- OVERVIEW: What every practitioner needs to know
Are you sure your patient has esophagitis? What are the typical findings for this disease?
What other disease/condition shares some of these symptoms?
What caused this disease to develop at this time?
- What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
Would imaging studies be helpful? If so, which ones?
- Confirming the diagnosis
If you are able to confirm that the patient has esophagitis, what treatment should be initiated?
What are the adverse effects associated with each treatment option?
What are the possible outcomes of GERD and esophagitis?
What causes this disease and how frequent is it?
How do these pathogens/genes/exposures cause the disease?
What complications might you expect from the disease or treatment of the disease?
How can GERD and esophagitis be prevented?
What is the evidence?
Ongoing controversies regarding etiology, diagnosis, treatment
OVERVIEW: What every practitioner needs to know
Are you sure your patient has esophagitis? What are the typical findings for this disease?
A wide variety of symptoms and signs are associated with GERD and esophagitis in childhood (See
Clinical Manifestations of GERD in Children
The most common symptoms and signs of GERD depend on the age of the child.
Typical age-related symptoms and signs of GERD and esophagitis are:
1) infant: recurrent/persistent regurgitation with/without vomiting; arching during/after feeds; irritability, difficulty feeding;
2) child: recurrent regurgitation, Sandifer's syndrome (i.e. dystonic neck posturing, torticollis during and after feeds), recurrent/persistent cough,
3) adolescent: heartburn, dysphagia/odynophagia, recurrent/persistent regurgitation
Other common symptoms and signs of GERD and esophagitis are:
1) infant: feeding refusal, recurrent respiratory infection; choking with feeds, poor weight gain (decreased growth velocity), weight loss; apnea (when awake and temporally related to feeds); sleep disturbances
2) child: epigastric pain, supra-umbilical abdominal pain, hoarseness, persistent cough (particularly nocturnal); wheezing; stridor; recurrent pneumonia; dental erosions; anemia; dysphagia, odynophagia, anemia
3) adolescent: recurrent cough (particularly nocturnal); esophageal globus; anemia; dental erosion; laryngeal/pharyngeal inflammation; wheezing; stridor; recurrent pneumonia.
Key Concepts in understanding GERD:
Gastroesophageal reflux (GER) frequently resolves, most commonly by 1 year of age. However, gastroesophageal reflux disease (GERD) can become a chronic condition in some children.
Regurgitation is the predominant symptom in infantile GERD.
In older children, abdominal pain predominates; in adolescents (i.e. by age 15-16 years), heart burn is the predominant symptom.
Both groups can present with extra-esophageal symptoms (e.g., respiratory manifestations).
GERD is optimally diagnosed by clinical suspicion and a response to therapy (i.e. most frequently acid suppression), but diagnostic testing such as upper endoscopy may be indicated to assess for GERD-related complications and/or its mimics (e.g., eosinophilic esophagitis).
Conservative and life-style measures may be adequate to treat uncomplicated, mild GERD in infants, and should be employed in older children and adolescents with GERD, even in the face of pharmacological and/or surgical therapy.
Distinguishing Gastroesophageal Reflux (GER) versus Gastroesophageal reflux disease (GERD):
Gastroesophageal reflux (GER) refers to the passage of gastric contents into the esophagus or oropharynx; with or without vomiting. GER can be a daily, normal physiological occurrence in infants, children and adolescents. The prevalence of regurgitation in infants and children is shown in
Prevalence of regurgitation in infants and heartburn in children, by age. (Adapted from the Gold et al 328and Nelson et al. 4, 329)
Regurgitation or “spitting up” is the most obviously visible symptom. It is characterized by effortless emesis and is seen particularly in the very young child, occurring daily in about 50% of infants <3 month of age. Regurgitation resolves spontaneously in most healthy infants by 12-14 months of age. Reflux episodes sometimes trigger vomiting: the forceful expulsion of gastric contents from the mouth. Vomiting associated with GER is thought to be the result of stimulation of pharyngeal sensory afferents by refluxed gastric contents.
Rumination refers to the effortless regurgitation of recently ingested food into the mouth with subsequent mastication and reswallowing. Rumination syndrome is a distinct clinical entity with regurgitation of ingested food within minutes following meals due to the voluntary contraction of the abdominal muscles.
Gastroesophageal reflux disease(GERD), refers to the symptoms and complications that may develop secondary to persistent GER. Differentiating GER from GERD is criticalfor the clinician in order to avoid unnecessary diagnostic testing and exposure to medications. Recently, there have been three critically important publications which offer the clinician a complete characterization of the evidence-based definitions of GER and GERD, particularly, GERD-related complications as well as the diagnostic and therapeutic approach to the child with GERD. Complications of GERD in children include esophagitis, growth disturbance, and feeding aversion as well as extra-esophageal disease such as respiratory disorders.
