Journal of Pediatric Gastroenterology & Nutrition:
Original Articles: Gastroenterology
Health-related Quality of Life in Pediatric Patients With Long-standing Pancreatitis
Pohl, John F.*; Limbers, Christine A.†; Kay, Marie*; Harman, Annette‡; Rollins, Michael‡; Varni, James W.§
*Division of Pediatric Gastroenterology, Primary Children's Medical Center, University of Utah, Salt Lake City, UT
†Department of Psychology and Neuroscience, Baylor University, Waco, TX
‡Division of Pediatric Surgery, Primary Children's Medical Center, University of Utah, Salt Lake City, UT
§Department of Pediatrics, College of Medicine, Texas A&M University, College Station, TX.
Address correspondence and reprint requests to John F. Pohl MD, Associate Professor of Pediatrics, Department of Pediatric Gastroenterology, Primary Children's Medical Center, University of Utah, 100 N Mario Capecchi Dr, Suite 2650, Salt Lake City, UT 84113-1103, (e-mail: email@example.com).
Received 29 June, 2011
Accepted 10 October, 2011
This research was funded by Aptalis Pharma (Bridgewater, NJ). J.F.P. and J.W.V. have received investigator-initiated funding from Takeda Pharmaceuticals (Deerfield, IL). J.W.V. holds the copyright and the trademark for the PedsQL and receives financial compensation from the Mapi Research Trust, which is a nonprofit research institute that charges distribution fees to for-profit companies that use the Pediatric Quality of Life Inventory. The other authors report no conflicts of interest.
Objectives: There are limited data on health-related quality of life (HRQOL) in pediatric patients with long-standing pancreatitis (including acute relapsing and chronic pancreatitis) using age-appropriate measurement instruments.
Methods: We evaluated HRQOL in children with long-standing pancreatitis using the PedsQL 4.0 Generic Core Scales by patient self-report as well as parent proxy report. Additionally, patient self-reports and parent proxy reports were completed for the PedsQL Multidimensional Fatigue Scale.
Results: Across all of the dimensions, significantly impaired HRQOL and higher fatigue were noted for both pediatric patient self-report and parent proxy report in comparison with the matched healthy children samples. Higher fatigue was associated with lower HRQOL. There was moderate to good agreement between patient self-reports and parent proxy reports.
Conclusions: Given the impaired HRQOL and fatigue documented in the present study, future studies are needed to determine whether specific factors can modify HRQOL and fatigue in this patient population.
Pancreatitis consists of inflammation of the pancreas, and in most cases, resolution occurs with minimal long-term adverse effects. Up to 25% of patients with acute pancreatitis, however, can develop complications, including long-standing abdominal pain, pancreatic necrosis, and multisystem organ failure. Relapsing acute pancreatitis eventually can lead to chronic pancreatitis, which is defined by histologic evidence of inflammation and fibrosis with loss of both exocrine and endocrine cells (1–3). Additionally, chronic pancreatitis often can occur as a result of repetitive episodes of acute pancreatitis as seen with alcohol abuse, hepatobiliary disease, and genetic disorders (4–7).
Health-related quality of life (HRQOL) has been studied in adult patients with long-standing pancreatitis, including chronic pancreatitis (8,9). Adult patients with acute necrotizing pancreatitis, which eventually can lead to chronic pancreatitis, have been shown to have impaired HRQOL, especially with regard to physical functioning compared with healthy controls (8). A study using patients from 4 countries demonstrated that adult patients with chronic pancreatitis had significantly increased fatigue, sleep disturbances, and fear of future health problems (9). In many of these studies, the diagnosis of chronic pancreatitis is problematic because of lack of a standard and safe way to obtain tissue for histopathology (10).
Pancreatic enzyme replacement therapy (PERT) using standard pancreatic enzyme preparations for adults with chronic pancreatitis has been associated with improved HRQOL as well as other objective parameters, including a reduced defecation rate and improved weight gain (11). A Cochrane analysis, however, demonstrated equivocal results for PERT with regard to pain, steatorrhea, analgesic use, and other parameters (12).
HRQOL outcomes in pediatric patients with pancreatitis are not well understood, and to date only 1 peer-reviewed study has evaluated HRQOL in this patient population (13). The present study evaluated whether HRQOL improved among 19 pediatric patients with severe chronic pancreatitis with a mean age of 14.5 years undergoing total pancreatectomy (TP) with islet autotransplantation (IAT). The authors found that before TP/IAT, pediatric patients had lower HRQOL compared with US population norms and that HRQOL significantly improves after TP/IAT. Although the present study represents an important step in understanding HRQOL outcomes in this complex patient population, there are limitations to the present study including use of a small sample size and of a HRQOL measure developed for adult self-report (SF-36), which limited the assessment of both child self-report and parent proxy report (13). Additionally, fatigue was not assessed in the study.
