data indicating onset of IBD within the first year of life (16). The recently published results of the North American Pediatric IBD Consortium confirmed onset of IBD within the first 12 months of life in 1% of their patients (17). The occurrence of IBD during the neonatal period or within the first few months of life is challenging from both a clinical and pathophysiological point of view. The first months of life are a critical and vulnerable period in the initiation of a normal host immune response toward exogenous aggressions. Based on the observation that inflammatory flareups may be triggered by the commensal flora of the gut, it is tempting to speculate that patients with onset of IBD during the first months of life, the period during which the intestinal flora develops, may have particular pathophysiological features. To date, too few data exist to draw conclusions about the long-term evolution and outcome of this particular pediatric IBD group. Systematic long-term follow-up data will help to improve the care for children with IBD and eventually to further elucidate the pathogenesis of IBD. In the present study we analyzed 10 children with onset of IBD within the first 12 months of life and their evolution during a mean 5-year follow-up (range, 2.5–8.5 years, median, 4.5 years). We were particularly interested whether there was any link between bacterial infections, the use of antibiotics and the onset of GI symptoms. Our data indicate that half of our patients had a positive history of bacterial infection and antibiotics use before onset of IBD. All of the children had colonic involvement and 8 of 10 children had a severe and complicated evolution requiring prolonged use of immunosuppressors and surgery in 3 of them.
PATIENTS AND METHODS
The IBD database of patients followed between 1996 and 2002 at the Necker-Enfants Malades Hospital was screened for children with IBD who started their disease within the first 12 months of life. A total of 10 patients were included in this study, corresponding to 2.5% of all IBD patients followed in our center. All of the patients had a complete diagnostic workup (upper GI series with a small bowel follow-through, barium enema or abdominal CT scan, upper and lower GI endoscopy under anesthesia), and the diagnosis of CD or UC was based on standard clinical, biological, radiological, endoscopic and histological criteria (18). The diagnosis of CD was defined by the presence of epithelioid cell granulomas and giant cells in proximity to lymphoid follicules in any 1 biopsy of the upper and/or lower GI tract. On endoscopic examination, aphtous or deep ulcerations with typical skip lesions all along the GI tract (from the mouth to the anus) with microscopic findings of focal inflammatory changes were consistent with CD, as was the presence of perianal lesions and/or transmural inflammation (fistulizing or structuring disease). UC was defined as continuous inflammatory disease confined to the colon without any evidence of small bowel involvement (other than backwash ileitis). In children presenting with isolated colitis not allowing discrimination between CD and UC (especially with absence of specific histological features of CD), the diagnosis of indeterminate colitis (IC) was made. Infectious or allergic disorders (immunoglobulin E [IgE], skin prick and patch tests) as well as immunological disorders (lymphocyte phenotyping, immunoglobulin levels, autoantibodies, granulocytes function and oxidative burst) were carefully ruled out in all patients. Skin abnormalities were not observed except for a variable eczema in patient 6. During the initial workup, stool samples were routinely tested for the presence of bacterial pathogens (salmonella, shigella, yersinia, pathogenic Escherichia coli, Clostridium difficile toxins) as well as viruses (rotavirus, adenovirus) and parasites (entamoeba histolytica). Mycobacteria were routinely searched on ileal or cecal biopsies and intradermal skin testing was performed in all patients. The presence for perinuclear anti-neutrophilic cytoplasmic antibody (pANCA) or anti-Saccharomyces cerevisiae antibody-IgA (anti-ASCA-IgA) or IgG antibodies was routinely tested in all patients.
Ten children (6 boys, 4 girls) were admitted to our department with early-onset IBD between 1996 and 2002 (Table 1). Six children had a positive family history for IBD (n = 4) and/or autoimmune diseases (n = 4, diabetes mellitus, ankylosing spondylarthritis, Basedow, Hashimoto thyroiditis) in first-degree relatives. Two of them and their affected relatives had concordance for the type of disease (UC or CD), whereas the remaining children have IC. In 2 cases onset of IBD in relatives also occurred during childhood.