The first of the two “GERD definition” publications was the Montreal Definition of GERD in adults published by Vakil et al in 2006, and the second, using similar methodology for the establishment of the definitions, was the Global evidence-based consensus on the definition of GERD in children.
The diagram depicts the overall definition of GERD in children as determined by the Global Consensus Committee. In addition, the diagram provides the designated groups of esophageal and extra-esophageal diseases that the Global Consensus Committee determined to be most likely associated with GERD. In specific the Global Consensus definitions subdivide the esophageal GERD manifestations into symptoms purported to be due to GERD, symptomatic GERD syndromes and syndromes with esophageal injury, as well as those extra-esophageal manifestations that are definitively associated with GERD and those with possible association.
The Global Consensus Definition of Pediatric GERD divided GERD in childhood into two primary categories; esophagealand extra-esophageal. See
The esophageal manifestions were further subdivided into 3 sub-categories:
1) Symptoms purported to be due to GERD infants or younger child (0-8 years), or in older children who lack the cognitive ability to reliably report symptoms:
a) Excessive regurgitation
b) Feeding refusal/anorexia
c) Unexplained crying
e) Sleep disturbance
f) Abdominal pain
2) Symptomatic syndromes in an older child or adolescent who has the cognitive ability to reliably report symptoms:
a) Typical reflux syndrome (as detailed above)
3) Syndromes with esophageal injury (esophagitis and worse)
a) Reflux esophagitis
b) Reflux-associated stricture
c) Barrett's esophagus
d) Esophageal adenocarcinoma
The extra-esophagea manifestations were subdivided into two primary categories:
1) Definite associations
a) Sandifer's syndrome
b) Dental erosions
2) Possible associations
• Pulmonary fibrosis
• Bronchopulmonary dysplasia
b) Laryngotracheal and pharyngeal
• Chronic cough
• Chronic laryngitis
c) Rhinological and otological
• Serous otitis media
• Pathological apnea
• Apparent life-threatening events
What other disease/condition shares some of these symptoms?
Parents and some medical practitioners confuse vomiting with regurgitation, or use other terms for regurgitation (e.g., spitting up, spitting, or spilling). Clinicians should keep the following considerations in mind while working through the differential diagnosis for the infant, child or adolescent who presents with persistent regurgitation and/or vomiting:
Regurgitation: normal regurgitation appears to peak at 2-4 months of age and resolves soon after one year of age. It is typically effortless, although it may appear to be forceful and even projectile in some infants.
Vomiting is distinguished from regurgitation by the following physiologic factors:
1) a central nervous system emetic reflex;
2) retrograde upper intestinal contractions;
3) nausea (symptom reported)
Warning signs and symptoms that recurrent regurgitation and/or vomiting may be due to something other than GERD are shown in
Warning Signs Suggestive of a Non-GERD Diagnosis.(Vandenplas Y, Rudolph CD, Di Lorenzo C, et al. Pediatric gastroesophageal reflux clinical practice guidelines: joint recommendations of the North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition (NASPGHAN) and the European Society for Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN). J Pediatr Gastroenterol Nutr. 2009;49(4):498-547.)
The following diseases/conditions can mimic GERD/esophagitis and should therefore be considered in the differential diagnosis when evaluating the child with symptoms of suspected GERD.
Metabolic/Endocrine disorders: galactosemia, hereditary fructose intolerance, urea cycle defects, amino and organic acidemias, congenital adrenal hyperplasia
Toxic exposures: lead, iron, vitamin A & D, medications (ipecac, digoxin, theophylline, etc.)
Renal disease: obstructive uropathy, renal insufficiency
Cardiac conditions: congestive heart failure, vascular ring or slings (i.e. aberrant vasculature)
Neurologic disorders: hydrocephalus, subdural hematoma, intracranial hemorrhage, intracranial mass, infant migraine, chiari malformation
Gastrointestinal tract obstruction: pyloric stenosis, malrotation with intermittant volvulus, intestinal duplication, Hirschsprung disease, antral/duodenal web, foreign body, incarcerated hernia
Allergic manifestations of the GI tract: dietary protein and/or aeroallergen intolerance and allergy
Infectious conditions: sepsis, meningitis, urinary tract infection, pneumonia, otitis media, hepatitis, viral
Gastrointestinal mucosal and/or motility-related disorders: achalasia, gastroparesis, gastroenteritis, peptic ulcer, eosinophilic esophagitis/gastroenteritis, food allergy, inflammatory bowel disease, pancreatitis, appendicitis
Other general disorders: Pediatric falsification disorder (Munchausen syndrome by proxy), child neglect of abuse, self-induced vomiting, cyclic vomiting syndrome, autonomic dysfunction
Unusual Non-GERD causes of esophagitis in the pediatric patient are listed below:
1) Eosinophilic esophagitis
i) Candida albicans
ii) Herpes simplex
3) Crohn’s disease
4) Vomiting, bulimia
6) Graft-versus-host disease
7) Caustic ingestion
8) Post-sclerotherapy (i.e. chemical sclerosant)/esophageal variceal banding
10) Connective tissue disease
11) Bullous skin diseases
What caused this disease to develop at this time?
