Variation in Care
Variation in diagnostic interventions is shown in Table 3. Diagnostic interventions in which there was little or no variation were a complete blood count, erythrocyte sedimentation rate, colonoscopy with biopsy, and esophagogastroduodenoscopy with biopsy. In contrast, diagnostic interventions in which there was substantial variation in care were stool test for pathogens, upper gastrointestinal and small bowel series radiography, and TPMT. Small bowel imaging (with either radiography or CT scan) was not performed in 19% of patients.
When patients were treated with a thiopurine, there was variation in the selection of thiopurine: 70% were treated with 6-mercaptopurine and 30% were treated with azathioprine. Thiopurine methyltransferase was measured in 65% of patients before initiating thiopurine treatment in the thiopurine group and had been measured in 55% of patients in the infliximab group who were receiving thiopurine at the time infliximab treatment was initiated (Table 4). The TPMT was normal in 120 (85%) of those patients tested. Of the 120 patients in whom TPMT was normal, the dose of 6-mercaptopurine was between 0.55 and 2.78 mg/kg/day (31% of patients had a dose <1.0 mg/kg/day); the dose of azathioprine was between 0.85 and 3.45 mg/kg/day (66% had a dose <2.0 mg/kg/day). When the TPMT enzyme activity is normal, the recommended initial dose of 6-mercaptopurine is 1 to 1.5 mg/kg/day, and the recommended initial dose of azathioprine is 2 to 3 mg/kg/day (14,15). Thus, 40% of patients (48/120) were receiving doses of thiopurine that were lower than recommended. In the infliximab group, some of the patients on a maintenance dose may have had a decrease or increase in dose in response to blood concentrations of metabolites or to toxicity.
Screening for tuberculosis with either a skin test or a chest radiograph before starting treatment with infliximab was not performed in 30% of patients. There also appeared to be variation in the initial dose of infliximab. The recommended initial dose of infliximab is 5 mg/kg (14–17). The mean dose was 5.4 mg/kg, the median dose 5.1 mg/kg, and the range was 4.4 to 11.0 mg/kg. The dose was 4.4 to 5.0 mg/kg in 49% of patients, 5.1 to 6.0 mg/kg in 37% of patients, 6.1 to 7.0 mg/kg in 11%, and 10.1 to 11.0 mg/kg in 3%. Infliximab is dispensed in vials of 100 mg, and pediatric gastroenterologists commonly administer the entire contents of any vial used to reach a dose of 5 mg/kg, a practice that would result in a dose greater than 5 mg/kg. Such a practice could account for almost all of the doses above 5.0 mg/kg. Thus, only 3% of patients had an unexplained high dose of infliximab.
However, there was considerable variation in nutritional interventions: 37% of patients in both groups received a multivitamin supplement, 14% a calcium supplement, 4% a vitamin D supplement, 7% a formula supplement, and 4% tube feeding. Forty-seven patients (19%) were severely underweight (weight decreased >10%). Nutritional interventions performed in these patients are shown in Table 5; of note, 36% of patients had not received any of these interventions.
We also measured variation in other diagnostic tests. Liver tests had been performed in 95% of patients in both groups, C-reactive protein in 64%, serological tests for IBD in 36%, bone densitometry in 18%, and ophthalmologic examination in 15%.
The efficacy of 5-aminosalicylic acid medications, although well established in the treatment of ulcerative colitis, is controversial in Crohn disease, and the optimal dosage in pediatric patients is not known. In our study, 60% of the patients in both groups were treated with 5-aminosalicylic acid. The doses of sulfasalazine varied between 26 and 79 mg/kg/day; the doses of a pH 7-dependent mesalamine varied between 21 and 104 mg/kg/day; and the doses of a controlled-release mesalamine varied between 13 and 145 mg/kg/day.
The results of this study indicate there is significant variation in diagnostic and therapeutic care of children and adolescents with Crohn disease. There appears to be variation of certain diagnostic tests, including a stool test for pathogens, imaging of the small intestine, measurement of TPMT before starting treatment with a thiopurine, and testing for tuberculosis before starting treatment with infliximab. Nearly half of the patients starting treatment with a thiopurine (in the thiopurine group) and more than one quarter of patients on maintenance thiopurine (in the infliximab group) were treated with a dose of thiopurine that was less than recommended for initial treatment (14,15). In addition, more than one third of severely underweight patients were not receiving nutritional interventions.
When a test is not performed for a stool pathogen, it increases the risk of an undetected infection or misdiagnosis at onset (18,19). When small bowel imaging is not performed, the extent of disease cannot be delineated and the chance of detecting a stricture or penetrating disease is reduced, potentially leading to incorrect classification of the disease phenotype and suboptimal treatment (18–21). When patients initiating treatment with infliximab are not tested for tuberculosis, it increases the risk of the development of active tuberculous infection (15).
There is widespread recognition of the value of measuring TPMT before initiating treatment with 6-mercaptopurine or azathioprine, including by the Food and Drug Administration (22), by analyses of cost-effectiveness (23,24), by many insurance companies (25), and as part of clinical practice guidelines (14,15). When the TPMT is normal, treatment with 6-mercaptopurine can be initiated with a dose of 1 to 1.5 mg/kg/day, or azathioprine with a dose of 2 to 3 mg/kg/day. Yet only 61% of patients in the 2 groups had measurement of TPMT before thiopurine treatment. Some patients do not have TPMT testing because their medical insurance company will not pay for this test despite its importance. Nonetheless, even when the TPMT was normal, 40% of the patients were treated with a dose of thiopurine that was less than is recommended (14,15). Without receiving adequate doses, patients are significantly less likely to attain or maintain remission (26,27).
