Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 5-4

Sixteen-Year-Old Girl

MEGAN AYLOR

HISTORY OF PRESENT ILLNESS

A 16-year-old girl was admitted with joint pain and a 35 pound weight loss during the preceding 7 months. After completion of her gymnastics season 7 months prior to admission, the patient had noted decreased energy and stiff, slightly swollen peripheral joints bilaterally, including her elbows, wrists, knees, and ankles. She was diagnosed with juvenile rheumatoid arthritis and treated with naproxen, a nonsteroidal antiinflammatory drug (NSAID). Her pain improved slightly. Shortly after starting naproxen, she began having daily episodes of epistaxis that required 4-5 facial tissues to control the bleeding. Five months prior to admission she changed from naproxen to ibuprofen without significant change in the degree of joint pain.

Three months prior to admission she noticed a change in her bowel habits from two to three stools per week to daily stools that were frequently mixed with blood. One month prior to admission she developed intermittent cramping abdominal pain. She continued to have episodes of epistaxis and was treated with fluticasone nasal spray and an oral antihistamine for presumed allergic rhinosinusitis. Her weight decreased from 148 to 113 pounds. She complained of decreased appetite and activity level over the preceding few months. There were no fevers, flank tenderness, dysuria, urgency, or frequency. There was no change in mood or intentional weight loss. There was no change in her menstrual cycle. She had not traveled recently.

MEDICAL HISTORY

She had not previously required hospitalization. Menarche occurred at 11 years of age. Her periods were regular. There were no other medical problems. Her only medications were ibuprofen, fluticasone nasal spray, and oral antihistamines as previously mentioned. There was a family history of hypertension in older relatives.

PHYSICAL EXAMINATION

T 35.8°C; RR 18/min; HR 93 bpm; BP 123/66 mmHg

Weight 40 kg; Height 162 cm (50th percentile); Weight-for-height <5th percentile

Physical examination revealed a thin girl. Her palpebral conjunctivae were slightly pale. There were several superficial but actively bleeding erosions on the left medial nasal septum. There were no oral ulcers. Heart and lung sounds were normal. The abdomen was soft with mild right lower quadrant tenderness to palpation. There were no peritoneal signs. Bright red blood mixed with stool was detected on rectal examination. There was a small left knee effusion and bilateral ankle effusions. All joints had a normal range of motion.

DIAGNOSTIC STUDIES

Complete blood count revealed 8900 white blood cells/mm3; a hemoglobin of 9.6 mg/dL; and 463 000 platelets/mm3. Mean corpuscular volume was 70 fL. The reticulocyte count was 1.5%. Erythrocyte sedimentation rate (ESR) was 89 mm/h. Prothrombin time, partial thromboplastin time, and serum transaminases were normal. Serum albumin was 3.0 mg/dL. Urine pregnancy test was negative. There were no red blood cells or white blood cells on urinalysis. Stool was sent for bacterial culture, ova and parasite examination, and Clostridium difficile toxin detection. Abdominal radiograph revealed stool in the rectal vault.

COURSE OF ILLNESS

Upper gastrointestinal barium study with small bowel follow–through of contrast revealed the diagnosis (Figure 5-5).

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FIGURE 5-5. Upper gastrointestinal barium study with small bowel follow–through of contrast.

DISCUSSION CASE 5-4

DIFFERENTIAL DIAGNOSIS

In an adolescent, hematochezia with cramping abdominal pain has several potential causes. Patients with chronic NSAID use may develop gastrointestinal (GI) tract ulceration, though gastric and duodenal ulcers typically present with melena rather than bright red blood. Infectious enterocolitis may be caused by Salmonella species, Shigella species, Campylobacter jejuni, enteroinvasive and enterohemorrhagic Escherichia coli (including E. coli O157:H7), Yersinia entrocolitica, and Clostridium difficile. Parasitic causes include Entamoeba histolyticaCryptosporidium parvumSchistosoma, and Strongyloides stercoralis. Exposure to undercooked meat and clusters of patients with similar symptoms suggest a common infectious source. The absence of pertinent travel history makes some of the parasitic diseases less likely. Proctitis can be caused by Neisseria gonorrhoeae, herpes simplex virus, and Treponema pallidum. Henoch-Schönlein purpura (HSP) may present with bloody diarrhea. Vascular malformations of the GI tract often present with recurrent melena or hematochezia. Eosinophilic gastroenteropathy, a chronic, relapsing disorder characterized by eosinophilic inflammatory GI tract infiltrate, often manifests with abdominal pain and rectal bleeding. Abdominal complaints, including abdominal pain due to ileocecal ulcerations, are seen in up to 15% of patients with Behçet disease. Both Crohn disease and ulcerative colitis commonly present with abdominal pain and lower GI bleeding.