Thus, the objective of the present study was to evaluate HRQOL and fatigue by patient self-report and parent proxy report in a sample of pediatric patients with long-standing pancreatitis using age-appropriate measurement instruments specifically developed for pediatric populations. Based on the extant literature with adult patients with chronic pancreatitis, we hypothesized that pediatric patients with long-standing pancreatitis (but not necessarily chronic pancreatitis) would manifest impaired HRQOL in comparison with healthy children scores on the Pediatric Quality of Life Inventory (PedsQL) Generic Core Scales. Also, we hypothesized that pediatric patients with long-standing pancreatitis would manifest greater fatigue in comparison with healthy children on the PedsQL Multidimensional Fatigue Scale.
This single-institution study was reviewed and approved by the institutional review board of Primary Children's Medical Center (University of Utah, Salt Lake City, UT). A medical record search was performed to determine the number of patients that had been seen at Primary Children's Medical Center for long-standing pancreatitis during the last 10 years (2000–2010). Several International Classification of Disease, 9th Edition (ICD-9) codes were used to determine which patients would qualify for inclusion in the present study. These codes included 577.0 (acute pancreatitis), 577.1 (chronic pancreatitis), 577.2 (cyst or pseudocyst of pancreas), 577.8 (other specific diseases of pancreas, including atrophy calculus, cirrhosis, and fibrosis), and 577.9 (unspecified disease of the pancreas).
If patients had an ICD-9 code of “chronic pancreatitis,” they were considered eligible to be enrolled in the study. Charts of those patients with an ICD-9 code that did not designate specifically for chronic pancreatitis were reviewed to determine whether they met clinical inclusion criteria for long-standing pancreatitis symptoms. Specifically, medical records were evaluated for signs and symptoms of chronic abdominal pain with elevated serum lipase, chronic abdominal pain with elevated serum lipase associated with PERT usage, evidence of impaired exocrine pancreatic function (eg, documented decreased pancreatic enzyme levels obtained by endoscopic duodenal sampling or abnormal fecal elastase measurement), or impaired endocrine pancreatic function (eg, demonstrating an elevated hemoglobin A1c or using insulin preparations) with associated chronic abdominal pain and elevated serum lipase. We enrolled subjects with symptoms for a prolonged time to ensure enrollment of subjects with potential relapsing acute pancreatitis or chronic pancreatitis as opposed to patients with only a short interval of symptoms (14).
HRQOL surveys with consent letters were mailed to potential study subjects and their parents. Only children who returned survey forms in the mail were included in the study. A child was excluded from study participation if there was a medical history of developmental delay, if the child or family did not speak English, or if the child was deceased.
HRQOL data were obtained using standard survey research methodology (15). Specifically, PedsQL forms, a PedsQL Family Information Form, and a cover letter were sent to all of the eligible patients. A reminder postcard was mailed 7 to 10 days later. The PedsQL forms and a second-mailing cover letter were mailed 1 to 2 weeks after sending the reminder postcard to all of the nonrespondents. Approximately 3 weeks after the initial mailing, a telephone reminder call was made to all of the remaining nonrespondents. All of the nonrespondents also were offered the option of a telephone interview at the 3-week reminder call.
The 23-item PedsQL 4.0 Generic Core Scales encompass physical functioning (8 items), emotional functioning (5 items), social functioning (5 items), and school functioning (5 items), and were developed through focus groups, cognitive interviews, pretesting, and field testing measurement development protocols (16–18). The PedsQL 4.0 Generic Core Scales comprise parallel child self-report for ages 5 to18 and parent proxy-report for ages 2 to 18 formats.
The items for each of the forms are essentially identical, differing in developmentally appropriate language, or first- or third-person tense. The instructions ask how much of a problem each item has been during the last month. A 5-point response scale is used across child self-report for ages 8 to18 years (0 = never a problem, 1 = almost never a problem, 2 = sometimes a problem, 3 = often a problem, 4 = almost always a problem). Items are reverse scored and linearly transformed to a 0-to-100 scale (0 = 100, 1 = 75, 2 = 50, 3 = 25, 4 = 0), so that higher scores indicate better HRQOL. Scale scores are computed as the sum of the items divided by the number of items answered (this accounts for missing data). If >50% of the items in the scale are missing, then the scale score is not computed (16). Although there are other strategies for imputing missing values, this computation is consistent with the previous PedsQL peer-reviewed publications and other well-established HRQOL measures (16,19–29). To create the Psychosocial Health Summary Score (15 items), the mean is computed as the sum of the items divided by the number of items answered in the emotional, social, and school functioning scales.
