NASPGHAN Clinical Report on the Evaluation and Treatment of Pediatric Patients With Internal Penetrating Crohn Disease

Abstract

OVERVIEW Natural History of Pediatric Crohn Disease The natural history of pediatric Crohn disease (CD) remains unpredictable, although some trends are observed that differentiate children from adults. Pediatric CD often presents with more severe disease and more frequent need for immunosuppressive therapy (1). Growth failure, present in 15% to 20% of patients, is a unique characteristic of pediatric CD not seen in adult-onset CD (2). Colonic disease distribution is common in patients younger than 10 years (1). The need for surgical intervention also varies, with 1 study reporting the actuarial risk of having undergone an extensive intestinal resection being 48.6% ± 5% in a childhood-onset group versus 14.6% ± 2% in the adult-onset group (P < 0.001) (1). More recently, long-term follow-up of patients enrolled in pediatric registries shows a cumulative surgical rate of 14% to 17% at 5 years and 28% at 10 years (3,4). Pathogenesis of Internal Penetrating Disease in CD The postoperative evolution of recurrent CD is a helpful model to understand the pathogenesis of internal penetrating CD (5,6). In this model, a primary focal inflammatory infiltrate forms in the ileum proximal to the anastomosis. Aphthous ulcers may appear within 3 months of the operation. The superficial ulcers may evolve into deeper and more extensive transmural lesions. Transmural inflammation can progress to the formation of an inflammatory mass, or phlegmon, adjacent to the affected loop of bowel. A phlegmon is an acute suppurative inflammation of the subcutaneous tissue. The phlegmon may undergo liquefaction necrosis, resulting in an abscess, which is a circumscribed collection of pus. The tissue destruction involved in an enlarging abscess may lead to fistula formation. A fistula is an abnormal passage or tract resulting from a break in the integrity, or perforation, of the bowel wall, which then allows leakage of intestinal contents into the peritoneum or another adjacent organ. Deep ulceration and transmural inflammation may be followed by the formation of a stricture (7). Symptoms often are delayed for 2 to 3 years after the development of inflammatory lesions. These data indicate that the main risk factors for fistula formation appear to be severe luminal disease, ileal disease, and the presence of strictures. Perianal disease is related to perianal glands and is beyond the scope of this report. One of the special features of the ileum is the abundant lymphoid tissue in the Peyer patch. Patients with CD have been reported to have defects in the follicle-associated epithelium and an increase in the adherence of commensal bacteria (8). Adherent-invasive Escherichia coli bind to CEACAM6 on the gut mucosa and replicate in epithelial cells and macrophages and stimulate production of tumor necrosis factor (TNF) (9). The outer membrane porin molecule, pili, and flagella play a role in adherence, and these interactions may explain the presence of antibodies to these molecules as markers in CD (10). NOD2, a genetic marker for stricturing ileal disease, is a key sensor for intracellular bacteria (11). Recent evidence shows that NOD2 and the autophagy gene, also associated with CD, form a complex at the cytoplasmic membrane (12). Recognition of muramyl peptidase by NOD2 induces autophagy and bacterial clearance. Defects in autophagy prevent the killing of intracellular bacteria. Bacteria proliferate in epithelial cells, macrophages, and dendritic cells, which may provide the breach in the mucosa necessary for the start of an abscess or fistula. Opportunistic bacteria may then follow. The production of metalloproteases by these opportunistic bacteria, such as Clostridium perfringens, degrades basement membrane type IV collagen and the extracellular matrix, resulting in further tissue destruction (13). Morphologic studies show that internal fistulae from patients with CD have a lining of flattened intestinal epithelium without goblet cells (14). Nonepithelialized fistulae have a layer of myofibroblasts forming a new basement membrane. All fistulas are surrounded by granulation tissue and, in CD, inflammatory cells including memory T cells, B cells, and macrophages. This lining may prevent further invasion and dissemination, but it may also prevent complete healing without operative removal of the fistula tract. Risk Factors for Developing Complicated CD Longitudinal registry data show that children diagnosed between the ages of 13 and 16 years have an increased risk of bowel surgery compared with younger children (4). These surgeries included bowel resection, ostomy, strictureplasty, and appendectomy. The disease extent at baseline was associated with the occurrence of intestinal complications. Relative to a patient with colonic disease, a patient with isolated terminal ileal disease or ileocolonic disease was at a higher risk (6- to 9-fold) of developing stricturing or penetrating disease (15). The cumulative incidence at 5 years of stricturing or penetrating complications was 27% of 989 pediatric patients and complicated disease was lowest in isolated colonic disease (16). Children with esophageal involvement compared with children with nonesophageal CD had greater disease severity (Pediatric Crohn Disease Activity Index of 40 vs 24, respectively, P < 0.001) and more penetrating disease behavior (12% vs 2% respectively, P = 0.001) and greater frequency of perianal disease (51% vs 33% respectively, P = 0.005) at diagnosis (17). In comparing 270 cases with and without fistulas, cases with fistulas tended to have more intraabdominal abscesses (P = 0.044), more frequent operations for perianal fistulae and abscesses (P = 0.001) as well as a higher incidence of combined small bowel and colonic disease (18). In a study of serologic markers in 196 pediatric patients with CD, 28% developed internal penetrating and/or stricturing disease. The odds of developing internal penetrating/stricturing disease were highest in patients who were positive for all 4 immune responses (odds ratio 11, 95% confidence interval [CI] 1.5–80, P = 0.03). Patients positive for ≥1 immune response progressed to internal penetrating/stricturing disease soon after diagnosis as compared with those negative for all immune responses (P < 0.03) (19). Mutations in the NOD2 gene have been associated with ileal disease location and fibrostenotic behavior, but not penetrating disease behavior. EVALUATION Clinical Presentation: History and Physical Examination The commonly reported presenting symptoms and findings of internal penetrating disease include abdominal pain (84%), fever (49%), nausea and vomiting (41%), diarrhea (25%), and fistula (14%) (20). An abscess may present subacutely or with acute onset of abdominal pain and sepsis. Occasionally, there may be signs and symptoms of partial bowel obstruction, including colicky pain, abdominal distension, vomiting, and intermittent constipation (21). The right lower quadrant, specifically the ileocecal area, is the most common site of the abscess, with the pelvis being the next most common (22). Urinary symptoms may be present if the abscess is adjacent to the bladder. Refusal to walk may indicate irritation of the psoas muscles from the inflammatory process surrounding ileal disease. There can be shortness of breath and abdominal or shoulder pain with deep breathing when there is irritation of the diaphragm. Physical examination may reveal localized tenderness and possibly a mass. There may be peritoneal signs, suggested by rebound tenderness. An abscess resulting from ileal disease may be difficult to distinguish from appendicitis or a ruptured appendix with abscess, with pain in the right lower quadrant and psoas signs, including pain with heel tap or straight leg raise. On rectal examination, there may be a warm, tender bulge into the rectum if the abscess is in the pelvis. With either abscess or fistula, there may be additional signs of active CD, including weight loss, poor growth or development, oral aphthous ulcers, erythema nodosum, arthritis, or perianal signs such as tags, fissures, or perianal fistula. Laboratory Evaluation Laboratory investigation should include a complete blood cell count with differential white blood cell count to look for signs of inflammation, anemia, and thrombocytosis. Erythrocyte sedimentation rate and C-reactive protein can be useful, especially when recent values can be compared. Measurement of the serum albumin level may be helpful to support a diagnosis of protein wasting or chronic malnutrition. In the patient with abdominal pain and vomiting, liver and pancreatic function tests should be evaluated as well. A urinalysis should be obtained if there is dysuria, urinary frequency, or pneumaturia. Blood and urine cultures should be obtained in an acutely ill patient with fever. Radiologic Evaluation Cross-sectional imaging plays an important role in patients suspected to have complicated CD. When complicated CD is suspected in the acute setting of an intraabdominal abscess, both ultrasonography (US) or computed tomography (CT) can be used as the initial imaging evaluation. US has the inherent advantage of imaging without the use of ionizing radiation, but is relatively operator dependent. CT is readily available and frequently used in the acute setting when US does not answer the clinical question. CT can readily demonstrate bowel wall thickening, bowel dilation, and mesenteric fat proliferation, and unlike US, CT is not limited by bowel gas. Magnetic resonance (MR) and CT enterography carry the added value of identifying the presence of a fistula that may be feeding into the intraabdominal abscess. The sensitivities of CT enterography (83%–95%) and MR enterography (90%–100%) are comparable with the small bowel follow-through (65%–90%) in the detection of active small bowel disease but are more sensitive for the detection of extraenteric complications involving the solid organs (23). CT enterography and MR enterography have similar sensitivity rates in the evaluation of active disease, with CT having a slight advantage in the evaluation of bowel wall enhancement because of less artifact from peristalsis (24). Expertise in CT enterography may be more readily accessible than MR enterography, but the latter is the preferred modality when available. Because of the increased risks of ionizing radiation in patients with CD, and the potential for this patient population to be exposed to a large number of imaging studies during the course of their lifetime, MR enterography is frequently the imaging modality of choice. Ultrasonography or MR imaging should be used to follow-up a previously identified abscess to avoid additional radiation exposure (24–26). Endoscopy Few studies in the literature define the role of endoscopy in fistulizing CD. Endoscopy may be necessary to further characterize