Comparing GERD Manifestations in Children and Adults

G&H Are the presenting symptoms of gastroesophageal reflux disease (GERD) the same in children as in adults?

BG The short answer is no, at least not until children hit adolescence. One of the things that truly separates pediatric reflux–related disease from adult GERD is that the type of GERD symptoms children present with varies with the age of the child. Many adults with GERD present with heartburn, the frequency and severity of which, when measured with validated symptom scales, act as a surrogate disease marker and allow gastroenterologists to conduct population-based epidemiologic studies. Children with GERD do not necessarily start complaining of heartburn until late childhood or early adolescence.

G&H What have these epidemiologic studies reported regarding the prevalence of GERD in children compared to that in adults?

BG The overall results of these studies are quite varied, and their methodologies are limited in their rigor. We really do not know the overall prevalence of GERD in children. The pharmaceutical industry has attempted to develop markers of overall prevalence and unmet need when planning the direction of their marketing for acid suppressants, but it is not clear whether they have over- or underrepresented the overall burden of GERD in pediatric populations. We are only beginning to use validated, age-appropriate symptom assessment instruments that can be utilized in studies. Additionally, we do not have large electronic databases that capture clinical data on ambulatory children to accurately determine the prevalence of GERD in children. The information we do have comes mainly from hospitalized children, who only represent the tip of the iceberg and do not necessarily reflect the overall population and prevalence. In a series of articles published as a supplement to Alimentary Pharmacology & Therapeutics, Francis Chan from Hong Kong and I reported that based on reports from representatives of a number of Indo-Asian countries, GERD appears to be on the rise. Thus, based on my interpretation of the evidence to date, I do think that the overall prevalence of GERD in children appears to be increasing; however, we really do not have a good handle on the overall numbers. One of my “single overriding communication objectives,” to borrow the term from the Center for Diseases Control, is that more research is clearly needed in pediatric populations.

G&H Has it historically been believed that children with GERD may grow up to be adult refluxers?

BG A good disease paradigm to learn from, that parallels our historic understanding of childhood and adulthood GERD, is that of eosinophilic esophagitis. Most adult gas-troenterologists once considered eosinophilic esophagitis to be a pediatric disease that they did not have to worry about. Recently, we have witnessed an explosion of articles identifying and describing eosinophilic esophagitis in adults and, in particular, the process of obtaining an esophageal biopsy for its diagnosis, which was formerly an uncommon endoscopic procedure for adult gastroenter-ologists. Similarly, until the last 5–7 years, both adult and pediatric healthcare providers considered GERD to be a condition that flared and subsided, and invariably was “outgrown” except in a select group of “at-risk” children. There are now longitudinal pediatric and retrospective adult data, including a paper my colleagues and I recently published comparing adult refluxers to adult nonrefluxers that demonstrates that some children with GERD grow up to be adults with GERD, particularly in a few specific at-risk groups (eg, children with cystic fibrosis [CF], neurologic impairment, or obesity).

Nevertheless, the biggest misconception currently in this area remains that children with GERD do not grow up to be adults with GERD. Multiple disease paradigms, including that of inflammatory bowel disease, Helicobacter pylori, functional abdominal pain/functional bowel disease have compelling substantive data demonstrating that children can grow up with these conditions persisting into adulthood. Thus, GERD is not outgrown in all children.

G&H Could you expand on the recent and ongoing research findings on this topic?

BG Hashem El-Serag and Mark Gilger from Baylor College of Medicine have published several papers demonstrating compelling evidence supporting the possibility of pediatric GERD being a lifelong disease. In addition, a paper by Kaijser and associates published in Gastroenterology in 2005 raised a lot of eyebrows when it demonstrated that the risk of esophageal adenocarcinoma was much higher in preterm babies and small-gestational-age babies than in term or normal-for-gestational-age babies. Whether or not this finding will necessarily hold true in future studies is uncertain.

