ORIGINAL ARTICLE: GASTROENTEROLOGY
Seasonality and Pediatric Inflammatory Bowel Disease Grace J. Lee, Jennifer L. Dotson, yMichael D. Kappelman, zEileen King, z Jesse M. Pratt, §Richard B. Colletti, Sarah Bistrick, jjJennifer L. Burkam, and Wallace V. Crandall, for the ImproveCareNow Network
ABSTRACT Objectives: Seasonal and geographic variations of inflammatory bowel disease (IBD) exacerbations have been described in adults, with inconsistent findings. We sought to determine whether disease activity in pediatric-onset IBD is associated with a seasonal pattern. Methods: We examined children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Collaborative between December 2008 and November 2010. We compared the proportion of patients in continuous remission for all recorded visits in each season. We also compared the distribution of all recorded visits with a physician global assessment (PGA) of remission or active disease across seasons. Results: A total of 1325 patients with CD (6102 visits) and 587 patients with UC (2394 visits) were included. The proportion of patients with UC in continuous remission during each season was highest in the summer (67%) and lowest in the winter (55%) (P ¼ 0.01). A similar pattern was found for CD but was not significant. Similarly, the proportion of visits in remission was highest in the summer and lowest in the winter for both UC (29%, 21%; P < 0.001) and CD (28%, 23%; P < 0.001); however, the distribution of visits with active disease was not significantly different across seasons. Conclusions: The higher proportion of patients with UC in continuous remission in the summer may be related to the higher proportion of remission
Received August 15, 2013; accepted February 28, 2014. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, Columbus, OH, the yDivision of Gastroenterology and Hepatology, Department of Pediatrics, University of North Carolina at Chapel Hill, the zDivision of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, the §Department of Pediatrics, University of Vermont, Burlington, and the jjDepartment of Pediatrics, Nationwide Children’s Hospital/Ohio State University, Columbus. Address correspondence and reprint requests to Grace Jennifer Lee, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205 (e-mail: [email protected]). Participating ImproveCareNow centers and their physician leaders are as follows: Advocate Lutheran General Children’s Hospital, James Berman; Children’s Healthcare of Atlanta/Emory Children’s Center, Bess T. Schoen; Barbara Bush Children’s Hospital at Maine Medical Center, Rebecca Carey; Inova Pediatric Digestive Disease Center, Ian Leibowitz/ Lynn Duffy; Massachusetts General Children’s Hospital, George Russell/Esther Israel; Nationwide Children’s Hospital, Wallace Crandall/ Brendan Boyle; Oakland Children’s Hospital, Sabina Ali; Oklahoma University Medical Center, John Grunow; Pediatric Gastroenterology and Nutrition Associates, Howard Baron; University of North Carolina at Chapel Hill, Michael Kappelman; UT Southwestern Medical Center, Ashish Patel; Vermont Children’s Hospital, Richard Colletti. The present project was supported by a grant from the Agency for Healthcare Research and Quality (R01 HS020024). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000362
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visits in the summer, because the proportion of visits with active disease was similar across seasons. These findings do not support any strong associations between season of the year and disease activity in pediatric IBD. Key Words: Crohn disease, inflammatory bowel disease, pediatrics, seasonality, ulcerative colitis
(JPGN 2014;59: 25–28)
I
nflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC), is a chronic, relapsing inflammatory disorder that primarily affects the digestive tract. Environmental factors in genetically susceptible individuals may contribute to the development of the disease. The specific factors that induce disease activity remain poorly defined. Infections and other environmental exposures that can vary by season have been postulated to trigger relapses (1–4). Conflicting data have been reported regarding seasonal variation of IBD exacerbations in adult populations. Studies have found that UC exacerbations can peak in any season, including the fall (5–9), winter (5–7), spring (8–11), or summer (11). Others have found no association between season of the year and hospital admissions (12–15). CD exacerbations have been reported to peak in the fall and winter (16), although the majority of studies have not found any seasonality of disease activity (5,10,12–15). The natural course of IBD in children may differ from that in adults, potentially because of differential environmental effects. No study has focused solely on pediatric patients with IBD. In the United States, traditional temporal seasons are more distinct in the northern region. Seasonality of disease activity may be more prominent in northern states if IBD exacerbations are related to a factor that varies by seasons. Exploring this possible association may help to elucidate the natural course of IBD. The present multicenter study examined whether season is associated with disease activity in patients with pediatric-onset IBD and whether results are consistent across regions.
