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Original Articles: Gastroenterology

Surgery in Children With Crohn Disease Refractory to Medical Therapy

Pacilli, Maurizio; Eaton, Simon*; Fell, John M; Rawat, David; Clarke, Simon; Haddad, Munther J

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Journal of Pediatric Gastroenterology and Nutrition: March 2011 - Volume 52 - Issue 3 - p 286-290
doi: 10.1097/MPG.0b013e3181e999af
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Abstract

Crohn disease (CD) in children is associated with significant impairment of growth and nutrition leading to delayed puberty (1–3). Kanof et al (4) reported that 88% of prepubertal children with CD were found to have decreased height velocity before diagnosis, and Sawczenko et al (5) reported a mean height deficit of −0.5 standard deviations (SDs) at diagnosis. If the onset of puberty is delayed beyond 14 years of age, then final height may be compromised, and it is important to induce remission before the onset of puberty (1). Poor growth in CD has been explained by different theories including low energy intake, exposure to corticosteroids, and the growth inhibitory effects of the inflammatory process itself (6–10). Surgery is generally advocated in children with growth failure not responding to medical therapy. Homer et al (11) reported a recurrence rate of 30% following surgery and that catch-up growth occurs only in those children who are operated on before puberty and in whom there is no early recurrence. These findings were confirmed by other studies (12–14) reporting that surgical intervention leads to benefits in growth, particularly when performed before puberty. The results of surgery in children with CD are largely dated from the 1980s and early 1990s, a period in which immunomodulators were not widely used and biological therapy had not yet begun. The aim of our study was to evaluate the results of surgery in children with CD not responding to modern medical therapy and establish whether surgery improves growth and nutrition.

PATIENTS AND METHODS

A retrospective review of children with CD diagnosed at Chelsea and Westminster Hospital between 1998 and 2008 was performed. The study was approved by the Chelsea and Westminster Hospital research ethics committee. Presenting symptoms included diarrhoea with discharge of blood and mucus, abdominal pain, nausea/vomiting, weight loss, fever, and general malaise. Diagnosis of CD was made by the paediatric gastroenterologists in all of the patients by clinical, radiological, and endoscopic investigations (15) and confirmed by histological analysis of biopsies taken at endoscopy and from surgically resected specimens. Patients with nonspecific colitis were excluded from the study. All of the patients were medically managed in line with guidelines from the British Society of Paediatric Gastroenterology, Hepatology, and Nutrition (16). Exclusive enteral nutrition (eg, Modulen IBD) for 6 to 8 weeks was the first-line therapy in all of the patients. Nonresponse or early relapse was treated with oral prednisone at an initial dose of 1 to 2 mg · kg−1 · day−1 for 2 weeks before weaning. In steroid-dependent patients, the prednisone was “minimized” at least 2 weeks before surgery. Antibiotics, including metronidazole 7.5 mg · kg−1 · dose−1 3 times daily and ciprofloxacillin 5 mg · kg−1 · dose−1 twice daily, were given to treat perianal disease. Aminosalicylates (eg, mesalazine 50–100 mg · kg−1 · day−1, sulfasalazine 40–60 mg · kg−1 · day−1) were used in patients with mild disease. Patients in whom standard induction therapy had failed or patients with early relapse (<6 months) were treated with azathioprine 2 to 2.5 mg · kg−1 · day−1 continued until the day before surgery. Infliximab 5 mg · kg−1 · dose−1 at weeks 0, 2, and 6 and then 8 weekly was given in patients refractory or intolerant to steroids in combination with immunomodulators (after 2001). Medical notes of children not responding to medical therapy and requiring surgery were reviewed and are the object of this study. Surgery was considered for isolated ileocaecal disease or diffuse disease in patients who were steroid dependent for more than 6 months and had poor growth, and in those with disease refractory to therapy. Surgery was also advocated in the presence of significant intestinal stricture with symptoms of acute or subacute obstruction (ie, chronic colicky abdominal pain, recurrent vomiting, constipation/chronic diarrhoea) and/or fistulae. Emergency surgery was performed in the presence of acute complications including perforation, peritonitis, and intestinal haemorrhage. Resection and end-to-end anastomosis were the treatments of choice in patients with isolated ileocaecal disease involving the ileocaecal valve with variable extent of the terminal ileum and in patients with other localized disease of small or large bowel (<50 cm of intestine affected). Stricturoplasty was performed in patients with isolated stricture <1.5 cm in length and involving no more than one third of the lumen of the small or large bowel. Stoma formation was the preferred treatment in the presence of diffuse disease and/or complications including perforation with abscess formation, generalized peritonitis, and acute haemorrhage. All of the children were kept on maintenance therapy with azathioprine (2–2.5 mg · kg−1 · day−1) after surgery. Patients’ characteristics, weight, height, haemoglobin, and albumin were reviewed from inpatient and outpatient records. All of the patients had weight, height, haemoglobin, and albumin recorded before surgery, 6 months and 1 year after surgery. Weight and height were measured by standard balance scales and a wall-mounted stadiometer, respectively. Body mass index (BMI) and weight and height SD scores were calculated for each individual patient and were derived using British 1990 standards (17). Disease activity following surgery was defined by a modified Harvey-Bradshaw index (18). Relapse was confirmed by an index >5. Data, reported as median (range), were compared by Fisher exact test and repeated-measures ANOVA with Tukey post-test.

