ORIGINAL ARTICLE: GASTROENTEROLOGY

Urinary Tract Infection in Infancy Is a Risk Factor for Chronic Abdominal Pain in Childhood 

John M. Rosen, yAlyssa Kriegermeier, yPapa N. Adams, zDavid J. Klumpp, and yMiguel Saps

ABSTRACT Objective: Adverse early life events are key factors for development of functional gastrointestinal disorders (FGIDs). Urinary tract infection (UTI) is associated with chronic pelvic pain in adults, a finding that has been recapitulated in murine models, but the relation between UTI and chronic pelvic and abdominal pain has not been studied in children. We hypothesized that UTI in infancy increases the risk of FGIDs and chronic abdominal pain (CAP) in childhood. Methods: The present study included children, ages 4 to 18 years, with a single UTI in the first year of life and their siblings with no history of UTI. Parents completed the Questionnaire on Pediatric Gastrointestinal Symptoms–Rome III Version (QPGS-III) by telephone. Children meeting QPGS-III criteria for FGIDs but with pain less than once weekly were considered to have CAP. Results: A total of 57 patients with UTI and 58 sibling controls were identified. Mean age at UTI was 4.8 months, and mean time since UTI was 9.3 years. At the time of survey, mean age of patients was 9.7 years (5–16 years, 40% boys) and that of controls was 9.6 years (range 4–17 years, 57% boys). FGIDs were diagnosed in 6 of 57 (11%) patients, and 1 of 58 (2%) controls (P ¼ 0.06). CAP was identified in 10 of 57 (18%) patients and 2 of 58 (3%) controls (P ¼ 0.02). Predominant sex (female), infecting organism (E coli), and treatment (thirdgeneration cephalosporin) were similar in patients with UTI with and without CAP. Conclusions: We show for the first time that UTI is associated with CAP in childhood. We speculate that pelvic organ sensory convergence explains our findings. Key Words: chronic pain, dyspepsia, irritable bowel syndrome, urinary tract infection

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ediatric functional gastrointestinal disorders (FGIDs) affect 2% to 35% of children (1–4). Children with FGID-associated abdominal pain are at risk of developing anxiety, depression, poor quality of life, and school absenteeism (5). Growing evidence implicates early life events and infection in the pathogenesis of Received August 20, 2014; accepted October 8, 2014. From the Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Hospital, Kansas City, MO, the yDivision Pediatric Gastroenterology, Hepatology, and Nutrition, Ann & Robert H. Lurie Children’s Hospital of Chicago, and the zDepartments of Urology and Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL. Address correspondence and reprint requests to John M. Rosen, MD, Division of Pediatric Gastroenterology, Hepatology, and Nutrition, Children’s Mercy Hospital, Kansas City, MO 64108 (e-mail: jmrosen @cmh.edu). The authors report no conflicts of interest. Copyright # 2015 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000599

FGIDs (6,7); however, known risk factors explain only a small percentage of FGIDs in children and other risk factors remain undiscovered. Urinary tract infections (UTI) are the most common serious bacterial infection in the first year of life. In children without anatomic abnormalities, uncomplicated UTIs generally resolve with treatment and are not associated with long-term consequences (8). This seems to contradict murine studies showing that chemical cystitis or acute infection with specific Escherichia coli isolates causes chronic visceral sensitivity that persists long after cystitis resolves (9–11). The demonstration of long-term nonurologic consequences of acute UTI in children would change our understanding of pediatric UTI prognosis and support existing evidence of sensory and functional overlap between organ systems. It would also advance knowledge of risk factors and mechanisms involved in the pathogenesis of one of the most common gastrointestinal complaints in children. Understanding the etiology of FGIDs may provide opportunities for their prevention and treatment. Our study is the first to investigate the relation of early life UTI with chronic abdominal pain (CAP) in children. We hypothesized that having a single uncomplicated UTI in the first year of life increases the risk of developing CAP and FGIDs in childhood.