When considering comorbid conditions (ie, conditions that might confer more risk for GERD development), there is a growing body of evidence supporting obesity as a cofactor for GERD, with adult studies demonstrating a direct correlation with increased body mass index and severity of GERD and GERD-related complications. Moreover, some researchers have suggested that the increasing prevalence of obesity in the United States may explain in part the perceived increased prevalence of GERD in pediatric and adult populations. Additionally, there are ample data that demonstrate that if a child, particularly a girl, is obese or morbidly obese by their 12th birthday, there is a significant risk that the child will be obese as an adult. These cause-and-effect data provide additional evidence to suggest that reflux, once established, may not necessarily be outgrown.

Nimish Vakil and a group of international thought leaders in adult GERD published the Montreal classification of GERD in the American Journal of Gastroenterology in 2006. Similarly, a group of international thought leaders in pediatric GERD are developing a set of global definitions for pediatric patients with GERD. Interestingly, GERD phenotypes in adults are thought to remain fairly “fixed” once they present, and some adult researchers believe that there are few GERD phenotypes that progress. However, there are little to no data that help clinicians identify GERD phenotypes in children or whether the disease will progress once diagnosed. For example, it is unclear what it means when an infant with endoscopically diagnosed esophagitis becomes 5, 10, 25, or 40 years old. Research is clearly needed to answer this question.

G&H Do you know of any research refuting the suggestion that there is no relationship between childhood GERD and adult GERD?

BG I do not know that any research has been specifically designed to refute the suggestion that GERD is outgrown, but there clearly has been much commentary on this topic in the recent literature. For one such example, one only needs to read the paper by Susan Orenstein and coworkers in the American Journal of Gastroenterology in 2006 (the same issue in which I wrote an editorial on the topic) and the articulate interchange in the subsequent letters-to-the-editor between Eric Hassall and Susan Orenstein. I think that the reason that pediatricians, on the one hand, and adult physicians, on the other hand, did not consider reflux to be lifelong was due to the lack of longitudinal studies. When examining a 40-year-old patient with erosive esophagitis, adult physicians do not necessarily ask questions regarding the patient's history at 5, 10, or 15 years of age. Unfortunately, the literature is limited on both sides because the critically designed studies that need to be performed have not yet been performed. Furthermore, as mentioned, it would be helpful if we had a biologic marker that could be obtained noninvasively that served as a surrogate of GERD, as we have with tissue transglutaminase or antiendomyseal antibody for celiac disease. Because we have a relatively reliable, validated biologic marker for celiac disease that can be obtained in a blood test, epidemiologic studies and data have demonstrated, surprisingly, that celiac disease is much more prevalent than previously believed in both children and adults. At present, no similar blood test exists for GERD to detect and monitor disease progression in the long term.

G&H Could you expand on the need for longitudinal studies to further study this issue?

BG Longitudinal studies that characterize the chronic nature of childhood-onset GERD and its natural history are certainly needed. One of the substantial problems with accomplishing this task is that these types of studies are not only expensive, but can be logistically difficult to conduct. A well-funded research infrastructure is needed, including research nurses, data-entry and management personnel, and bio-informatics support. In addition, although pediatric patients tend to be more stable until they turn 18–21 years of age and leave home, we live in a society that tends to move, making it difficult to follow these patients longitudinally. Tat being said, there is a big push from the US Food and Drug Administration to set up drug safety and monitoring strategies that are more protocol-driven, systematic, and rigorous than the current MedWatch system. With the need to monitor drug safety, therapy, and side effects in the long term, there is a potential opportunity to make the first step toward setting up the necessary registries, particularly considering that nearly everyone around the world is Internet savvy and has some access, even if limited, to the World Wide Web. In fact, if a biological marker (ie, noninvasive disease surrogate) is identified, the Internet may provide a way to track these patients. If it is possible to identify a group of patients that require monitoring long term and if by treating these at-risk patients aggressively we could potentially reduce overall disease burden by decreasing office visits, emergency room visits, and hospitalizations, it may be possible to decrease overall healthcare costs.

G&H What are the subgroups of children previously alluded to that appear to be at greater risk of having GERD as adults?