RESULTS

Surgery for Crohn Disease

During the 10-year period 141 children, ages 12.7 years (3.5–16.8), were diagnosed as having CD. During this period, 27 (19%) children not responding to medical therapy required surgery at 14.3 years (5.0–16.4). Time from diagnosis to surgery was 14.5 months (1.1–61.8). Twenty-one had elective surgery based on clinical, endoscopic, and radiological findings. Indications for surgery included symptoms of chronic subacute obstruction (n = 9), steroid dependency (n = 14), steroid-refractory disease, (n = 9), and poor growth (n = 16). Six patients developed an acute abdomen and required emergency surgery for life-threatening conditions. Findings at surgery are reported in Table 1. Median follow-up after surgery was 2.5 years (1–9.4). All of the patients were on maintenance therapy with azathioprine after surgery. Fifteen patients (55%) relapsed with a modified Harvey-Bradshaw index of 8 (6–11). Of these, 5 patients (18%) relapsed within 1 year. Age at relapse was 15.4 years (9.2–16.7). Five patients (18%) required further surgery (2 anastomotic strictures, 2 diseased stomas, and 1 enterocutaneous fistula). The proportion of patients remaining relapse free as a function of time is shown in Figure 1; median time before relapse was 20 months.

T1-6
TABLE 1:
Findings at surgery, type of surgery, and number of relapse after surgery
F1-6
FIGURE 1:
Time to relapse in patients undergoing surgery for refractory Crohn disease.

Growth and Nutrition

Growth, in terms of both height and weight, was poor before surgery, so that weight (P < 0.0001) and height (P < 0.0001) were significantly <0 SD scores (ie, 50th centile) at the time of surgery. Nine (33%) patients had a decrease of more than 0.5 weight SD scores in the 6 months preceding surgery. Following surgery, there was a highly significant increase in both weight and height SD scores compared with those at surgery (Fig. 2A, P < 0.001 for weight SD score at both 6 and 12 months compared with weight SD score at surgery, P < 0.01 at 6 months, P < 0.001 at 12 months for height SD score compared with height SD score at surgery). Thus, there was a highly significant (P < 0.001) increase in both weight and height velocity in the year following surgery; this increase was greatest in the 6 months following surgery (Fig. 2B). BMI was below the 50th centile in 22 (81.5%) of children before surgery and below the 50th centile in 14 (52%) of children 12 months after surgery (P = 0.04). BMI was improved in 20 (74%) children 12 months after surgery. Five of the 7 patients with no improvement 12 months after surgery were among the ones who relapsed, with 3 relapsing within 1 year. Nutrition was also significantly improved following surgery (Fig. 3) as documented by increased albumin (30 [13–36] vs 39 [30–46] vs 40 [33–45], P < 0.0001) and haemoglobin (10 [6.8–13.2] vs 11.7 [8.2–13.7] vs 12.0 [9.3–14.7], P < 0.0001).

F2-6
FIGURE 2:
A, Weight and height SD score 6 months before surgery (−6), at surgery (0), 6 (+6), and 12 months (+12) after surgery. B, Weight and height velocity are also shown for the 6 months preceding surgery, the 6 months immediately following surgery, and between 6 and 12 months following surgery.
F3-6
FIGURE 3:
Levels for haemoglobin and albumin before and after surgery.