METHODS Patient Population ImproveCareNow (ICN) is a multicenter network of health care providers established in January 2007 to improve the quality of care of children and adolescents with IBD. The ICN patient registry contains disease and treatment data collected prospectively and longitudinally during outpatient encounters. Patients were diagnosed and managed according to the usual practice of the primary gastroenterologist, although quality improvement methodology was used to reduce any unintended variation. Model care guidelines, emphasizing correct dosing of medications and frequency of laboratory tests, are available to all ICN sites, and include the recommendation that patients be seen at least twice yearly.
25
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Lee et al The present study analyzed data from patients diagnosed as having CD and UC before age 21 seen from December 2008 to November 2010 (8 seasons) at 12 secondary and tertiary centers in the United States. These centers were selected because of their near-complete enrollment of their patients with IBD during this time period.
Study Design We first compared the proportion of patients in continuous remission based on physician global assessment (PGA) during each season after combining the seasons across the 2 years. Physicians classified patients’ disease activity as quiescent (in remission), mild, moderate, or severe based on the clinical and laboratory data available at the time of the assessment (17,18). Clinical and laboratory indicators that may have influenced PGA classification included reported symptoms of abdominal pain, number of daily stools, level of functioning and well-being, height and weight indicators, physical examination, hemoglobin, hematocrit, erythrocyte sedimentation rate, C-reactive protein, albumin, and others as available to the clinician at the time of classification. To be classified as continuous remission, a given patient must have received an assessment of remission for all visits recorded during a given season. The proportion was calculated with the numerator defined as the number of patients seen who were in remission (by PGA) at all visits during that season. The denominator was defined as the total number of patients with at least 1 visit occurring in the given season, regardless of disease activity. Each patient was counted only once per season for the 8 seasons. Seasons were defined as winter (December, January, February), spring (March, April, May), summer (June, July, August), and fall (September, October, November) for each of 2009 and 2010. We tested for consistency of seasonal effects across regions and across years. We then investigated whether any significant differences found in the proportion of patients in continuous remission each season were related to the distribution of visits in remission in each season. Correspondingly, we determined the distribution of visits with active disease in each season to evaluate for any seasonal effect. In this secondary analysis, we first evaluated whether the proportion of all visits with a PGA of remission was constant across the 4 seasons (eg, 25% for each season) after combining the seasons across the 2 years. The proportion of visits in remission each season was calculated with the numerator defined as the number of visits with a PGA of remission for that season and the denominator defined as the total number of visits with a PGA of remission across all seasons. Similarly, we then compared the proportion of visits with active disease (calculated as noted above for remission) that occurred in each of the 4 seasons to an expected rate of 25%. For this ‘‘visit-based’’ analysis, all visits for patients were included. To investigate potential sex differences in patient visits across the seasons, we determined the proportion of girl and boy patients seen during each season. Similarly, we investigated potential race differences across the seasons. Patients were categorized as white, black, or other. The proportion of each category of patients seen was determined for each season. To evaluate whether the effect of season may have varied by region, we performed a subanalysis stratifying northern versus southern region. Seven centers (Vermont Children’s Hospital at Fletcher Allen Health Care, VT, 448N; Barbara Bush Children’s Hospital at Maine Medical Center, ME, 448N; Advocate Lutheran General Children’s Hospital, IL, 428N; Massachusetts General Hospital for Children, MA, 428N; Nationwide Children’s Hospital, OH, 408N; Inova Fairfax Hospital for Children, VA, 398N; Children’s Hospital and Research Center Oakland, CA, 388N) were
26
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located in the northern region, and 5 centers (Pediatric Gastroenterology & Nutrition Associates, NV, 368N; North Carolina Children’s Hospital at University of North Carolina Health Care, NC, 368N; The Children’s Hospital at Oklahoma University Medical Center, OK, 368N; Children’s Healthcare of Atlanta at Egleston, GA, 348N; Children’s Medical Center at University of Texas Southwestern Medical Center, TX, 338N) were located in the southern region using 378 latitude to bisect the country. Consistency of seasonal effect was also tested across centers. For all analyses, CD and UC were analyzed separately.