Primary Mechanisms of GERD
Transient LES relaxation
Impaired esophageal clearance
Secondary Mechanisms of GERD
Decreased gastric compliance
Delayed gastric emptying
Reduced esophageal capacitance
Mechanisms of Esophageal Complications
Defective tissue resistance
Noxious composition of refluxate
Mechanisms of Airway Complications (Extra-esophageal manifestations)
Impaired airway protection
Altered motor function of the esophagus and/or stomach leading to increased GERD risk and/or esophagitis:The patterns of normal physiological reflux change as a child ages; i.e. in particular, the frequency and quantity of normal reflux are greater in the very young compared to older children, adolescents and adults.
The increase in normal physiological reflux in infants and young children as compared to older children, adolescents or adults is due primarily to a number of factors namely:
1) Higher frequency of feeds infants (i.e. thus increased time over the 24 hour day that the stomach is full);
2) A shorter esophagus and wide angle between the esophagus and stomach in the ≤ 24 months old population, thereby allowing reflux to occur more readily, and
3) The increased amount of time infants spend in the supine rather than upright position.
Mechanisms for GERD in age groups have been carefully studied and characterized, and, are similar across age groups, whether comparing infants, older children or adolescents, and adults (even those that are premature) with GERD to those subjects of similar age that have no GERD. Aerodigestive reflexes (oral, pharyngeal, and esophageal coordinated functions) are fully developed in most children before delivery, by an estimated 38 weeks of gestational age.
If there is dysfunction of motility, troublesome GER-related symptoms can ensue.
These mechanisms include:
1) Transient relaxations of the lower esophageal sphincter
2) Inhibition of esophageal body persistalsis
3) Persistent decrease of absence of LES resting tone
Reflux episodes occur most often during transient LES relaxations unaccompanied by swallowing, which permit gastric contents to flow upward into the esophagus. A minor proportion of reflux episodes occur when the LES fails to increase pressure during a sudden increase in intra-abdominal pressure, or when LES resting pressure is chronically reduced.
Alterations in protective mechanisms allow physiologic GER to become GERD, and can predispose the individual child to esophagitis (microscopic or macroscopic). These include:
1) Insufficient clearing or buffering of refluxate
2) Delayed gastric emptying
3) Abnormalities in esophageal epithelial repair
4) Decreased protective reflexes
5) Hiatal hernia
In hiatal hernia, the anti-reflux barriers at the LES (including the crural support, intra-abdominal segment, and angle of His) are compromised and transient LES relaxations also occur with greater frequency. Erosive esophagitis by itself may promote esophageal shortening and cause hiatal herniation. Hiatal hernia is prevalent in adults and children with severe reflux complications, and hernia size is a major determinant of GERD severity.
Genetic factors leading to increased GERD and/or esophagitis risk: Significant clustering of reflux symptoms, hiatal hernia, erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma can occur in families, suggesting heritability of GERD and its complications. A large Swedish Twin Registry study found increased concordance for reflux in monozygotic, compared to dizygotic, twins. In another more recent study, collagen type III alpha I was determined to be a GERD susceptibility gene and a male risk factor for hiatus hernia in adults.
Therefore, it is important for the clinician who is evaluating the child with suspected GERD to obtain a detailed family history of gastroesophageal reflux disease, upper gastrointestinal disease or esophageal disorders. Several other pediatric patient populations appear to be at higher risk of GERD symptoms, disease and its sequelae (see below).
Other risk factors for GERD and esophagitis in children: High-risk groups include individuals with neurologic or developmental impairment, obesity, many genetic syndromes, esophageal atresia, chronic lung diseases and those with a history of premature birth. These individuals are at increased risk for acute, complicated GERD and for long-term GERD and its sequelae. Additionally, these individuals are at risk for microscopic and macroscopic (visually detected via the endoscope) esophagitis. Persistent GERD also occurs in children who have none of these risk factors.