Joint involvement occurs in some of the abovementioned conditions. Reactive arthritis can be associated with Campylobacter enteritis as well as with SalmonellaShigella, and Yersinia enteritis. However, arthritis usually begins 1-6 weeks after the onset of diarrhea and resolves within 3 weeks. Arthritis or arthralgias occur in 65%-85% of children with HSP. Although HSP may recur, prolonged, unremitting symptoms without rash or nephritis are unusual. Children with Behçet disease usually have recurrent oral ulcers, genital ulcers, and iritis or uveitis in addition to the joint findings. Arthritis may be seen in 10%-15% of children with Crohn disease and ulcerative colitis.

DIAGNOSIS

During the GI barium study, contrast pursued a normal course through the duodenum, jejunum, and proximal ileum. However, only a thin line of barium connected the ileum to the cecum (Kantor string sign) indicating significant terminal ileal edema (Figure 5-5). Severe mucosal irregularity was noted in the distal ileum and ascending colon. These radiologic findings combined with bloody stool, arthritis, nasal ulceration, anemia, and elevated ESR strongly suggested Crohn disease. Colonoscopy revealed linear ulcerations and luminal edema in the ascending colon. She was treated with oral sulfasalazine, intravenous methylprednisolone, bowel rest, and parenteral nutrition support. Her symptoms improved during the course of 1 week. Three months later her weight had increased to 140 pounds.

INCIDENCE AND EPIDEMIOLOGY OF CROHN DISEASE

Crohn disease, a major form of inflammatory bowel disease (IBD), can segmentally involve any part of the GI tract from the esophagus to the colon. The inflammation involves the terminal portion of the ileum in approximately 90% of cases. Inflammation occurs in the ileum and colon together in 60% of cases, while the upper portion of the GI tract is involved in approximately 30% of cases. In contrast, inflammation in ulcerative colitis is continuous, beginning in the rectum and extending into the colon, while sparing more proximal portions of the GI tract. Isolated colonic involvement occurs in 10% of cases of Crohn disease, making distinction from ulcerative colitis difficult in some cases.

The prevalence of Crohn disease in North America ranges from 26 to 198 cases per 100 000 persons, with higher rates occurring in the northern latitudes. Crohn disease is most common among Caucasians and least common among Hispanics and Asian-Americans. Peak incidence occurs in young adulthood and a second smaller peak occurs during the sixth decade of life. Approximately 15% of patients with Crohn disease are diagnosed during childhood. The mean age of diagnosis in pediatric patients is 12.5 years. The etiology of Crohn disease, though not known, is likely a combination of environmental, genetic, and immunoregulatory factors. Up to 25% of patients with Crohn disease have a first-degree relative with IBD.

CLINICAL PRESENTATION

Approximately 80% of children present with abdominal pain, diarrhea, anorexia, and weight loss with or without extraintestinal manifestations. Recurrent oral ulcers are common. Abdominal pain in the right lower quadrant suggests ileocecal involvement, epigastric pain suggests gastroduodenal involvement, and periumbilical pain suggests generalized small bowel disease. Fifty percent of children will have gross or microscopic blood in the stool. Perirectal diseases such as fissures, fistulas, skin tags, and abscesses are present in up to 40% of patients.

Extraintestinal manifestations predominate in 8% to 10% of patients and are likely to be associated with diagnostic confusion and delay (Table 5-5). While more than 100 localized extraintestinal manifestions have been described, only the more common ones will be discussed. Joint complaints, including arthritis, are the most frequent extraintestinal manifestation in children occurring in 15%-30% of cases. Approximately 50% of children with Crohn disease and peripheral arthritis develop ocular or skin findings (Table 5-5). Sclerosing cholangitis develops in 1% of children with Crohn disease. Symptoms of sclerosing cholangitis include jaundice, generalized pruritis, and abdominal pain. Pancreatitis can occur as both an extraintestinal manifestation of Crohn disease, and a complication of duodenal inflammation, sclerosing cholangitis, or drug therapy. Renal stones complicating Crohn disease may be due to calcium oxalate, calcium phosphate, or uric acid. Erythema nodosum tends to occur when intestinal disease is active but does not correlate with disease severity. Rashes due to trace mineral deficiencies may occur as a consequence of malabsorption.