Clinical Presentation and Disease Location
Median age at onset of disease was 5 months (range, 15 days–12 months), with first symptoms occurring within the first month of life in 2 children (Table 1). Three patients started experiencing IBD symptoms while still exclusively breast-fed, whereas in 3 others, symptoms appeared shortly after weaning or introduction of complementary formula. In 5 children, GI symptoms suggestive for IBD occurred within 3 weeks after 1 or several episodes of bacterial infections, treated in 4 cases by antibiotics (Table 2). Two patients (1 and 6) had several infectious episodes requiring several courses of antibiotics for 6 and 4 months, respectively, until the onset of specific GI symptoms leading to the diagnosis of IBD. Both boys with onset of IBD at 2 weeks of life had a positive history of antibiotic use at birth for supposed or confirmed materno-fetal infection. A further child was reported to have viral infections causing acute gastroenteritis preceding the onset of IBD. All of the children presented with recurrent or protracted bloody diarrhea and fever. Recurrent episodes of diarrhea before hospitalization were observed in 7 children. Significant bleeding (Hb <8 g/dL) requiring blood transfusion was observed in 4 cases. Significant weight loss (≥10%) was present in all 10 patients. Aphtous pharyngeal lesions and anoperineal lesions (perianal erythema, fissures, abscess) were seen in patients 2 and 6 (Table 2), with a tendency to superficial fistulization in patient 2. No liver or extradigestive disease was diagnosed at presentation or during follow-up. Infectious colitis and/or cow's milk allergy were excluded and immunological evaluations were normal in all children, excluding congenital or acquired immunodeficiency disorders, septic granulomatosis and autoimmune diseases or enteropathies.
Pancolitis was initially present in 7 children (with discontinuous lesions in 3 patients), whereas 3 children presented with left-sided colitis (sparing of the rectum in 1). Ileal involvement was observed in 1 patient (Table 1). Upper GI tract manifestations were seen in 1 child with UC (gastritis) and 1 child with CD (duodenitis, gastritis). Complete initial diagnostic workup led to the diagnosis of CD in 2 children, based on the presence of granuloma on colonic biopsies (patient 10) and ileal involvement (identified by small bowel follow-through). Two additional patients were diagnosed with UC, whereas 6 patients presented with IC during the initial workup (Table 1). In 2 children with an initial diagnosis of IC follow-up permitted a change in diagnosis to CD after 12 and 25 months, respectively, when granulomas were identified in a Meckel's diverticulum after surgery along with the occurrence of recurrent perianal abscesses, and within the piece of colonic resection. Four children are still diagnosed with IC with follow-up of 2.5 to 8.5 years. Serological markers remained negative in all patients for ASCA, even the 4 children with CD, whereas pANCA were positive in 1 girl with UC and 1 boy with IC.
Treatment and Evolution
Onset of disease was severe in 8 patients (all 4 CD, 1 UC and 3 IC), requiring bowel rest, in association with intravenous methylprednisolone and total parenteral nutrition (TPN) in all except 1 patient with CD who received enteral nutrition. This initial regimen helped to control disease progression in 7 of 8 patients; in 1 patient (IC) intravenous cyclosporine was used as a second-line treatment. Finally, complete initial remission was achieved in all patients. The 2 patients (1 UC, 1 IC) who did not require intravenous steroids and TPN presented with a moderate to severe form of pancolitis in one and left-sided colitis in the second. In both patients, food allergy was suspected initially (despite negative IgE, Rast, prick and patch testing), however, no improvement was seen on hydrolysate alimentation. The introduction of sulfasalazine medication thus rapidly stopped symptoms, and no reactivation was observed after the reintroduction of a cow mild protein–based formula. Anti-inflammatory treatment could be stopped within 1 year and both children remained in prolonged remission without treatment to the present (follow-up, 2.5 and 4 years, respectively). However, all of the other children had at least 1 severe relapse of the disease during the first year after onset. Upon relapse, 3 patients failed to come into remission, requiring prolonged TPN and intravenous steroids (2 patients had a final diagnosis of CD and 1 had UC). Finally, all 3 children were weaned form TPN after surgery (colectomy in 1 patient with UC and CD, respectively, and ileostomy in 1 patient with CD) and remained stable under immunosuppressive therapy (azathioprine). All 8 patients required prolonged azathioprine medication to control disease activity (follow-up, 2–6 years).
Enteral nutrition (Modulen IBD, Nestlé) was successful in all 4 patients with CD, but it was not sufficient to induce remission, except in 1 girl who was highly responsive to the first course. Recurrent courses of enteral nutrition were administered in 3 of them, with good response in each patient.
Incidence and prevalence of IBD, mainly CD, markedly rose during the last several decades, and it is well established that both CD and UC can occur in children younger than 10 years (7,8,16,17,19). Few series have been published analyzing the onset and outcome of IBD in different pediatric age groups, with 1 series dealing specifically with children younger than 5 years old (16). Here, we present the first series with a detailed clinical course over a mean of 5 years of 10 children presenting with IBD during the first weeks or months of life. Diagnosis of IBD in this age group is particularly difficult because its presentation is often atypical and neonatal IBD has seldom been described. As in our IBD cohort, reports of other pediatric centers indicate that about 1% to 2% of children have disease onset during the first 2 years of life (5,8,16,17). Infectious or allergic diseases causing colonic inflammation are the most common diagnoses in this age group; a second class of rare but important diseases mimicking IBD are immune defects, such as septic granulomatosis or glycogen storage disease type 1b. All of them were ruled out in our patients. In this series, all 10 children presented with a predominant, most often isolated colonic disease, in keeping with the report of Mamula et al. (19) or Heyman et al. (17). This contrasts with older children or adults with CD who most often have a predominant small bowel or ileocecal disease, whereas colonic involvement is less frequent. The clinical course and response to treatment confirmed the initial suspicion of IBD, and finally on repeated analyses typical histological signs of CD or UC were observed in 6 of 10 patients. Similar to the data reported by Mamula et al. (19), serological markers for IBD such as pANCA or ASCA were not helpful in the diagnosis of IBD in this age group, in contrast to older children with IBD (20). The occurrence of ASCA in CD may reflect a leaky intestinal epithelial barrier, allowing a sensitivity to S. cerevisiae over time, which in turn results in an adaptive immune response with production of specific antibodies. Recent reports (21) indicate that ASCA positivity reflects small bowel or ileocecal CD, whereas colonic CD patients are most often ASCA negative or they have only low ASCA titers (20).