METHODS In the present study, we queried Ann & Robert H. Lurie Children’s Hospital (formerly Children’s Memorial Hospital) medical records for patients 4 to 18 years old with International Classification of Diseases, 9th edition designation for UTI (599.0 UTI NOS, 771.82 UTI newborn) in the first year of life. Institutional medical records of all of the patients with UTI were reviewed to confirm inclusion and exclusion criteria, demographics, and UTIspecific documentation of positive culture by urethral catheterization, infecting organism, and treatment course. Patients were excluded in cases of unconfirmed or recurrent UTI, abnormal renal ultrasound or vesicoureterogram, surgery, systemic illness associated with pain, or inability to report pain because of developmental delay. Because of the large number of potential children meeting inclusion/exclusion criteria, the patient list was randomized by assigning unique randomly generated integers to each patient and then sorting in an ascending numeric order. Families were contacted by telephone to explain the study. Consenting families underwent a telephone interview that included the parental form of the Questionnaire on Pediatric Gastrointestinal Symptoms—Rome III Version (QPGS-III) (12). The QPGS-III is a validated questionnaire for diagnosing FGIDs according to the Rome III criteria and assesses FGID severity and related disabilities. Rome III requires a minimum of 1 abdominal pain episode per week for at least 8 weeks to meet criteria for abdominal pain–associated FGID. Children with a history of abdominal pain less than once weekly but otherwise meeting Rome III criteria were considered in the present study to have CAP, whereas children who fulfilled all of the Rome criteria were considered to be having abdominal pain– associated FGID. We selected siblings of included patients with

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UTI in Infancy Is a Risk Factor for CAP in Childhood

UTI but without a personal history of UTI, surgery, or systemic disease as control patients because of their similar genetic and socioeconomic background. The study was approved by the Ann & Robert H. Lurie institutional review board. Sample size calculation was based on the estimate that 30% of the patients with UTI would develop CAP, compared with 5% of controls. Considering a 0.05 and power 0.80, 43 patients per group were required to detect this level of difference. Estimates for this calculation were based on data from previous studies by our group using parental telephone interview and the QPGS-III to assess abdominal pain–associated FGIDs in patients and their siblings (13–16). Statistical analysis was conducted with GraphPad Prism (version 4.0; GraphPad Software, La Jolla, CA) using Fisher exact test (2-tailed) and Student t test with significance considered at P < 0.05.

RESULTS A total of 57 patients with UTI (40% boys) and 58 control siblings (57% boys) were enrolled in the study. Mean age at UTI diagnosis was 4.8 months (median 3.8, range 0.2–11), and mean elapsed time since UTI was 9.3 years (median 9.0, range 6–16). At the time of survey, mean age of patients was 9.7 years (median 9.1, range 5–16) and that of controls was 9.6 years (median 9.0, range 5–17). Review of electronic medical records confirmed that performed vesicoureterograms (n ¼ 26) demonstrated no grade III to V vesicoureteral reflux and performed renal ultrasounds (n ¼ 24) were normal. FGIDs were diagnosed in 6 of 57 (10.5%) patients with UTI and 1 of 58 (1.7%) sibling controls (P ¼ 0.06). CAP was identified in 10 of 57 (17.5%) patients with UTI and 2 of 58 (3.4%) sibling controls (P ¼ 0.02) (Table 1). Age at the time of survey was mean 9.7 years in patients with UTI with and without CAP. There was no significant difference in sex between patients with UTI with CAP (30% boys) and without CAP (43% boys) (P ¼ 0.51). Patients with and without CAP also had similar mean age at UTI diagnosis (5.2 months vs 4.8 months) and elapsed time since UTI (9.3 years vs 9.3 years). E coli was the predominant infecting organism by catheterized culture in patients with UTI with and without CAP (6/10 vs 26/47). Other infections included Klebsiella pneumonia, Klebsiella oxytoca, Enterococcus faecalis, Ewingella americana, and E coli/ group B Streptococcus unspecified. Urine culture data were not available for 2 of 10 patients with CAP, and 16 of 47 patients without CAP. Third-generation cephalosporins were the most common antibiotic treatment identified in patients with UTI with CAP (3/10) and without CAP (21/47). One patient without CAP was treated with a second-generation cephalosporin. Other patients did not have explicit documentation of antibiotic therapy. No patient had documentation of UTI-related complication or recurrence, which was verified during the telephone interview.

DISCUSSION Abdominal pain–predominant FGIDs are among the most common disorders in children and adults. The pathogenesis of

