Functional gastrointestinal disorders (FGIDs) constitute one of the most common reasons for medical consultation in pediatrics (1). Forty-five percent of school-age children experience at least 1 gastroenterological symptom weekly (2). Twenty-eight percent of children miss at least 1 day of school due to abdominal pain (AP) during the school year. Children with functional AP (FAP) have higher anxiety and depression scores and worse quality of life in standardized psychological testing. The pathogenesis of FGIDs is multifactorial. The notion that environmental agents may be involved in the pathogenesis of FGIDs is becoming increasingly accepted. Multiple studies have shown that irritable bowel syndrome (IBS) can develop as a sequela of an acute bacterial gastrointestinal (GI) infection in 4% to 36% of adult patients (3–7). A multicenter study from our group has demonstrated the presence of FGIDs in children following an acute gastroenteritis (AGE) infection of bacterial origin (8).
The onset of postinfectious FGIDs following an episode of AGE of viral origin has been reported in adults (9). Viral AGEs are among the most prevalent infections in children (10) and rotavirus constitutes the most common cause of diarrhea in children. Rotavirus gastroenteritis accounts for 500,000 outpatient visits each year in the United States (11) and one third of hospitalizations for diarrhea worldwide (10). Yet, the possible development of FGIDs following viral AGE in general and specifically due to rotavirus infection in children has not yet been investigated. Establishing a relation between these conditions may advance our understanding of the pathogenesis of FGIDs and could lead to modifications in our current approach to GI infections.
The aim of the present study was to investigate the prevalence of postinfectious FGIDs in children with a history of AGE secondary to rotavirus.
PATIENTS AND METHODS
This is a multicenter cohort study. The results of stool studies from all of the children who presented for acute diarrhea at 2 university hospitals (Children's Memorial Hospital, Chicago, IL and Federico II School of Medicine, Naples, Italy) from January 2002 through December 2004 were reviewed. Inclusion criteria included children from 4 to 18 years with a history of AGE and a microbiological determination of rotavirus infection by stool studies. Exclusion criteria included children unable to communicate, receiving immunosuppression therapy or carrying a diagnosis of inflammatory bowel disease, celiac disease, organ transplant, food allergies, rheumatologic conditions, or those who had positive stool testing for other bacterial or viral infections. The families of children meeting the criteria were contacted by telephone at least 2 years after the positive rotavirus testing. Telephone contacts were attempted until the sample size in the rotavirus-exposed group was complete. Subsequently, each index case was matched with a healthy control from the same hospital of similar age and sex that consulted in the emergency department or at an outpatient site for a well-child visit or an acute nonabdominal trauma within 4 weeks of the index case. The parents were asked a set of questions selected for relevance from the parental report form of the Questionnaire on Pediatric Gastrointestinal Symptoms (QPGSs). The QPGS (12,13) is a validated questionnaire designed to assess symptoms associated with pediatric FGIDs and to establish diagnosis according to the Rome II criteria (1) in children. The QPGS has been previously used in American and Italian children by our research team (8,14). The questionnaire included assessment of the children's bowel habits, GI symptoms, and limitations of activities due to FGIDs. Children complaining of AP were further classified as suffering from IBS, dyspepsia, or FAP. All of the parents and patients provided informed consent and/or assent before their participation. The study was approved by the institutional review board of Children's Memorial Hospital and Federico II Hospital.
Sample Size and Data Analysis
Data for sample size calculation was based on information obtained from a pediatric study on postinfectious bacterial FGIDs (8). It was estimated that 44 exposed children and 44 controls were necessary to achieve a unidirectional α of 0.05 with a power of 0.80, assuming that 36% of those exposed and 11% of controls would develop an FGID. The number of children who reported FGIDs on follow-up in both groups was compared and the relative risk was calculated. Significance between groups was evaluated by χ2 and Fisher exact tests.
We were able to match every exposed child with a child of the same age and sex consulting within 4 weeks of the index case with the exception of 2 children who could not be matched in sex and 1 child who could not be matched in age. The families of 88 patients (46 boys) were successfully contacted. Demographic characteristics and descriptive results for those reporting AP at the time of follow-up are presented in Table 1. There was no statistically significant difference in any of the variables investigated between cases and controls.