disease extent and severity, to evaluate possible infectious complications of immunosuppression (cytomegalovirus, Clostridium difficile), and to facilitate therapeutic decision making, especially in light of impending surgical intervention. The optimal timing for performing colonoscopy following treatment of an intraabdominal abscess is also unclear, although some clinicians recommend waiting 4 to 6 weeks (27). Infectious Disease Evaluation Empiric antibiotics should be initiated in the presence of an intraabdominal abscess, and abscess drainage for both therapeutic and diagnostic purposes should be pursued to allow specific antimicrobial coverage. Aerobic and anaerobic cultures of blood and abscess fluid should be sent, with at least 1 mL of fluid for reasonable culture yield. Culture yield can be increased with larger samples. Abscess fluid should be placed in clearly labeled blood culture bottles and sent to the microbiology laboratory immediately. Yeast (Candida) will grow in a routine blood culture, so dedicated fungal cultures are not necessary under most circumstances. TREATMENT Medications Antimicrobials Initial Choice of Antimicrobials Recently updated guidelines published jointly by the Surgical Infection Society and the Infectious Diseases Society of America are helpful in the management of abdominal infections, including in the setting of CD, and should be followed (28). Most patients with CD with an abdominal abscess will have had multiple experiences with the health services system and should be classified as health care associated; hence, coverage for potential nosocomial organisms (Gram-negative aerobic and facultative bacilli: Pseudomonas aeruginosa, Enterobacter species, Klebsiella species), in addition to community-acquired pathogens (coliforms and anaerobes: Escherichia coli, Enterococcus species, Bacteroides species, Peptostreptococcus species), should be provided initially. Initial empiric antibiotics should be selected from one of the accepted broad-spectrum intravenous regimens: a carbapenem (imipenem, meropenem, or ertapenem), a β-lactam/β-lactamase-inhibitor combination (piperacillin-tazobactam or ticarcillin-clavulanate), or an advanced-generation cephalosporin (ceftazidime, cefepime) with metronidazole (28) (Table 1). Enterococcal species (eg, Enterococcus faecalis) are the most susceptible to the penicillins and vancomycin. Vancomycin should be used empirically if the patient has had recent cephalosporin exposure, a history of previous infection, or colonization with enterococcal organisms (28). Drainage with aerobic and anaerobic cultures of the abscess material should be attempted and antibiotics tailored when culture and susceptibility reports become available. Generally, aggressive therapy for methicillin-resistant Staphylococcus aureus, enterococcus, or fungus should be prompted only by a positive culture, methicillin-resistant S aureus colonization, or a previous infection. Fluoroquinolones should only be used if of coli are a or with therapy should be if there is a frequency of to or at the initial for treatment of pediatric Crohn intraabdominal of Antimicrobials therapy is reasonable to in the of pain, to oral and to (28). The oral used be active all oral include a or cephalosporin combined with or if the isolated organisms are A or may be used to susceptible and species (28). or is metronidazole should be A accepted is to for more to can on so be used with and with follow-up of the clinical When are the for the this should be and with the the small potential for or should but should not prevent the from the antibiotics In patients younger than the risk of or was not in those who and 95% compared with those who 95% the incidence of these in children of of antimicrobial therapy is for in which complete or drainage is (28). In most cases of abdominal abscess in the setting of CD, is difficult to An abdominal abscess in the setting of CD be complete has been by an imaging a abscess, antibiotics should be for at least 3 to of the abdominal pain and intestinal with response to A course of with should be if clinical is not seen within 3 to 5 of therapy (27). There are data that are in the treatment of internal penetrating CD. the most these are for the management of active bowel disease. There are studies the use of for Crohn fistula. should be in fistulizing disease because of an increased risk of abscess In patients who are therapy at the of abscess there does not to be additional in therapy for as as the abscess is although one should to the to but not the to avoid the increased risk of complications should a surgical intervention be necessary Pediatric studies have the of and in in pediatric CD studies in show that at least of fistulas complete or partial with is necessary to fistula studies in show that intravenous is in fistula but will not response the In the of clinical may be in the acute setting of an abdominal abscess in are often with the of to or therapy in the setting of an intraabdominal abscess. A of patients with opportunistic that most opportunistic from immunosuppressive used for inflammatory bowel disease were from or pathogens a response for The study data were to abscess development was affected by exposure of the patients in the group compared with patients in the group developed at least 1 new abscess (P = that does not in increased abscess development in fistulizing CD. In there was increase in postoperative abdominal abscesses observed after surgery