TABLE 5-5. Extraintestinal manifestations of Crohn disease.

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DIAGNOSTIC APPROACH

Initial screening tests should include a complete blood count, ESR, liver function tests, and stool testing for blood, bacteria, and parasites. The results of the initial screening determine the need for further testing.

Complete blood count. Anemia is present in 40%-70% of cases. Mean corpuscular volume may be low due to the combination of iron deficiency and chronic inflammation. Vitamin B12 and folate deficiencies also contribute to anemia. The white blood cell count is typically normal. Thrombocytosis occurs in more than half the cases.

Acute phase reactants. C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) are elevated in most cases but a normal CRP or ESR does not preclude the diagnosis of Crohn disease.

Hepatic function tests. Serum transaminases and gamma-glutamyltransferase (GGT) may be mildly elevated in the absence of complications. Crohn-related complications, such as sclerosing cholangitis and chronic active hepatitis, lead to more significant elevation of the transaminases and GGT. Hypoalbuminemia reflects compromised nutritional status and diffuse inflammation.

Stool studies. Stool bacterial culture, ova, and parasite examination, and C. difficile detection should be performed in all children with bloody diarrhea and suspected Crohn disease to exclude other causes. Stool calprotectin and lactoferrin are nonspecific markers of inflammation that can help distinguish Crohn from noninflammatory illnesses such as irritable bowel syndrome.

Endoscopic evaluation. Endoscopic evaluation of the colon is the gold standard for diagnosis and should precede barium radiography in the presence of bloody diarrhea. Colonic mucosa biopsy, even if the mucosa appears normal, is required since microscopic inflammation with granuloma formation may be present. If possible, the examination should extend to the terminal ileum. Esophagogastroduodenoscopy may be required to assess upper GI tract symptoms. Video capsule endoscopy is increasingly being used to evaluate the small bowel of older children and adults. In a meta-analysis of adult patients with Crohn disease, the yield of capsule endoscopy was 63% compared with a yield of 46% for colonoscopy with ileoscopy, and 23% for small bowel barium radiography. Across all studies, the number needed to test with capsule endoscopy was three to yield one additional diagnosis of Crohn disease over small bowel barium radiography and seven to yield one additional diagnosis over colonoscopy with ileoscopy.

Upper GI tract barium study with small bowel follow through. This study is important early in the evaluation since the terminal ileum is involved in 90% of patients with Crohn disease. Features suggestive of Crohn include terminal ileal thickening (Kantor string sign), nodularity, ulcers, and fistulous connections.

Other studies. Serologic testing for inflammatory bowel disease may help differentiate Crohn disease from ulcerative colitis; however, these tests are not recommended as screening tests for inflammatory bowel disease. Serologic tests include anti-IgA and anti I-gG to Saccharomyces cerevisiae (Crohn disease) and perinuclear antineutrophil cytoplasmic antibody (p-ANCA; ulcerative colitis). Biomarkers such as fecal calprotectin show promise as screening tools. The following additional studies may be useful in assessing the patient’s nutritional status: folic acid, vitamin B12, fat-soluble vitamins (especially vitamin D), prothrombin time, partial thromboplastin time, zinc, iron, total iron-binding capacity, calcium, magnesium, phosphorus, and prealbumin.

TREATMENT

Therapeutic strategies include a combination of medical and surgical interventions. Medical therapy includes corticosteroids, 5-aminosalicylates, immunomodulators, and antibiotics. Corticosteroids are the mainstay of treatment for moderate to severe symptoms of Crohn disease. They exert antiinflammatory effects by decreasing cytokine release, capillary permeability, and neutrophil and monocyte function. Newer corticosteroids have a strong affinity for intestinal steroid receptors leading to high topical antiinflammatory potency. Since they are rapidly transformed into inactivated metabolites by the liver following absorption, they cause fewer systemic side effects. For example, budesonide binds to intestinal receptors 15 times more efficiently than prednisolone but undergoes rapid hepatic metabolism and hence systemic bioavailability is only 10% compared with 80% for prednisolone. Delayed-release (time- and pH-dependent) formulations of budesonide permit more effective delivery of the drug to the terminal ileum and proximal colon.