The 18-item PedsQL Multidimensional Fatigue Scale encompasses 3 scales: general fatigue (6 items, eg, “I feel tired,” “I feel too tired to do things that I like to do”), sleep/rest fatigue (6 items, eg, “I feel tired when I wake up in the morning,” “I rest a lot”), and cognitive fatigue (6 items, eg, “It is hard for me to keep my attention on things,” “It is hard for me to remember what people tell me”) (18–20,27,28). The format, instructions, Likert response scale, and scoring method are identical to the PedsQL 4.0 Generic Core Scales, with higher scores indicating better HRQOL (lower fatigue symptoms). The instructions for the standard version ask how much of a problem each item has been during the last month (30,31).
Patient charts were reviewed for patients who returned the HRQOL study forms. The following patient aspects were obtained from chart review: age at diagnosis of pancreatitis, years since initial diagnosis of pancreatitis, sex, ethnicity (defined as black, Hispanic, white/non-Hispanic, other, or unknown), use of maintenance pain medication (eg, narcotics, tricyclic antidepressants, gabapentin, tramadol), use of PERT, last recorded baseline body mass index (BMI, kg/m2), history of cystic fibrosis, history of pancreatic fibrosis or pancreatic pseudocyst formation, history of impaired exocrine pancreas function, and history of impaired endocrine pancreas function.
Descriptive statistics of the study participants with pancreatitis were performed. Scale scores across the pediatric pancreatitis sample and a matched healthy sample were compared. In dependent samples t tests were used to compare groups differing in known health status (pediatric patients with pancreatitis and healthy children) on the PedsQL 4.0 Generic Core Scales and PedsQL Multidimensional Fatigue Scales (32,33). To determine the magnitude of the differences between pediatric patients with pancreatitis and healthy children, effect sizes were calculated. Effect size was calculated by taking the difference between the healthy sample mean and the pancreatitis sample mean, divided by the pooled standard deviation. Effect sizes for differences in mean were designated as small (0.20), medium (0.50), and large (0.80) in magnitude (34).
An analysis of Pearson product moment correlations among the PedsQL 4.0 Generic Core Scales and the PedsQL Multidimensional Fatigue Scales also was performed. Based on the conceptualization of disease-specific symptoms as causal indicators of generic HRQOL, it was anticipated that more severe fatigue would be associated with more impaired generic HRQOL. Pearson product moment correlation coefficient effect sizes were designated as small (0.10–0.29), medium (0.30–0.49), and large (≥50) (34).
Child self-report and parent proxy report agreements were determined through intraclass correlation coefficients (ICCs). The ICC provides an index of absolute agreement given that it takes into account the ratio between subject variability and total variability. ICCs were designated as ≤0.40, poor-to-fair agreement; 0.41 to 0.60, moderate agreement; 0.61 to 0.80, good agreement; and 0.81 to 1.00, excellent agreement (35–37). Statistical analysis was conducted using SPSS version 18.0 for Windows (SPSS Inc, Chicago, IL).
We initially identified 607 patients ages 18 years or younger who had been seen at our institution with a diagnosis of long-standing pancreatitis based on ICD-9 codes during the last 10 years. When we evaluated the records of these patients, we found 123 subjects who potentially fit the criteria for long-standing pancreatitis. Surveys were sent to these families, and initially, 55 families returned surveys. A further review of the medical records eliminated 17 of these study subjects because they had never been diagnosed as having pancreatitis nor had diagnostic testing consistent with pancreatitis. In total, 38 parent–child dyads qualified for the present study based on their medical history. The surveys for 3 of these dyads were completed by telephone interview.