patients were on and the suggested that there may be a in the setting of an acute abdominal abscess been that be in the setting of treatment of an active abscess that immunosuppressive therapy can be soon after drainage of the abscess (27). This so that can be in the pediatric has been to be in the treatment of CD or fistula in There are studies the of for internal A the of in 5 children with CD and fistulas, 3 of were and 2 surgical resection abscess drainage was in patients with CD because of the of a fistula. studies indicate that is an treatment for intraabdominal abscesses in CD. abscesses well to with rates to and lower rates for complex abscesses and postoperative can be in the patient should be as initial therapy in in a although can be used for to a for Most abdominal abscesses will US abscesses in the pelvis will CT or a combined with US and A is commonly used in which the fluid collection is with an A fluid is obtained followed by of a tract dilation, a is The is to the with and to with is and When to in and the patient is the can be there is then an is with to evaluate for the presence of a fistula. In some with therapy may avoid the need for surgical intervention in the acute especially when a fistula is not with drainage bowel and have been used to fistulae with in the of with drainage in addition to intravenous and bowel may in of the fistula, the need for surgery in the acute This management has to some patients operations in the for as as the fistula remains and the active Crohn inflammation is the fistula having the in the advantage of less intraabdominal inflammation and as well as of the of the patient to allow for surgical removal of the of bowel. intervention is necessary when therapy Surgical Abscess One in fistulizing CD is or the of the abscess. drainage of the abscess with antimicrobial in for the of treatment and recurrent reports in have a higher long-term rate when fistulae are intervention is for an abscess that is to a combination of and CD and of and are for abdominal A to operative management of an intraabdominal abscess is to the infectious which can be with the use of broad-spectrum antibiotics and is to the of with treatment of the associated abscess and inflammatory can The interval between and surgical resection of bowel from to and may from to weeks after initial the in the surgical management of CD is of intestinal In the of or fistulas, the primary is of the fistula with limited intestinal In of colonic is less than of small bowel. In either resection are the in abdominal surgery has been the use of The of include postoperative risk of formation of intraabdominal and in pediatric patients to be a and reasonable to the complications of CD in the surgical patient who of the with a necessary in or is necessary but is in the following intraabdominal with colonic perforation, inflammatory of intestinal wall, and additional operative to an anastomosis. risk factors for complications should be identified and The most commonly risk factors are the use of and The presence of either the risk for and infectious complications should be to the as as the patient will with a of Patients who were a higher were at least more to an abscess. of is related to disease with luminal and/or can be used to facilitate the as well as in the setting of inflammatory luminal and reports also that some patients may be with complete of the intraabdominal abscess without need for further surgery (27). 16 patients with intraabdominal abscesses that were patients not have of the abscess during a follow-up of months for the study group A recent of 13 patients with a phlegmon, of had an associated abscess, were with a combination of antibiotics and 2 of these patients following of of an intraabdominal abscess with present therapy to an than the larger studies with data are but it that some intraabdominal abscesses may to management without need for intestinal An important to in children is that management of their may avoid long-term to their in the form of need for or chronic or is unclear, at this the of of a of involved in penetrating CD chronic of development in management of the and abscess with resection of the in a to and more of should be including to of disease and of serum and should be to bowel the abscess is the abscess has been and to not a of feeding is and often The presence of an fistula is another for bowel a patient with an fistula will increase the the fistula. should be the clinical is with of the fistula. A is an to be with and can be at a lower as an In the of of should be used and should be in a of abscess in pediatric CD at the be with of should be used for abscesses that be An abscess is to In the setting of clinical and a in to the is and the patient is to complete the antimicrobial with to for in 1 to 2 of clinical 3 to 5 following should of the abscess. of the abscess will surgical drainage with resection of the affected intestinal 1). should be to a of of therapy of CD should be and may include of therapy to the severe intestinal inflammation or fistula that initiated the intraabdominal abscess. that immunosuppressive therapy can be soon after drainage of abscess to healing of the bowel and prevent abscess for initial management of intraabdominal abscess in pediatric Crohn disease. = abscess surgical management of the abscess and intestinal should be used when small bowel or intraabdominal in of the with complicated CD to to growth and The and for their and for in the of this