In a previous report of variation in the initial management of children with Crohn disease, there was significant variation in the frequency of use of medications, including immunomodulators, antibiotics, 5-aminosalicylates, and infliximab at the 10 centers studied (28). Another study found that adults with IBD referred for a second opinion often were not receiving optimal medical therapy (29). There was suboptimal dosing of immunomodulatory medications, prolonged use of corticosteroids, failure to use steroid-sparing agents, inadequate measures to prevent metabolic bone disease and inadequate screening for colorectal cancer.
This is the first study to report variation of both diagnostic and therapeutic interventions in pediatric IBD care and potential gaps between recommended and actual care. Strengths of this study include the participation of a large number of practice sites, providing a broad representation, and Web-based data entry that facilitated the process of data collection. Limitations of the study include the lack of verification that consecutive patients were recruited; auditing of site records was not performed. Investigation is necessary to determine to what extent a reduction in the variation in care reported here would result in better outcomes. In addition, the paucity of recommendations for standard diagnostic testing and initial evaluation limits the interpretation of the variation in testing for stool pathogens, small bowel imaging, and less commonly performed tests.
The causes of variation in the care provided are likely multifactorial. The absence of an evidence-based pediatric clinical practice guideline from a North American authority could contribute to variation in care. It is likely that the lack of a single, promulgated, widely accepted guideline with recommendations for standard diagnostic testing and initial evaluation, as well as for indications for medications and their proper dosages, is an important factor. The habits and preferences of physicians could be an important factor. Patient preferences and adherence to medication regimens, particularly when influenced by financial concerns, are also important. The refusal of medical insurance companies to pay for necessary testing is a factor. Not all diagnostic tests are necessary in some clinical situations; for example, when Crohn disease is diagnosed by gross and histopathological examination of a surgical specimen, it may not be necessary to perform a colonoscopy or to test for stool pathogens. In addition, many physicians practice in a delivery system that does not provide the structure, including the information systems and decision-making support, necessary to deliver consistent, reliable care.
Randomized trials have demonstrated that quality improvement can lead to a reduction in unnecessary variation in care and significant improvements in care and outcomes of adults with chronic illness (30). A prospective controlled cohort study of 65 adults with IBD demonstrated that practice guidelines for IBD used by physicians can reduce practice variation (31). The findings of our study indicate that there is variation in the care of children and adolescents with IBD, and gaps exist between recommended and actual care. These results suggest there is an opportunity to apply quality improvement methods at multiple institutions to evaluate the effectiveness of a pediatric IBD guideline to reduce variation and improve clinical outcomes.
All of the authors have indicated they do not have any affiliations with or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or material discussed in the manuscript, with the following exceptions: Richard B. Colletti (investigator, Abbott Laboratories; investigator and consultant, Centocor; Consultant, Accordant Health Services); Athos Bousvaros (speakers' bureau, Abbott Laboratories); Wallace Crandall (investigator and consultant, Centocor; investigator, Abbott Laboratories; speakers' bureau, TAP Pharmaceuticals); Marla Dubinsky (consultant, Prometheus).
All people named in the Acknowledgment have provided written permission to be named.
Other PIBDNet Network Physicians who contributed patient data to this study include C. Allan Pratt (Anchorage, AK), Shehzad Saeed (Birmingham, AL), Sesi Ogunbi (Montgomery, AL), Timothy Bohane (Sydney, Australia), Saied Dallalzadeh (Encino, CA), Elizabeth Gleghorn (Oakland, CA), Philip McDonald (Sacramento, CA), Melvin Heyman (San Francisco, CA), Jeffrey Hyams (Hartford, CT), Jonathan Evans (Jacksonville, FL), Alan Sacks (Pensacola, FL), Jay Hochman (Atlanta, Georgia), Claire Wilson (Honolulu, HI), Richard Sandler (Chicago, IL), Jean Molleston, Joseph Fitzgerald, Steven Steiner, Mark Corkins (Indianapolis, IN), Adrienne Scheich, Alan Leichtner, Anne Wolf, Daniel Kamin, Menno Verhave, Laurie Fishman (Boston, MA), Maria Oliva-Hemker (Baltimore, MD), Mark Integlia (Portland, ME), Pamela Brown (Ann Arbor, MI), Harold Conrad (Grand Rapids, MI), Robert Rothbaum (St. Louis, MO), Jon Vanderhoof (Omaha, NE), Jeffrey Critch (St. John's, Newfoundland), Jonathan Teitelbaum (Long Branch, NJ), Iona Monteiro (Newark, NJ), Anthony Otley (Halifax, Nova Scotia), Howard Baron (Las Vegas, NV), Abraham Jellin (Brooklyn, NY), Keith Benkov (New York, NY), John Bucuvalas (Cincinnati, OH), Carlo DiLorenzo, Hayat Mousa, Jane Balint, John Barnard, John Russo (Columbus, OH), John Grunow (Oklahoma City, OK), Sulaiman Bharwani (London, Ontario), David Mack (Ottawa, ON), David Piccoli, Edisio Semeao, Janice Kelly, Jonathan Markowitz, Joshua Friedman, Kathleen Loomes, Mei Lun Wang, Randolph Matthews, Ritu Verma (Philadelphia, PA), Manisha Dave, Alka Goyal (Pittsburgh, PA), Corey Strobel (Knoxville, TN), Abiodun Johnson (Amadillo, TX), George Ferry (Houston, TX), John Pohl (Temple, TX), Lynn Duffy, Otto Louis-Jacques, Peter Lee, Catherine Chao (Fairfax, VA), Michael Stephens, Subra Kugathasan (Milwaukee, WI).
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Keywords:© 2009 Lippincott Williams & Wilkins, Inc.
Crohn disease; Inflammatory bowel disease; Quality improvement; Variation in care