DISCUSSION

The results of surgery in children with CD reported in the literature largely date from the 1980s and early 1990s, a period in which immunomodulators were not widely used and biological therapy had not yet begun. The aim of this study was to evaluate the results of surgery in children with CD not responding to modern medical therapy and establish whether surgery improves growth and nutrition.

Several authors have reported that CD in children is associated with significant impairment of growth and nutrition leading to delayed puberty (1–3). Kanof et al (4) reported that 88% of prepubertal children with CD were found to have decreased height velocity before diagnosis. Sawczenko et al (5) recently reported a mean height deficit of −0.5 standard deviations (SDs) at diagnosis with final adult height significantly less than target height in one-fifth of patients. Pfefferkorn et al (19) recently demonstrated that growth abnormalities continue to be present in a large number of children with CD up to 2 years after diagnosis despite the use of immunomodulators. Growth suppression in CD can be due to the combined effects of different factors such as reduced nutritional intake, hormonal and therapeutic influences, and the growth inhibitory effects of the inflammatory process itself (6–10). Surgery may remove areas of chronically inflamed intestine causing growth-inhibitory effects and improve absorption of nutrients following removal of strictures, and it is generally accepted that it is indicated only when there is a failure of medical treatment to induce remission. Results of surgery are encouraging, and several authors have reported good growth response after surgery. Sadoun et al (20) showed that an increase in weight and height velocity occurred in 20 patients with CD who underwent surgery. Puntis et al (12) reported that 55% of children with growth failure treated surgically demonstrated a reversal in growth impairment. Indeed, recent guidelines (21) indicate that surgery is indicated in paediatric patients with stricture or fistula formation and complicated by persistent growth failure despite medical therapy and that the optima time for surgery is thought to be before epiphyseal plates have been closed. If the onset of puberty is delayed beyond age 14 years, then final height may be compromised, and the importance of inducing the remission before the onset of puberty is stressed (1). Similar studies also confirm that surgical intervention leads to benefits in growth in children particularly when surgery is performed before puberty (14). In our study we found that nutrition was significantly improved following surgery as documented by increased albumin (P < 0.0001) and haemoglobin (P < 0.0001). We also found that there was a significant increase in weight z score (P < 0.0001) and height z score (P < 0.0001). Benner et al (22) reported that of 26 patients who underwent bowel resection for CD, 22 were below the third centile for weight preoperatively, and more than 60% subsequently gained weight postoperatively. In our study 74% of children demonstrated an improvement in BMI by 12 months after surgery, with the majority of children experiencing no BMI improvement 12 months after surgery being the ones who relapsed within 1 year. This finding is similar to that previously reported by Homer et al (11) that catch-up growth occurs only in those children in whom there is no early recurrence, and by Lipson et al (13) that height velocities increased significantly 6 and 12 months after surgery. The relapse rate in our population is 55%, with a median time before relapse of 20 months and 18% of patients relapsing within 1 year. All of the patients were on maintenance therapy with azathioprine after surgery. Some authors (23) have reported a low recurrence rate following surgery, but many authors have reported results similar to our data with a recurrence rate of 30% to 50%, with most recurrences occurring within 2 years of the initial resection (11,24). This disease-free interval after surgery, in our experience, is associated with improved nutrition and growth and may be important for pubertal development. Davies et al (24) reported that outcome after surgery for CD in children is mainly related to disease location, but is influenced by the type of primary operation performed. In this study anatomical location of disease, indication for surgery, and preoperative duration of symptomatic disease were the only factors that significantly influenced the duration of the recurrence-free interval. Patients with diffuse ileocolonic inflammation experienced earlier recurrence (50% at 1 year) than children with predominantly small bowel disease. Furthermore, failure of medical therapy independent of disease location as the sole indication for surgery was associated with an earlier relapse than when surgery was performed for a specific intestinal complication such as abscess or obstruction. In our study based on the localization of the disease, it was not possible to adequately assess whether there was a significant difference in growth between patients who underwent ileocaecal resection and those who underwent strictureplasty due to the limitations of sample size.

In conclusion, our study indicates that growth and nutrition significantly improve following surgery for CD. The relapse rate remains high, up to 55% following surgery, even with the modern medical therapy. The majority of children relapse more than 1 year after surgery, and this disease-free interval may provide an important time for improved growth and pubertal development and justify surgery in children not responding to medications.

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Keywords:

Crohn disease; growth; nutrition; outcome; puberty; relapse

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