BG Five groups merit attention with respect to their increased risk for severe GERD and GERD-related complications. One group that clearly has been shown to be at risk is children with neurologic impairment. As a society, particularly within the US healthcare system, we are struggling with the fact that these children are now growing into adulthood but adult facilities are not necessarily equipped to handle these patients, causing them to be sent back to pediatric facilities. Neurologically impaired children are at much greater risk for having GERD and GERD-related complications for multiple reasons. Moreover, because these children tend to be nonarticulate, they are a difficult group to study, monitor, and conduct surveillance on in clinical trials and epidemiologic studies.

Another group of children at greater risk of experiencing GERD as adults are obese children. Clearly, cross-sectional and longitudinal studies, as mentioned above, are needed that include both adults and children, even if only pre-adolescents and adolescents. It is easy to surmise that this group is clearly at risk for both short- and long-term disease.

The third group of children at risk for severe GERD and its related complications involves those with C F. A nationwide registry of all patients with CF is available and now that CF patients are living longer, data show that these patients are at higher risk for having more severe GERD both in the short- and long-term for multiple physiologic reasons, demonstrating the need for follow-up surveillance of these children.

The fourth group of children involves those with upper gastrointestinal (GI) tract congenital anomalies, for example, children born with trachealesophageal fistulae and esophageal atresia. There have been a number of recent studies demonstrating “adult-type” end-stage GERD complications, including Barrett and esophageal cancer, as well as strictures, in this particular group of children. Yet, because we do not have enough research to guide clinical practice, we do not know how to monitor these children long term. Thus, at present, there are no data to guide a pediatric gastroenterologist with a 16-year-old esophageal atresia patient on how often the patient should be endoscoped or whether this patient should be treated with a high-dose proton pump inhibitor (PPI) therapy until the age of 21 or indefinitely. This group of children is particularly at risk for long-term GERD complications, and ongoing monitoring must be conducted.

The last group with evidence suggesting risk for long-term GERD consists of children with a family history of GERD. There has been a lot of exciting research progress within this area, including compelling data supporting a familial predilection with respect to all esophageal disorders, ranging from GERD symptoms and hiatal hernia to Barrett esophagus. Although pediatric studies need to be performed in larger population-based studies, there does appear to be a greater risk of these children growing up to experience adult GERD.

G&H In patients who experience GERD in both childhood and adulthood, does the GERD usually progress or resolve and return?

BG This is one of the questions we struggle with on a day-to-day basis as clinicians and researchers because the data are just not there yet. Stuart Spechler published a paper in the Journal of the American Medical Association several years ago examining chronic GERD that found that once a patient has erosive esophagitis or severe GERD, most likely they will experience it for most of their life, an observation that has been mirrored in pediatric patients.

Whether there is a progression of disease is the critically important question, which is why Susan Orenstein's paper engendered so much response and counterresponse back-and-forth in the literature—in essence, we just do not have that data. However, it is my impression that GERD does progress in children. If a 15-year-old patient presents with esophageal strictures, I would ask this patient and parent(s) for a history of the perinatal period and early childhood, in addition to the most recent medical history. Anecdotal information shows that these patients experience waxing and waning symptoms, and some patients who were diagnosed with GERD in earlier childhood present later with strictures, providing circumferential evidence that GERD does tend to progress in some patients; however, we do not know for sure. A recent study published in the American Journal of Gastroenterology evaluated erosive esophagitis patients in whom PPI therapy was started and then discontinued. When the researchers examined these patients in follow up, they found that the symptoms had not returned. One might argue that the researchers did not look long enough, but this finding raises the need for more research.

G&H Should the possibility of GERD being a lifelong disease affect the treatment of children with GERD?

BG My cautious, conservative pediatrician answer is that this possibility should be part of the decision-making process. However, I would not necessarily subject a child to long-term PPI treatment unless they really needed it. Thus, the pediatrician's focus should be on treating the individual patient and letting their clinical condition drive treatment. If I was attempting to wean a child off a PPI who was within one of the at-risk groups mentioned above and the disease symptoms returned, I would restart and continue PPI treatment indefinitely. To help gastroenterologists with these decisions, more research and clinical trials clearly need to be performed to provide evidence-based guidelines for guiding length of therapy and methods for monitoring success. In many instances, symptoms tend to recur when the child is taken off PPIs after an initial response to a first course of PPI therapy. Thus, recurrence, which can be the norm, is a dilemma for many gastroenterologists, and it can sometimes be easier to write a prescription than to go through the process of stopping the medicine and observing the effects.