Long-standing Pancreatitis Patient Demographics
The demographics of the pediatric patients with long-standing pancreatitis are detailed in Table 1. The mean age at diagnosis of the initial event of pancreatitis was 7.2 years, and the mean number of years that had passed since the initial episode of pancreatitis until data were reviewed was 3.6 years. Female sex was noted in 50% of the study subjects, and 87% of subjects were noted as white/non-Hispanic with regard to ethnicity. All of the patients had experienced abdominal pain and a prolonged elevation of serum lipase. The average number of months in the medical record that an elevated lipase was noted with associated abdominal pain was 16 months, although many of these patients had a longer history of abdominal pain with no recorded lipase level. It was noted that 21% of patients had been taking some type of maintenance pain medication during their clinical course, which included hydrocodone, hydromorphone, oxycodone, or morphine, whereas 40% were maintained on PERT as part of their medical therapy. Three patients had imaging that was consistent with chronic pancreatitis (1 patient with fibrotic pancreas seen on computed tomography scan and 2 patients with pancreatic calcifications seen on magnetic resonance imaging). Nine patients (24%) had radiographic evidence of a pancreatic pseudocyst (by either abdominal ultrasound or computed tomography). Four patients had pancreatic exocrine insufficiency documented either by 72-hour fecal fat or fecal elastase testing, and 6 patients had documented endocrine insufficiency and were receiving insulin therapy. Of the 6 patients with endocrine insufficiency, 3 required insulin before the diagnosis of pancreatitis because of a diagnosis of type 1 diabetes mellitus. It is unknown whether the children with preexisting diabetes had experienced earlier episodes of pancreatitis that could have led to the development of diabetes (38).
The most common cause of long-standing pancreatitis was either genetic (1 subject with a PRSS1 mutation, 1 subject with a SPINK1 mutation, and 5 patients with at least 1 CFTR mutation) or idiopathic consistent with findings of earlier studies evaluating causes of relapsing pancreatitis in children (39). Other documented causes of long-standing pancreatitis included anatomic abnormalities, medication adverse effect, trauma or postsurgical infection, abdominal tumor, hemolytic uremic syndrome, celiac disease, autoimmune hepatitis, or other cause (eg, possible Schwachman syndrome). Only 3 of the study participants had a BMI <5% for age and sex, and only 1 patient had cystic fibrosis.
Healthy Sample: PedsQL 4.0 Generic Core Scales
The healthy children sample for the PedsQL 4.0 Generic Core Scales was derived from the previously conducted PedsQL 4.0 initial field test and a State's Children's Health Insurance Program evaluation in California (16,40). The healthy children sample was randomly matched by age, sex, and race/ethnicity to the long-standing pancreatitis sample. The average age of 587 boys (49.8%) and 591 girls (50.2%) was 10.30 years (standard deviation 3.82). With respect to race/ethnicity, the sample contained 1087 (92.3%) white non-Hispanic, 61 (5.2%) Hispanics, and 30 (2.5%) Asian/Pacific Islanders.
Healthy Sample: PedsQL Multidimensional Fatigue Scale
The healthy children sample for the PedsQL Multidimensional Fatigue Scale was derived from 2 previously conducted studies (21,22). The sample was randomly matched by age, sex, and race/ethnicity to the long-standing pancreatitis sample. The average age of 90 boys (49.7%) and 89 girls (49.2%) was 11.37 years (standard deviation 4.06). With respect to race/ethnicity, the sample contained 143 (79.0%) white non-Hispanics, 10 (10.5%) Hispanics, 8 (4.4%) Asian/Pacific Islanders, and 11 (6.1%) other.
HRQOL and Fatigue
Internal consistency reliability α coefficients for the PedsQL 4.0 Generic Core Scales and Multidimensional Fatigue Scales are presented in Tables 2 and 3. All of the patient self-report scales and parent proxy report scales on the PedsQL 4.0 Generic Core Scales and Multidimensional Fatigue Scale exceeded the minimum reliability standard of 0.70 required for group comparisons, whereas the total scale scores for both measures exceeded the reliability criterion of 0.90 recommended for analyzing individual patient scale scores.
Patients with long-standing pancreatitis and their parents reported significantly lower HRQOL and higher fatigue than healthy children (Tables 2 and 3). Effect sizes were in the medium-to-large range on the PedsQL 4.0 Generic Core Scales, with the smallest effect sizes found on the Social Functioning Scale for both child self-report and parent proxy report. All of the effect sizes for the PedsQL Multidimensional Fatigue Scale were in the large range, with the greatest effect sizes demonstrated on the Total Fatigue Scale score for both child self-report and parent proxy report.
The intercorrelations among the PedsQL 4.0 Generic Core Scales and Multidimensional Fatigue Scale for child self-report and parent proxy report are presented in Table 4. Overall, more impaired generic HRQOL was significantly correlated with higher fatigue, with the majority of intercorrelations in the medium-to-large effect size range. The ICCs between long-standing pancreatitis patients and their parents on the PedsQL Scales were in the moderate-to-good agreement range (Table 5). Highest agreement between parents and children was demonstrated on the Physical Health Scale (ICC 0.78).
The present study evaluated HRQOL in pediatric patients with long-standing pancreatitis at a single institution. Significantly impaired HRQOL and fatigue were reported by children with pancreatitis as well as their parents.