Statistical Analysis All calculations were performed using SAS 9.3 (SAS Institute Inc, Cary, NC). For the primary analysis, data were analyzed using a generalized linear mixed model with a logit link to evaluate variation of disease activity by season with terms for season, year, region, site nested within region, season-by-year, and season-byregion interactions. For the secondary analyses, multinomial x2 tests of proportions were used to test the distribution of percent of all visits in remission to hypothesized values of 25% for each season. A similar test was used testing the percent of all visits with active disease across seasons. The x2 tests were used to determine whether there was a difference in sex or race categories for patient visits across seasons. A linear model with fixed effects including site, season, year, and season-by-site interaction was used to determine whether the seasonal effect was consistent across centers. P values
Seasonality and Pediatric Inflammatory Bowel Disease Grace J. Lee, Jennifer L. Dotson, yMichael D. Kappelman, zEileen King, z Jesse M. Pratt, §Richard B. Colletti, Sarah Bistrick, jjJennifer L. Burkam, and Wallace V. Crandall, for the ImproveCareNow Network
ABSTRACT Objectives: Seasonal and geographic variations of inflammatory bowel disease (IBD) exacerbations have been described in adults, with inconsistent findings. We sought to determine whether disease activity in pediatric-onset IBD is associated with a seasonal pattern. Methods: We examined children with Crohn disease (CD) and ulcerative colitis (UC) using data from the ImproveCareNow Collaborative between December 2008 and November 2010. We compared the proportion of patients in continuous remission for all recorded visits in each season. We also compared the distribution of all recorded visits with a physician global assessment (PGA) of remission or active disease across seasons. Results: A total of 1325 patients with CD (6102 visits) and 587 patients with UC (2394 visits) were included. The proportion of patients with UC in continuous remission during each season was highest in the summer (67%) and lowest in the winter (55%) (P ¼ 0.01). A similar pattern was found for CD but was not significant. Similarly, the proportion of visits in remission was highest in the summer and lowest in the winter for both UC (29%, 21%; P < 0.001) and CD (28%, 23%; P < 0.001); however, the distribution of visits with active disease was not significantly different across seasons. Conclusions: The higher proportion of patients with UC in continuous remission in the summer may be related to the higher proportion of remission
Received August 15, 2013; accepted February 28, 2014. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, Columbus, OH, the yDivision of Gastroenterology and Hepatology, Department of Pediatrics, University of North Carolina at Chapel Hill, the zDivision of Biostatistics and Epidemiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, the §Department of Pediatrics, University of Vermont, Burlington, and the jjDepartment of Pediatrics, Nationwide Children’s Hospital/Ohio State University, Columbus. Address correspondence and reprint requests to Grace Jennifer Lee, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Nationwide Children’s Hospital, 700 Children’s Dr, Columbus, OH 43205 (e-mail: [email protected]). Participating ImproveCareNow centers and their physician leaders are as follows: Advocate Lutheran General Children’s Hospital, James Berman; Children’s Healthcare of Atlanta/Emory Children’s Center, Bess T. Schoen; Barbara Bush Children’s Hospital at Maine Medical Center, Rebecca Carey; Inova Pediatric Digestive Disease Center, Ian Leibowitz/ Lynn Duffy; Massachusetts General Children’s Hospital, George Russell/Esther Israel; Nationwide Children’s Hospital, Wallace Crandall/ Brendan Boyle; Oakland Children’s Hospital, Sabina Ali; Oklahoma University Medical Center, John Grunow; Pediatric Gastroenterology and Nutrition Associates, Howard Baron; University of North Carolina at Chapel Hill, Michael Kappelman; UT Southwestern Medical Center, Ashish Patel; Vermont Children’s Hospital, Richard Colletti. The present project was supported by a grant from the Agency for Healthcare Research and Quality (R01 HS020024). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000362
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Volume 59, Number 1, July 2014
visits in the summer, because the proportion of visits with active disease was similar across seasons. These findings do not support any strong associations between season of the year and disease activity in pediatric IBD. Key Words: Crohn disease, inflammatory bowel disease, pediatrics, seasonality, ulcerative colitis
(JPGN 2014;59: 25–28)
I
nflammatory bowel disease (IBD), which includes Crohn disease (CD) and ulcerative colitis (UC), is a chronic, relapsing inflammatory disorder that primarily affects the digestive tract. Environmental factors in genetically susceptible individuals may contribute to the development of the disease. The specific factors that induce disease activity remain poorly defined. Infections and other environmental exposures that can vary by season have been postulated to trigger relapses (1–4). Conflicting data have been reported regarding seasonal variation of IBD exacerbations in adult populations. Studies have found that UC exacerbations can peak in any season, including the fall (5–9), winter (5–7), spring (8–11), or summer (11). Others have found no association between season of the year and hospital admissions (12–15). CD exacerbations have been reported to peak in the fall and winter (16), although the majority of studies have not found any seasonality of disease activity (5,10,12–15). The natural course of IBD in children may differ from that in adults, potentially because of differential environmental effects. No study has focused solely on pediatric patients with IBD. In the United States, traditional temporal seasons are more distinct in the northern region. Seasonality of disease activity may be more prominent in northern states if IBD exacerbations are related to a factor that varies by seasons. Exploring this possible association may help to elucidate the natural course of IBD. The present multicenter study examined whether season is associated with disease activity in patients with pediatric-onset IBD and whether results are consistent across regions.