A significant proportion of adults with endoscopically-proven GERD have a history of GERD-related symptoms in childhood, compared to adults without GERD. Once GERD is clinically or endoscopically evident in a child or adolescent, it continues as chronic life-long condition in a substantial percentage of these patients. Although no population-based epidemiological studies have been performed, it is apparent that GERD is being increasingly recognized in children both in the United States and abroad. There also appears to be a rising prevalence of severe GERD-related outcomes such as erosive esophagitis and Barrett esophagus.
What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?
The diagnosis of GERD is often made clinically based upon troublesome symptoms or signs that may be associated with GER and that bring that child into the pediatrician or pediatric subspecialist for evaluation of the reportable symptoms. However, as mentioned above, subjective symptom descriptions are unreliable in infants and children less than 8 to12 years of age, and many of the purported symptoms of GERD in infants and children are non-specific.
The definition of GERD has been stated previously, and is shown in
Although many tests have been used to diagnose GERD, there are relatively few published studies which compare their utility. More importantly, it is not known whether the diagnostic tests often employed in the evaluation of a child with suspected GERD can predict an individual patient’s response to therapy. Thus, diagnostic investigations are useful to document the presence of GER(D), to detect complications, to establish a causal relationship between GER and symptoms, to evaluate therapy and to exclude other conditions (i.e. GERD masqueraders).
Since there is no test present which can address all these questions, tests must be carefully selected according to the information sought by the clinician evaluating that child with suspect GERD.
Therefore, there really are no specific "laboratory tests" which accurately and solely diagnosis GERD. The major role of the history and physical examination in the evaluation of GERD is to exclude other more worrisome disorders that present with vomiting and to identify complications of GERD. Moreover, it cannot be stressed enough that the typical presenting symptoms of GER in childhood vary with age and underlying medical condition(s) of that child.
As mentioned, for the clinician evaluating a infant, child or adolescent with suspected reflux disease, a thorough history and physical examination can be the key to diagnosis of GERD, with specific attention to the child’s age, as well as the character and frequency of GERD-related symptoms.
The original 2001 North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition clinical practice guidelines for GERD published in children recommended that a trial of acid suppression (i.e. called the proton pump inhibitor, PPI, test) should be considered, based on history and physical examination.
This “PPI test” has been effective in adults, with resolution of symptoms being the diagnostic test for GERD. However, the more recently updated guidelines do not support that approach as strongly.
In adults, a trial of empiric treatment with acid-suppression using a defined dose, defined duration of therapy and clear endpoints has been called the PPI test. The PPI test has particularly been used in adults to differentiate cardiac from non-cardiac chest pain as well as GERD-related complaints of heartburn, chronic cough, and dyspepsia.
Empiric therapy in the adult with suspected GERD has variable sensitivity and specificity as a diagnostic test for GERD, depending upon the comparative gold standard used (endoscopy, pH monitoring, or symptom questionnaires). In children however, the appropriate duration of PPI as the "test" length and the optimal (least but most-effective) dose have not been determined. This has particularly been problematic in the less than 12 months population in which four randomized placebo controlled clinical trials with different PPIs (i.e. omeprazole, lansoprazole, esomeprazole and pantoprazole) did not show a difference at trial conclusion/end point in clinical symptoms of GERD.
The treatment period required to achieve uniform therapeutic responses with PPI therapy probably varies with disease severity, treatment dose and specific symptoms or complications. A 2-week “PPI test” lacks adequate specificity and sensitivity for use in clinical practice, particularly in the pediatric patient. In an older child or adolescent with symptoms suggesting GERD, an empiric PPI-trial is justified for up to 4 weeks. Additionally, improvement following treatment does not absolutely confirm a diagnosis of GERD, since symptoms may improve spontaneously or due to the placebo effect.
Finally, as mentioned, data suggests there is no evidence to support an empiric trial of pharmacologic treatment in infants less than 2 months of age with symptoms suggestive of GERD. Therefore, a high index of suspicion, careful and thoughtful questioning of the child (if older than 6-8 years) and primary caretaker(s) as well as a thorough physical exam in conjunction with an understanding of GERD's spectrum of manifestations and the specific presentations at various ages should lead the clinician to the appropriate management plan.
Would imaging studies be helpful? If so, which ones?
Barium swallow/upper gastrointestinal series
A survey of a random sample (~6,000 members; general pediatricians and subspecialists) of the American Academy of Pediatrics revealed that that the upper gastrointestinal (GI) series is the preferred test of pediatricians for children with suspected GERD. However, the upper gastrointestinal series with barium contrast as a diagnostic approach for GERD is neither sensitive nor specific for diagnosing this condition.
The upper GI series is useful to detect anatomic abnormalities such as esophageal stricture, hiatal hernia, achalasia, tracheoeospahgeal fistula, intestinal malrotation, or pyloric stenosis which may be considered in the differential diagnosis.