Because our study included patients with time to follow-up that ranged from 2 to 4 years, we investigated whether children with shorter time to follow-up were more likely to develop FGIDs. The prevalence of FGIDs by year of infection was 30% in 2002, 9% in 2003, and 12.5% in 2004. No significant correlation was found between time to follow-up and outcome.
This is the first study designed to investigate the relation between proven viral AGE and FGIDs in children. Different from what was previously reported in both adult and children with bacterial AGE and in adults with viral AGE, no significant relation between rotavirus AGE and FGIDs in a long-term follow-up was found.
There has been only 1 published study correlating viral AGE and FGIDs (9). In this study, a group of nurses attending a convention in Canada ingested food tainted with norovirus, resulting in 77% of participants acquiring an acute enteric illness. Twenty-four percent of those who developed acute symptoms developed postinfectious IBS at 3 months versus 3% of those who remained asymptomatic. On follow-up, the prevalence of IBS at 6, 12, and 24 months was similar among exposed and nonexposed individuals. A pediatric study on postviral gastroparesis, a condition that shares with postinfectious FGIDs the absence of an anatomical or biochemical underpinning and an onset that follows a viral infection, found that GI symptoms resolved in all children by 2 years after the acute infection (15). Both studies seem to indicate that postviral GI sequelae are short lived. The design of our study required contacting patients at least 2 years after the exposure. Children in our study may have had GI symptoms that resolved with time before follow-up. However, the fact that we did not find a higher prevalence of FGIDs in patients with more recent exposure to rotavirus seems to suggest otherwise. Although our design precluded us from assessing the intermediary period, we considered it appropriate because our aim was to evaluate the long-term effect of viral conditions. The short-term outcome is being evaluated in a prospective study. We decided against evaluating symptoms during the previous 2-year period due to concerns of accuracy of recall and bias and because such data will be more accurately obtained in the prospective study.
Due to the frequency and importance of rotavirus infection in children we selected this viral strain to conduct our study. It would have also been impossible to achieve an appropriate sample size for other viral infections because obtaining viral cultures is not the standard of care in AGE. The Marshall et al study followed an outbreak of a different viral strain (9). Different strains may result in diverse outcomes. There are no studies in adults following rotavirus infection, and we cannot exclude that postviral FGIDs in children may indeed occur after exposure to other viruses. Studies on adults with postinfectious IBS have shown that those patients with longer and more severe AGE symptoms are more likely to develop FGIDs (3). Although the clinical course of the acute infection was not investigated in our study, viral AGEs are frequently milder than bacterial AGE. A lesser severity in presentation of viral AGE could explain our negative study.
The conclusions of our study may not be applicable to older children. The mean age of the children in our sample was 5.3 years. Our previous study on postinfectious bacterial FGIDs investigated a sample of older children (mean age 8.1 years). Although FGIDs are prevalent in young children (16), these conditions are more commonly diagnosed in older children. Both an epidemiological study on recurrent AP and a study of consultations for AP showed a peak prevalence from 7 to 9 years of age (17,18). We cannot exclude that viral infections could result in postinfectious GI disorders in older children when FGIDs are more common. Although we have based our sample size calculations on existing data on postinfectious FGIDs following a bacterial AGE, we cannot rule out that a different sample size may be required to study children with postinfectious viral conditions.
Our negative study provides valuable information. Establishing causation is always a difficult task. Avoiding confounders is important for research and clinical management. Acute diarrhea and FGIDs are among the most common pediatric conditions. The fact that acute diarrhea is more common in preschool children and FGIDs frequently manifest for first time in school-age children results in many children presenting to the pediatrician with a history of a previous viral diarrhea and GI symptoms of recent onset. This study helps demonstrate that 2 common GI conditions affecting similar organs that present at different times may not be related. The data from our study could also be helpful in the design of future studies. Future larger, prospective studies should focus on short-term effect of AGE or other risk factors to develop FGIDs to increase our understanding of the pathogenesis of FGIDs and the consequences of viral AGE.
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