In addition, we should take lessons from the CF registry and the Children's Oncology Group. The latter is a wonderful model because any child in North America who has cancer of any kind is enrolled into a clinical research trial or protocol and database. For most cancers, blood and tissue samples are obtained from the patients, as well as their siblings and parents, and placed into a tissue bank for genetic studies. I think that this is the direction in which we have to head first. A number of pediatric gastroenterologists are trying to loosely form consortia/data registries to start tracking children with chronic GERD. In addition, the Children's Digestive Research Foundation, North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition, in conjunction with the American Board of Pediatrics, is developing an electronic Quality Improvement Module that will be used by pediatricians and pediatric subspecial-ists for board recertification in 2009/2010. However, to my knowledge, at present, there is no systemic or formal proposed study to actually begin looking at these important clinical questions.

G&H Is there any concern about lifelong use of PPIs and their adverse effects, such as damage to the digestive tract?

BG There have been a number of PPI studies recently, the majority of which have been retrospective, have lacked proper control groups, and have limited study designs, which have attributed some type of serious adverse effect to long-term PPI use (such as bone demineralization/ bone fractures, Clostridium difficile, GI/enteric infections, pneumonia, or respiratory infections). Some of the studies have been conducted in pediatric patients, but the majority of studies have been performed in adults. Prospective well-designed studies that carefully characterize long-term use of PPIs accompanied by an accurate assessment of 24hour intragastric pH are critically needed. On the whole, however, PPIs as a class of agents are generally well-tolerated. Eric Hassell and Hashem El-Serag published a paper in the Journal of Pediatrics in 2007 that evaluated long-term use of PPIs and adverse effects in a cohort of 166 children who, at study entrance, were 4 weeks old to 17 years old. Some of these children evaluated had been on PPIs for as long as 11 continuous years. Overall, the investigators found minimal long-term effects. These observations demonstrated that the individual patient's clinical condition should drive whether they should continue on therapy indefinitely or whether the therapy should be discontinued. Being aware of what has been reported in the literature is important for monitoring guidelines.

I would never recommend using a dexa scan on every child placed on a PPI to assess for bone demineralization, but we do employ this test on “at-risk” patients on occasion. If I was treating a 15-year-old who has been on a PPI for 10 years and I have been following him since the age of 5 (and I have several such patients), I would make sure to periodically monitor him for an increase in respiratory infections and signs of abnormal bone metabolism. Most importantly, being transparent and informing the parents about the potential risk of PPIs is essential. Interestingly, no study has carefully weighed the risks and costs of not treating versus treating a patient. Most pharmaco-economic data are based on how costly medicines are; no research has factored into the outcome a patient not receiving therapy in the face of documented disease who would benefit from the intervention.

G&H Is there any evidence of patients developing resistance to PPIs after being on them for a long time?

BG Once we have addressed the need for biomarkers and validated assessment instruments to identify GERD, as mentioned above, we should start compiling groups of centers with the expertise to investigate long-term side effects and monitor drug therapy. Using multicenter consortia and data registries would be an optimal method to address these issues. Unlike with H2 receptor antagonists, there are no data implying that pediatric patients develop resistance to PPIs. A small percentage of patients appear to respond better to one PPI than another. However, although no head-to-head comparative studies with different PPIs in children have been performed, as a whole, there does not appear to be any difference across the board between PPIs with respect to risk of adverse effects and/or tolerance. Several pharmacogenetic studies of cytochrome CYP P450 enzymes in the liver demonstrated that certain ethnic groups are slow metabolizers of the PPIs, whereas others are fast metabolizers. These findings suggest that PPI resistance is not the issue but instead response to therapy relates to how the drug is metabolized.