METHODS Patient Population ImproveCareNow (ICN) is a multicenter network of health care providers established in January 2007 to improve the quality of care of children and adolescents with IBD. The ICN patient registry contains disease and treatment data collected prospectively and longitudinally during outpatient encounters. Patients were diagnosed and managed according to the usual practice of the primary gastroenterologist, although quality improvement methodology was used to reduce any unintended variation. Model care guidelines, emphasizing correct dosing of medications and frequency of laboratory tests, are available to all ICN sites, and include the recommendation that patients be seen at least twice yearly.
25
Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
Lee et al The present study analyzed data from patients diagnosed as having CD and UC before age 21 seen from December 2008 to November 2010 (8 seasons) at 12 secondary and tertiary centers in the United States. These centers were selected because of their near-complete enrollment of their patients with IBD during this time period.
Study Design We first compared the proportion of patients in continuous remission based on physician global assessment (PGA) during each season after combining the seasons across the 2 years. Physicians classified patients’ disease activity as quiescent (in remission), mild, moderate, or severe based on the clinical and laboratory data available at the time of the assessment (17,18). Clinical and laboratory indicators that may have influenced PGA classification included reported symptoms of abdominal pain, number of daily stools, level of functioning and well-being, height and weight indicators, physical examination, hemoglobin, hematocrit, erythrocyte sedimentation rate, C-reactive protein, albumin, and others as available to the clinician at the time of classification. To be classified as continuous remission, a given patient must have received an assessment of remission for all visits recorded during a given season. The proportion was calculated with the numerator defined as the number of patients seen who were in remission (by PGA) at all visits during that season. The denominator was defined as the total number of patients with at least 1 visit occurring in the given season, regardless of disease activity. Each patient was counted only once per season for the 8 seasons. Seasons were defined as winter (December, January, February), spring (March, April, May), summer (June, July, August), and fall (September, October, November) for each of 2009 and 2010. We tested for consistency of seasonal effects across regions and across years. We then investigated whether any significant differences found in the proportion of patients in continuous remission each season were related to the distribution of visits in remission in each season. Correspondingly, we determined the distribution of visits with active disease in each season to evaluate for any seasonal effect. In this secondary analysis, we first evaluated whether the proportion of all visits with a PGA of remission was constant across the 4 seasons (eg, 25% for each season) after combining the seasons across the 2 years. The proportion of visits in remission each season was calculated with the numerator defined as the number of visits with a PGA of remission for that season and the denominator defined as the total number of visits with a PGA of remission across all seasons. Similarly, we then compared the proportion of visits with active disease (calculated as noted above for remission) that occurred in each of the 4 seasons to an expected rate of 25%. For this ‘‘visit-based’’ analysis, all visits for patients were included. To investigate potential sex differences in patient visits across the seasons, we determined the proportion of girl and boy patients seen during each season. Similarly, we investigated potential race differences across the seasons. Patients were categorized as white, black, or other. The proportion of each category of patients seen was determined for each season. To evaluate whether the effect of season may have varied by region, we performed a subanalysis stratifying northern versus southern region. Seven centers (Vermont Children’s Hospital at Fletcher Allen Health Care, VT, 448N; Barbara Bush Children’s Hospital at Maine Medical Center, ME, 448N; Advocate Lutheran General Children’s Hospital, IL, 428N; Massachusetts General Hospital for Children, MA, 428N; Nationwide Children’s Hospital, OH, 408N; Inova Fairfax Hospital for Children, VA, 398N; Children’s Hospital and Research Center Oakland, CA, 388N) were
26
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located in the northern region, and 5 centers (Pediatric Gastroenterology & Nutrition Associates, NV, 368N; North Carolina Children’s Hospital at University of North Carolina Health Care, NC, 368N; The Children’s Hospital at Oklahoma University Medical Center, OK, 368N; Children’s Healthcare of Atlanta at Egleston, GA, 348N; Children’s Medical Center at University of Texas Southwestern Medical Center, TX, 338N) were located in the southern region using 378 latitude to bisect the country. Consistency of seasonal effect was also tested across centers. For all analyses, CD and UC were analyzed separately.
Statistical Analysis All calculations were performed using SAS 9.3 (SAS Institute Inc, Cary, NC). For the primary analysis, data were analyzed using a generalized linear mixed model with a logit link to evaluate variation of disease activity by season with terms for season, year, region, site nested within region, season-by-year, and season-byregion interactions. For the secondary analyses, multinomial x2 tests of proportions were used to test the distribution of percent of all visits in remission to hypothesized values of 25% for each season. A similar test was used testing the percent of all visits with active disease across seasons. The x2 tests were used to determine whether there was a difference in sex or race categories for patient visits across seasons. A linear model with fixed effects including site, season, year, and season-by-site interaction was used to determine whether the seasonal effect was consistent across centers. P values