For the diagnosis of "true" GERD, the sensitivity, specificity and positive predictive value of the upper GI series ranges from 29%-86%, 21%-83% and 80%-82%, respectively, when compared to esophageal pH monitoring.
The brief duration of the upper GI series produces false negative results, while the frequent occurrence of non-pathological reflux during the examination produces false positive results. Therefore, routine performance of upper GI series to diagnose GER and GERD is not justified
In gastro-esophageal scintigraphy, food or formula labeled with 99Technitium is introduced into the stomach, following which the stomach, esophagus and lungs are continuously imaged for evidence of GER and aspiration. The nuclear scan evaluates postprandial reflux and demonstrates reflux independent of the gastric pH. Scintigraphy can also provide information about gastric emptying, which may be delayed in children with GERD. A lack of standardized techniques and the absence of age-specific norms limit the value of this test.
Sensitivity and specificity of a one hour scintigraphy for the diagnosis of GERD are 15%-59% and 83%-100%, respectively, when compared to 24-hour esophageal pH monitori. Late postprandial acid exposure detected by pH monitoring may be missed with scintigraphy. Comparisons of scintigraphy to MII, pH monitoring, and with symptom-based diagnosis are lacking.
Gastroesophageal scintigraphy scanning can detect GER episodes and aspiration of gastric contents occurring during or shortly after meals, but its reported sensitivity for microaspiration is relatively low.
Evidence of pulmonary aspiration may be detected during a one-hour scintigraphic study or on images obtained up to 24 hours after administration of the radionuclide. A negative test does not exclude the possibility of infrequently occurring aspiration. One study of children with refractory respiratory symptoms found that half had scintigraphic evidence of pulmonary aspiration. However, aspiration of both gastric contents and saliva also occurs in healthy adults during deep sleep.
At present, there is no role for nuclear scintigraphy in the diagnosis and management of GERD in pediatric patients.
Ultrasonography is relatively new technique for diagnosing gastroesophageal disease in adults. However, at present, although there is potential for utility as the technology and methodology become more refined, ultrasound is not recommended as a test for pediatric GERD.
Ultrasonography of the GE junction can detect fluid movements over short periods of time and thereby can detect non-acid reflux events. Ultrasound can also detect hiatal hernia, measure the length and position of the LES relative to the diaphragm and demonstrate the gastroesophageal angle of His.
When compared to the results of 24 hour esophageal pH testing as a diagnostic test for GERD, the sensitivity of color Doppler ultrasound performed for 15 minutes post-prandially is about 95% with a specificity of only 11%, and there is no correlation between reflux frequency detected by ultrasound and reflux index detected by pH monitoring.
Esophageal pH monitoring
Intraluminal esophageal pH monitoring measures the frequency and duration of acid esophageal reflux episodes reaching the distal esophagus. Most commercially available systems include a catheter for nasal insertion with one or more pH electrodes (antimony, glass or ion-sensitive field effect) arrayed along its length and a system for data capture, analysis and reporting.
Slow electrode response times (antimony being the slowest) do not substantially alter the assessment of total reflux time, but may affect the accuracy of correlation between symptoms and reflux episodes.
Wireless capsule for prolonged pH monitoring: Recently, wireless sensors that can be clipped to the esophageal mucosa during endoscopy (i.e. Bravo™ capsule) have allowed pH monitoring without a nasal cannula for up to 48 hours of monitoring. Placement of wireless electrodes requires upper endoscopy, and the accompanying sedation or anesthesia, and comfort has been an issue in some studies. The size of current wireless electrodes precludes their use in small infants. Benefits, risks and indications for wireless electrode monitoring have also not been fully defined in children.
By convention, a drop in intraesophageal pH below 4.0 for greater than 5 seconds is considered an acid reflux episode. This cut-off was initially chosen because heartburn induced by acid perfusion of the esophagus in adults generally occurs at pH <4.0. Note: the paradigm for symptom and/or disease causation may not be the same for younger children and particularly infants. However, the duration of esophageal acidification necessary to cause symptoms or induce mucosal injury has not been clearly established, particularly in the pediatric patient population.
Although interpretation of pH monitoring data is simplified by computerized analysis, visual inspection of the tracing is required to detect artifacts and evaluate clinical correlations.
Common parameters obtained from pH monitoring include the total number of reflux episodes, the number of reflux episodes lasting >5 minutes, the duration of the longest reflux episode, and the reflux index or RI (percentage of the entire record that esophageal pH is <4.0). The RI is the most commonly used summary score.