Across all of the subscales on the PedsQL 4.0 Generic Core Scales, pediatric patients with long-standing pancreatitis demonstrated significantly worse HRQOL compared with a matched healthy sample. The majority of effect sizes were in the medium-to-large effect size range for both child self-report and parent proxy report, indicating that pediatric patients with long-standing pancreatitis experience significantly diminished functioning across both physical and psychosocial domains. This finding is consistent with a study that investigated HRQOL among pediatric patients with severe chronic pancreatitis who reported impairments in both physical and emotional domains before TP/IAT (13). Some of the largest effect sizes for both child self-report and parent proxy report were seen on the PedsQL Psychosocial Health Summary Score, largely due to greatest differences between children with long-standing pancreatitis and healthy children in school functioning. Increased days of missed school and work have been correlated with constant abdominal pain but not pain severity in adult patients with chronic pancreatitis (41). Thus, our finding that school functioning was affected most in this pediatric population may not be surprising given that pancreatitis symptoms (eg, chronic pain) would likely also affect a child's school absences and ability to focus in school (the 2 domains captured by the PedsQL School Functioning Scale). These data suggest that concerted efforts are needed to develop interventions that mitigate the effect of long-standing pancreatitis on school functioning in this pediatric population.
In an adult population, HRQOL has been shown to be impaired in patients with constant (as opposed to intermittent) abdominal pain from pancreatitis and in patients who have alcohol use as a cause of pancreatitis (42,43). Additionally, adult patients with or without sphincter of Oddi dysfunction associated with relapsing acute or chronic pancreatitis have demonstrated equally low HRQOL (43). The presence of pain, pancreatic exocrine insufficiency (diabetes), steatorrhea, low BMI, and loss of employment also appear to be factors that decrease HRQOL in adult studies. Conversely, increased BMI and patient social support are associated with an improvement in HRQOL, whereas disease etiology, disease duration, and changes in pancreatic morphology noted on imaging have shown no effect on HRQOL in adult studies (44–46). The BMI of most of our patients was not impaired.
In the present study, pediatric patients with long-standing pancreatitis also exhibited significantly higher fatigue than a matched healthy sample, with all of the effect sizes in the large effect size range. The medium-to-large correlations between higher fatigue and impaired generic HRQOL suggest that fatigue possibly as a result of abdominal pain may be an important construct to target in intervention work with this pediatric population (42). Data from the present study suggest that lower levels of fatigue should be positively associated with better overall HRQOL in this pediatric population; however, longitudinal analyses are needed to confirm these cross-sectional findings.
Our finding that children and parents showed moderate-to-good agreement on the PedsQL Scales suggests that in general, parents and children in this population are seeing the child's HRQOL and fatigue symptoms similarly. It should be noted, however, that this finding may in part be an artifact of the mail survey methodology used in the present study. Future studies should investigate the agreement between child and parent reports in this population using other survey methodologies to determine whether our findings hold true across other modes of administration.
There are some limitations to the present study. Our study sample included a small number of predominantly white/non-Hispanic patients from a single center, which matched the demographics of Utah but limited the generalizability of our findings (47). The small sample size also limited us from performing subgroup analyses of HRQOL and fatigue with regard to sex, presence of comorbidities, pain medication use, or other categories. Only a small number of completed surveys were returned (31%) relative to the number of surveys initially mailed to potential study subjects. As such, the returned surveys may represent a sampling bias and could represent patients with more severe symptoms. The use of ICD-9 codes to retrospectively identify patients with symptoms of long-standing pancreatitis could have led to an underestimate of the actual number of patients with this condition at our institution.
The diagnosis of chronic pancreatitis in this patient sample was difficult. Our patients could have had early development of chronic pancreatitis or recurrent acute pancreatitis; however, this possibility could not be documented in the medical record in a retrospective manner (48). It was also difficult to determine whether the abdominal pain experienced by these patients resulted from another cause, with the documented elevated lipase level simply being associated with the rare but benign finding of macrolipasemia (49). Finally, we were not able to evaluate whether other comorbidities affected HRQOL in this patient population (50).
Nevertheless, our study demonstrates significantly impaired HRQOL and fatigue in pediatric patients with symptoms of long-standing pancreatitis. We recommend a multicenter study to corroborate these findings and studies to evaluate the effect of dietary intake, BMI, and PERT on the effect of HRQOL and fatigue in pediatric patients with long-standing pancreatitis (including patients with chronic pancreatitis). Clinical guidelines for the diagnosis and treatment of pediatric patients with potential chronic pancreatitis also are needed.
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health-related quality of life; pancreatitis; pediatrics; PedsQL
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