Oral sulfasalazine consists of 5-aminosalicylic acid (5-ASA) bound to sulfapyridine. The sulfa moiety functions as a carrier, facilitating delivery of the agent to the colon where it is cleaved by resident bacteria into therapeutically active 5-ASA. The 5-ASA decreases colon inflammation by inhibiting leukotriene synthesis via the lipoxygenase pathway of arachidonic acid metabolism. It also decreases neutrophil-mediated tissue damage by interfering with myeloperoxidase activity and scavenging reactive oxygen species. Newer oral 5-ASA analogues (e.g., mesalamine) function by either pH-dependent or timed-release mechanisms that allow the drug to be distributed throughout the small bowel.

Immunomodulators are becoming the standard of care in the management of Crohn disease. Azathioprine and 6-mercaptopurine interfere with purine synthesis and are used to maintain remission; however, their maximum effect is not realized for up to 6 months. Methotrexate is a second-line immunomodulator for refractory patients.

Biologic therapies are useful in the management of moderate to severe Crohn disease. Tumor necrosis factor-alpha (TNF-alpha), a cytokine, activates components of the immune system involved in Crohn disease. Infliximab, a chimeric (mouse-human) anti-TNF-alpha IgG antibody, binds to TNF-alpha and neutralizes its activity. Infliximab infusions administered at 4-12 week intervals induce remissions in patients with moderate to severe Crohn disease and facilitate healing of fistulas. Infliximab also permits significant reduction in steroid use in children.

Protein-calorie malnutrition is common. Nutritional support will help the patient maintain functional status and mitigate the loss of lean tissue. Elemental formula can itself help decrease bowel inflammation. The antibiotic metronidazole may reduce Crohn disease activity and is used to treat perianal fistulas and abscesses. Surgical intervention may be indicated for intractable disease, severe fistula formation, uncontrolled hemorrhage, and bowel perforation. More than 50% of children with Crohn’s disease will require intestinal surgery within 10-15 years of diagnosis. The disease is not usually limited to one portion of the GI tract so surgery is not curative. Recurrent disease after bowel resection is common.

The course of Crohn disease is characterized by periods of symptom exacerbation and remission. Only 1% of children with well-documented Crohn disease will have no relapses after diagnosis and initial therapy. Many children with Crohn disease also suffer from medication- and central venous catheter-related complications. In the long term, impaired height velocity is common. Approximately 8% of patients with severe Crohn disease will develop colorectal cancer. Death from Crohn disease in childhood is rare; however, the risk of death is 1.5 times higher in affected adults compared with age-matched controls.

SUGGESTED READINGS

1. Di Nardo G, Alio M, Oliva S, Civitelli F, Casciani E, Cucchiara S. Investigation of the small bowel in pediatric Crohn’s disease. Inflamm Bowel Dis. 2012;18:1760-1776.

2. Hyams JS. Inflammatory bowel disease. Pediatr Rev. 2000;21:291-295.

3. Hyams JS. Extraintestinal manifestations of inflammatory bowel disease in children. J Pediatr Gastroenterol Nutr. 1994;19:7-21.

4. Hyams JS. Inflammatory bowel disease. In: Altschuler SM, Liacouras CA, eds. Clinical Pediatric Gastroenterology. Philadelphia: Churchill Livingstone; 1998:213-221.

5. Mamula P, Telega GW, Markowitz JE, et al. Inflammatory bowel disease in children 5 years of age and younger. Am J Gastroenterol. 2002;97:2005-2010.

6. Stephens MC, Shepanski MA, Mamula P, Markowitz JE, Brown KA, Baldassano RN. Safety and steroid-sparing experience using infliximab for Crohn’s disease at a pediatric inflammatory bowel disease center. Am J Gastroenterol. 2003;98:104-111.

7. Thomas DW, Sinatra FR. Screening laboratory tests for Crohn’s disease. West J Med. 1989;150:163-164.

8. Triester SL, Leighton JA, Leontiadis GI, et al. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with nonstricturing small bowel Crohn’s disease. Am J Gastroenterol. 2006;101:954-964.

9. Glick SR, Carvalho RS. Inflammatory bowel disease. Pediatr Rev. 2011;32:14-25.