The value of esophageal pH-metry for diagnosis and management of pediatric GERD has been questioned as having a lack of utility overall. Esophageal pH-metry is insensitive to weakly acid and non-acid reflux events, and the response times of the most widely used electrodes are slow. These barriers are overcome by multiple intraluminal impedance (MII) monitoring and/or by the use of ion-sensitive field effect electrodes.
Esophageal pH monitoring can correlate poorly with symptom severity and with response to therapy in pediatric patients. In infants with suspected GERD, an abnormal pH study (RI>10%) was associated only with pneumonia, apnea with fussing, defecation less than once a day and constipation. An abnormal RI is more frequently observed in adults with erosive esophagitis than in normals or those with non-erosive reflux disease, but there is substantial overlap among groups. In pediatric patients, the calculated area under the pH 4.0 curve has been associated with erosive esophagitis (Gold B, et al, unpublished data).
Esophageal pH monitoring may be abnormal in patients with other disorders, including gastric outlet obstruction, motility disorders and esophagitis due to other disorders, including eosinophilic esophagitis.
Esophageal pH monitoring may be useful for evaluating the efficacy of anti-secretory therapy. In children with esophagitis, normal esophageal pH monitoring suggests a diagnosis other than GERD.
Multichannel intraluminal esophageal impedance
Multichannel intraluminal impedance (MII) is a procedure for measuring the movement of fluids, solids and air in the esophagus. MII is a relatively new technology that, in comparison to pH monitoring, provides a more detailed description of substances within the esophageal lumen and correlation with symptoms. MII measures changes in the electrical impedance (i.e., resistance) between multiple electrodes located along an esophageal catheter.
Esophageal impedance tracings are analyzed for the typical changes in impedance caused by the passage of liquid, solid, gas or mixed boluses. If the impedance changes of a liquid bolus appear first in the distal channels and proceed sequentially to the proximal channels, they indicate retrograde bolus movement, i.e.,gastroesophageal reflux. The direction and velocity of a bolus can be calculated using the defined distance between electrodes and the time between alterations in the impedance pattern of sequential electrode pairs. The upward extent of the bolus and the physical length of the bolus can also be evaluated. Note: MII can detect very small bolus volumes and these need to be correlated via the expert interpreter/reader with clinical symptoms of the presenting patient.
For improved performance, MII and pH electrodes can be combined on a single catheter. The combined measurement of pH and impedance (pH/MII) provides additional information as to whether a refluxed material is acid, weakly acidic or non-acidic.
Recent studies have found variable reproducibility of MII studies in pediatric patients. However, more recently, evaluation of MII recordings is aided by automated analysis tools which may improve accuracy. Until the currently available automatic analysis software has been validated, a visual reading of the data is still required.
It is important to note that normal values for all age groups with this newer technology, as promising as it will be for the diagnosis and characterization of GERD in children have not yet been established.
The combination of pH/MII with simultaneous monitoring of other parameters using video polysomnography or manometry has proven useful for the evaluation of correlations between reflux episodes and apnea, cough, other respiratory symptoms and behavioral symptoms. The technology is especially useful, compared to the pH-only study, when gastric contents are non-acidic, as in the post prandial period or when patients are taking acid blockers. Whether this new technology will provide measurements that vary directly with disease severity, prognosis and response to therapy has yet to be determined.
Endoscopy and beyond...
There are a number of invasive approaches to support the diagnosis of clinically suspected GERD in the pediatric patient. Clinicians employ laryngoscopy, bronchoscopy and alveolar lavage, endoscopy, esophageal and laryngeal biopsies, pH monitoring in the hypopharynx and multi-channel intraluminal impedance monitoring to diagnose GERD in pediatric patients presenting with extraesophageal symptoms. However, none of these tools independently establishes the diagnosis of GERD with extraesophageal symptoms.
When hematemesis or occult bleeding occurs in the face of GERD symptoms, esophagogastroduodenoscopy (EGD) or upper gastrointestinal endoscopy may be indicated to assess for the presence and severity of GERD. EGD can also detect erosive (macroscopic) or histologic (microscopic) esophagitis, strictures, Barrett’s esophagus, and eosinophilic esophagitis, a potential GERD masquerader.
EGD allows the pediatric gastroenterologist to have direct visual assessment of the esophageal mucosa; giving the clinician a macroscopic perspective. Random or targeted biopsies enable evaluation of the microscopic anatomy. Macroscopic abnormalities associated with GERD include esophagitis, erosions, ulcers, strictures, hiatal hernia, areas of possible suspected esophageal metaplasia, and polyps.
While endoscopy can detect strictures, subtle degrees of narrowing are better shown on barium contrast study. Unfortunately, anatomic abnormalities like malrotation and achalasia cannot be diagnosed by endoscopy. These and other anatomic and motility disorders of the esophagus are better evaluated by barium radiology or motility studies.