FGIDs remains unclear. The prevailing model postulates that FGIDs result from biopsychosocial factors and identifies early life as an age of particular vulnerability. Most clinicians and researchers agree on the importance of early life events; however, investigators have not yet established a time line or defined all of the events predisposing to the development of FGIDs. The few early events that have been linked to the development of FGIDs (17,18) cannot explain the majority of cases in children and adults. If adverse events of early life increase the risk of FGIDs in a substantial proportion of patients, then it holds that new etiologies and mechanisms remain undiscovered. The present study is the first study demonstrating that an extraintestinal infection increases the risk of developing CAP. We identify UTI as a new etiological factor linked to the development of CAP in children. Children with a history of UTI had nearly 6 times odds of developing CAP compared with their siblings. Our results are in line with previous studies showing that acute gastrointestinal infections in children increase the risk of CAP and FGIDs (postinfectious irritable bowel syndrome) years after the infection resolved (19) and that noninfectious gastrointestinal inflammation in the first year of life predisposes to CAP years later (15). Based on clinical research, the potential impact of early life events and intestinal inflammation to chronically alter visceral sensation and increase the rates of FGIDs is well accepted. Although we did not find a significant difference in rates of FGIDs between children with and without a history of UTI (P ¼ 0.06), the study was not powered specifically for FGIDs and it is possible that a larger sample size would demonstrate a link. The results of the present study are strengthened by the fact that prevalence of abdominal pain in our control group is similar to prevalence found in siblings in another of our studies using the same methods (prevalence of CAP in present study 3.4%, prevalence of CAP in a previous study on 246 children 2.4%) (1). UTIs are among the most common serious bacterial infections in childhood. The prevalence of UTIs in childhood is estimated at 7.8% (20) and up to 17% in febrile infants (21). The frequency of UTI in children signifies the importance of identifying possible postinfection sequelae such as CAP. Few studies investigate the overlap between gastrointestinal and genitourinary pain disorders in children. A single pediatric study identified frequent comorbidity between lower urinary tract symptoms and disorders of defecation (22), but did not evaluate overlap of gastrointestinal and genitourinary pain; however, comorbid pathophysiologic alterations of colon and bladder are frequently described in adult patients. Interstitial cystitis (IC) is a common but incompletely understood disorder characterized by chronic pelvic pain and similar psychological comorbidities to FGIDs (23). IC is frequently identified in adults with irritable bowel syndrome (24). Similar to postinfectious FGIDs, antecedent UTI increases the rates of IC after the resolution of infection (25). Coordinated motor and sensory activity among the pelvic viscera relies on neural overlap and ‘‘cross-talk’’ among different organ systems. Although the design of the present study does not allow us to identify the possible mechanisms responsible

TABLE 1. Abdominal pain classification Patients with UTI (n ¼ 57) CAP (%) FGID (%) Functional abdominal pain Irritable bowel syndrome No pain (%)

10 6 5 1 47

(17.5) (10.5) (8.8) (1.8) (82.5)

Sibling controls (n ¼ 58)

Odds ratio (95% CI)

2 (3.4) 1 (1.7) 1 (1.7) 0 56 (96.6)

5.96 (1.24–28.55) 6.71 (0.78–57.60)

CAP ¼ chronic abdominal pain; CI ¼ confidence interval; FGID ¼ functional gastrointestinal disorder; UTI ¼ urinary tract infection.

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for our findings, our study supports experimental data demonstrating that acute cystitis can lead to long-term alterations of intestinal sensitivity (10,26). Persistent cross-organ sensory excitation long after resolution of an acute inflammatory process may constitute 1 mechanism responsible. In rodents, chemical cystitis lowers the sensory threshold to colonic distension through an effect on colorectal afferent sensory nerves (27). Transient neonatal chemical cystitis in rodents leads to adult colonic hypersensitivity in the absence of alterations of bladder or colon histology (10). Pelvic organ cross-sensitization may occur in the opposite direction demonstrated by acute chemical colitis that leads to hyperactive bladder (28,29) and chronic hyperexcitability in both colonic and bladder dorsal root ganglia (30). Experimental studies have also shown cross-organ analgesic effects. In rodents without colonic inflammation, intracolonic lidocaine treatment ameliorated pelvic pain resulting from infection-mediated neurogenic cystitis (26). Our study has several limitations that should be considered. The cohort study design and small sample size does not allow us to conclude that the preceding UTIs are responsible for our findings; however, the sample size used is likely sufficient to detect proportional differences between groups based on a priori power calculations. Each case identified by International Classification of Diseases, 9th edition code was confirmed by medical record review and parent interview to assure that all were true infections. It is possible that some patients with UTI were excluded from the initial cohort because of lack of specific diagnostic code, and information is not available to compare included patients and nonparticipants. Review of medical records did not include all of the UTI treatment and outcomes, so it is unclear whether antibiotic selection or length of therapy affected rates of CAP. Other interventions or events during infancy could confound our results by affecting rates of chronic pain. In conclusion, the present study is the first study linking transient early life cystitis and chronic gastrointestinal symptoms in children. Our study suggests that UTI early in life increases rates of CAP in children; however, this link requires further investigation, given limitations inherent in our study design. Mechanisms postulated to explain the functional and sensory interaction between the genitourinary and gastrointestinal organ systems include central convergence of sensory afferent nerves and overlapping function of pelvic floor musculature (11,31). Prospective studies should be conducted to validate our findings and assess whether different bacterial strains or antibiotic treatments affect the risk of FGID development in children with UTIs.