Theoretically, it is not surprising to observe early postnatal onset of IBD because CD and probably also UC have a genetic basis (22–24) and the majority of our patients were found to have a positive family history for IBD or autoimmune disorders, further confirming the notion of a genetic basis. The epidemiological data of Baron et al. (5) clearly identified a positive family history of IBD as the strongest risk factor for the development of either CD or UC. Several IBD loci associated with the development of IBD were described over the past few years (25,26). These mutations are not truly disease causing because, for example, asymptomatic heterozygous or homozygous carriers of NOD2/CARD15 mutations are known and only 10% to 30% of patients with CD carry mutations in this susceptibility gene. Because patients with NOD2/CARD15 mutations present with an ileal or ileocecal disease, genetic factors other than NOD2/CARD15 are more likely to contribute to the development of neonatal colonic IBD.
There is increasing clinical and animal experience indicating that an altered interaction between the normal gut flora and the intestinal mucosa is a major triggering factor of IBD (8,11,12). It is intriguing to observe that onset of IBD occurred in the majority of our patients during the process of initial colonization of the gut within the first postnatal months or modifications of the gut flora during weaning from breast-feeding to alimentary diversification. It is tempting to speculate that these children with neonatal IBD are particularly sensitive to normally harmless bacterial components of the intestinal flora. In animal models of IBD, such as interleukin-10 knockout mice or trinitrobenzesulfonic acid–induced colitis (27,28), intestinal inflammation only occurs upon bacterial colonization of the animal, whereas in the absence of the commensal flora no inflammatory reactions are seen. A different hypothesis could be that a disruption of the intestinal microbiological ecosystem by the use of antibiotics may contribute to the development of IBD, especially during this vulnerable period of the postnatal intestinal colonization or in genetically susceptible individuals. Some retrospective data indicate a link between antibiotic use and the development of IBD (29,30). In a Swedish case-control study by Ekbom et al. (31), patients with IBD had a higher rate of perinatal infections and antibiotic use compared with controls. Unfortunately, no good epidemiological data on the antibiotic use during the first months of life in France exist to further substantiate our hypothesis and our finding of a bacterial infection and/or antibiotic treatment in 5 of 10 patients. Larger cohort studies may uncover an answer to the hypothesis that in these children a microbial stimulation may unmask a defect of the intestinal immune system resulting in a loss of tolerance and triggering recurrent inflammatory reactions (8,11,12). Another interesting point is the fact that the colonization process of the gut is a major trigger of T cell responses. Physiologically, the newborn baby has a predominant TH2 lymphocyte response, whereas a switch toward a TH1 reaction is primed by a microbial stimulation during the first months of life (32). Alterations of this process are likely to initiate a dysregulation either in form of immunoallergic reactions (TH2 dominance) or dysimmune-inflammatory reactions (TH1 dominance), such as those seen in CD.
The clinical presentation of children in this series is characterized by a pure or at least predominant colonic inflammatory disease, along with a serious evolution in the majority of patients, requiring TPN and the use of immunosuppressors such as azathioprine early in the progression of the disease. Once these children were on azathioprine the situation was well controlled. However, within the first 12 months after onset, one third of our patients required surgical treatment, colectomy or ileal diversion to control the colonic disorder. The need for surgery was markedly higher and significantly earlier in this particular group compared with older children with IBD in our cohort (33) and other centers (7,34).
In summary, not only is the number of pediatric IBD patients steadily increasing but also affected children are increasingly younger. One major factor is a particular genetic predisposition to develop IBD, however, genes do not significantly change within 1 or 2 generations. Therefore, it is more likely that environmental trigger factors initiating the disease evolved over the years. Several arguments indicate that a change of the intestinal flora, probably secondary to changes in alimentary habits, along with particularly sterile living conditions make individuals prone to developing IBD. New treatment strategies should include modulating the interaction of commensal microbiota and the intestinal mucosa, enhancing the development of tolerance or reducing the inflammatory responses initiated by the innate immune system.
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