Recent Global Consensus guidelines define reflux esophagitis as the presence of endoscopically visible breaks in the esophageal mucosa at or immediately above the GE junction. Evidence from adult studies indicates that visible breaks in the esophageal mucosa are the endoscopic sign of greatest interobserver reliability. Mucosal erythema or an irregular Z-line are not reliable signs of reflux esophagitis.
Grading the severity of esophagitis, using a recognized endoscopic classification system is useful for evaluation of the severity of esophagitis and response to treatment.
Classification of Esophagitis
The diagnostic yield of endoscopy is generally greater if multiple samples of good size and orientation are obtained from esophageal mucosal biopsy sites that are identified relative to major anatomic features. Several variables impact on the validity of histology as a diagnostic tool for reflux-associated esophagitis, and/or the ability to rule out other etiologies of esophageal disease (e.g., eosinophilic esophagitis), including:
1) Sampling errors due to the patchy distribution of inflammatory changes,
2) A lack in standardization of biopsy location,
3) Variable methodologies for tissue processing and
4) Variable interpretation of morphometric parameters.
Histology may be normal even in some patients with erosive reflux esophagitis; conversely, it may be abnormal in non-erosive reflux disease. Moreover, symptom severity has not been shown to correlate with either macroscopic or endoscopic findings in the child who has undergone diagnostic upper endoscopy.
Histologic findings of eosinophilia, elongation of papillae (rete pegs), basal cell hyperplasia, and dilated intercellular spaces (DIS, or spongiosis) are neither sensitive nor specific for reflux esophagitis. These are nonspecific reactive changes that may be found in esophagitis of other causes. Recent studies have shown considerable overlap between the histology of reflux esophagitis and eosinophilic esophagitis. Many histologic parameters are influenced by drugs used to treat esophagitis or other disorders.
GERD is likely the most common cause of esophagitis in children, but other disorders such as eosinophilic esophagitis (EoE), Crohn disease, and infections also cause esophagitis. EoE and GERD have very similar symptoms and signs, and can be best distinguished by endoscopy with biopsy. A key difference endoscopically is that EoE is not generally an erosive disease, but has its own typical endoscopic features such as speckled exudates, trachealization of the esophagus, or linear furrowing. In up to 30% of cases, however, the esophageal mucosal appearance is normal.
When eosinophilic esophagitis is considered as part of the differential diagnosis, it is advisable for the clinician to take esophageal biopsies from the proximal, mid and distal esophagus. Mucosal eosinophilia may be present in the esophageal mucosa in asymptomatic infants <1 year of age and in symptomatic infants eosinophilic infiltrate may be due to milk protein allergy.
Thus, at present, although hotly debated by pediatric gastroenterologists, there is insufficient evidence to support the use of histology to diagnose or exclude GERD. Clearly, more multicenter studies need to be done, particularly those that utilize a standard approach to anatomic landmarks, biopsy collection and histological characterization in order to address this issue. Currently, the primary role for esophageal histology is to rule out other conditions in the differential diagnosis, in particular - esophagitides such as eosinophilic esophagitis, Crohn’s disease, Barrett esophagus, infection, and others.
Confirming the diagnosis
Clinical algorithms that can guide the clinician in managing the infant, child or adolescent with suspected GERD have been recently published by the North American and European Societies for Pediatric Gastroenterology Hepatology and Nutrition (NASPGHAN, ESPGHAN).
These algorithms are listed below and shown in
Approach to the infant with recurrent regurgitation and vomiting - See
Approach to the infant with recurrent regurgitation and weight loss - See
Approach to the older child or adolescent with heartburn - See
Approach to the child with asthma that may be worsened by GERD - See
Signs of complicated GERD - See
Approach to the Infant with Recurrent Regurgitation and Vomiting
Approach to the Infant with Recurrent Regurgitation and Weight Loss
Approach to the Older Child or Adolescent with Heartburn
Approach to Child with Persistent Asthma
Signs of Complicated GERD
Development of Clinical Guidelines for GERD
The guidelines were developed using the well described and previously published nominal group technique for consensus development . The levels of evidence were determined using published and previously validated methodologies. A member of the committee was an epidemiologist who was responsible for the literature search and initial article reviews; all articles were written in English and published between March 1999 (the date of the previous review) and October 2008 were identified using PubMed and CINAHL.
Letters, editorials, case reports, and reviews were eliminated from the initial evaluation. Additional articles were identified by members of the committee, from bibliographies found in other articles, and study results in the public domain on the U.S. National Institutes of Health website. These included review articles as well as articles that involved the care of adults. A total of 377 articles related to therapy, and 195 articles related to etiology, diagnosis and prognosis were reviewed for the guideline paper.