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8. Feld LG, Mattoo TK. Urinary tract infections and vesicoureteral reflux in infants and children. Pediatr Rev 2010;31:451–63. 9. Rudick CN, Jiang M, Yaggie RE, et al. O-antigen modulates infectioninduced pain states. PLoS One 2012;7:e41273. 10. Miranda A, Mickle A, Schmidt J, et al. Neonatal cystitis-induced colonic hypersensitivity in adult rats: a model of viscero-visceral convergence. Neurogastroenterol Motil 2011;23:683-e281. 11. Malykhina AP, Wyndaele JJ, Andersson KE, et al. Do the urinary bladder and large bowel interact, in sickness or in health? ICI-RS 2011. Neurourol Urodyn 2012;31:352–8. 12. Walker LS, Caplan-Dover A, Rasquin-Weber A. Questionnaire on pediatric gastrointestinal symptoms, Rome III version (QPGS-RIII). In: Drossman DA, Corazziari E, Delvaux M, eds. Rome III: The Functional Gastrointestinal Disorders. McLean, VA: Degnon Associates 2006:963–90. 13. Rosen JM, Adams PN, Saps M. Umbilical hernia repair increases the rate of functional gastrointestinal disorders in children. J Pediatr 2013;163:1065–8. 14. Saps M, Bonilla S. Early life events: infants with pyloric stenosis have a higher risk of developing chronic abdominal pain in childhood. J Pediatr 2011;159:551–4.e1. 15. Saps M, Dhroove G, Chogle A. Henoch-Schonlein purpura leads to functional gastrointestinal disorders. Dig Dis Sci 2011;56:1789–93. 16. Saps M, Lu P, Bonilla S. Cow’s-milk allergy is a risk factor for the development of FGIDs in children. J Pediatr Gastroenterol Nutr 2011; 52:166–9. 17. Beesley H, Rhodes J, Salmon P. Anger and childhood sexual abuse are independently associated with irritable bowel syndrome. Br J Health Psychol 2010;15 (pt 2):389–99. 18. Drossman DA. Irritable bowel syndrome and sexual/physical abuse history. Eur J Gastroenterol Hepatol 1997;9:327–30. 19. Saps M, Pensabene L, Di Martino L, et al. Post-infectious functional gastrointestinal disorders in children. J Pediatr 2008;152:812– 6816.e1. 20. Shaikh N, Morone NE, Bost JE, et al. Prevalence of urinary tract infection in childhood: a meta-analysis. Pediatr Infect Dis J 2008;27: 302–8. 21. Greenhow TL, Hung YY, Herz AM, et al. The changing epidemiology of serious bacterial infections in young infants. Pediatr Infect Dis J 2014;33:595–9. 22. Burgers R, de Jong TP, Visser M, et al. Functional defecation disorders in children with lower urinary tract symptoms. J Urol 2013;189:1886– 91. 23. Berry SH, Elliott MN, Suttorp M, et al. Prevalence of symptoms of bladder pain syndrome/interstitial cystitis among adult females in the United States. J Urol 2011;186:540–4. 24. Chelimsky G, Heller E, Buffington CA, et al. Co-morbidities of interstitial cystitis. Front Neurosci 2012;6:114. 25. Peters KM, Killinger KA, Ibrahim IA. Childhood symptoms and events in women with interstitial cystitis/painful bladder syndrome. Urology 2009;73:258–62. 26. Rudick CN, Chen MC, Mongiu AK, et al. Organ cross talk modulates pelvic pain. Am J Physiol Regul Integr Comp Physiol 2007;293: R1191–8. 27. Brumovsky PR, Feng B, Xu L, et al. Cystitis increases colorectal afferent sensitivity in the mouse. Am J Physiol Gastrointest Liver Physiol 2009;297:G1250–8. 28. Pezzone MA, Liang R, Fraser MO. A model of neural cross-talk and irritation in the pelvis: implications for the overlap of chronic pelvic pain disorders. Gastroenterology 2005;128:1953–64. 29. Ustinova EE, Fraser MO, Pezzone MA. Cross-talk and sensitization of bladder afferent nerves. Neurourol Urodyn 2010;29:77–81. 30. Malykhina AP, Qin C, Greenwood-van Meerveld B, et al. Hyperexcitability of convergent colon and bladder dorsal root ganglion neurons after colonic inflammation: mechanism for pelvic organ cross-talk. Neurogastroenterol Motil 2006;18:936–48. 31. Wolfe-Christensen C, Manolis A, Guy WC, et al. Bladder and bowel dysfunction: evidence for multidisciplinary care. J Urol 2013;190: 1864–8.

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Urinary tract infection in infancy is a risk factor for chronic abdominal pain in childhood.

Adverse early life events are key factors for development of functional gastrointestinal disorders (FGIDs). Urinary tract infection (UTI) is associate...
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