Articles were evaluated using the Oxford Centre for Evidence-based Medicine Levels of Evidence. Using the Oxford Grades of Recommendation11 the quality of evidence of each of the recommendations made by the Committee was determined and is summarized in Appendices A to C of the published manuscript.
Sections of the document were written by individual committee members then reviewed and edited by a separate committee member; in most instances both a NASPGHAN and ESPGHAN member participated in preparing the initial draft of each section. These sections and other evidence available in previously prepared tables that listed references and graded the quality of each reference were distributed, then reviewed and discussed to achieve consensus agreement in conference sessions. The document was then distributed to all NASPGHAN and ESPGHAN members for comment.
Further revisions were made based on their suggestions following a phone conference of committee members. Complete voting anonymity could not be maintained through the revision process but only one of the co-chairs (CR) was aware of EMAIL votes. Following final committee approval, the document was submitted to the Executive Councils of NASPGHAN and ESPGHAN for endorsement.
Categories of the quality of evidence for the management algorithms:
1) Level A: Consistent Randomised Controlled Clinical Trial, cohort study, all or none, clinical decision rule validated in different populations.
2) Level B: Consistent Retrospective Cohort, Exploratory Cohort, Ecological Study, Outcomes Research, case-control study; or extrapolations from level A studies.
3) Level C: Case-series study or extrapolations from level B studies
4) Level D: Expert opinion without explicit critical appraisal, or based on physiology, bench research or first principles.
If you are able to confirm that the patient has esophagitis, what treatment should be initiated?
The primary goals of treatment are to resolve symptoms, improve overall quality of life, and resolve and prevent complications of GERD.
In “uncomplicated” infantile GER, conservative measures such as thickening the formula, giving smaller feeds more frequently, and upright positioning for at least 30 minutes after feeds may be sufficient to decrease regurgitation. In addition, thickening can increase the caloric density of the formula, which may benefit infants who have weight gain issues as a result of GER (1 tablespoon of rice cereal per 2 ounces of formula increases the caloric density to 27 kcal per ounce). Prone positioning may decrease regurgitation but is not recommended due to the increased risk for sudden infant death syndrome.
If milk protein intolerance or allergy is suspected, a 2-4 week trial of protein (partial whey or casein) hydrolysate formula should be considered.
Lifestyle changes: feeding changes in infants
About 50% of normal 3-4 month old infants regurgitate at least once a day and up to 20% of caregivers in the United States seek medical help for this normal behavior. Breast-fed and formula-fed infants have a similar frequency of physiologic GER, although the duration of reflux episodes measured by pH probe may be shorter in breast-fed infants.
A subset of infants with allergy to cow’s milk protein experience regurgitation and vomiting indistinguishable from that associated with GER. In these infants, vomiting frequency decreases significantly (usually within 2 weeks) after the elimination of cow's milk protein from the diet, and re-introduction causes recurrence of symptom. Studies support a trial of up to 4 weeks of extensively hydrolyzed or amino-acid formula in formula-fed infants with bothersome emesis. Cow’s milk protein passes into human breast milk in small quantities. Breast-fed infants with regurgitation and vomiting may therefore benefit from a trial of withdrawal of cow's milk and eggs from the maternal diet. The symptoms of infant GER are almost never so severe that breast-feeding should be discontinued.
There are no studies specifically evaluating soy protein allergy in infants with regurgitation and vomiting, or the role of soy protein-based formula in the treatment of infants with regurgitation.
Adding thickening agents such as rice cereal to formula or milk does not decrease the time with pH<4 (reflux index) measured by esophageal pH studies, but does decrease the frequency of overt regurgitation. Studies with combined pH/MII show that the height of reflux in the esophagus is decreased with thickened formula. One study reported an improvement in esophageal pH parameters with cornstarch-thickened formula. Another study showed no change in esophageal impedance parameters of premature infants receiving corn-starch thickened human milk. In the United States, rice cereal is the most commonly used thickening agent for formula.
Note:Excessive calorie intake is a potential problem with long term use of feedings thickened with rice cereal or cornstarch. Thickening a 20 kcal/oz infant formula with one tablespoon of rice cereal per ounce increases the caloric density to 34 kcal/oz. Thickening with one tablespoon per two ounces of formula increases the caloric density to 27 kcal/oz. Rice cereal-thickened formula decreases the volume of regurgitation but may increase coughing during feedings. Formula with added rice cereal usually requires using a nipple with an enlarged hole to allow adequate flow.
Commercial anti-regurgitant (AR) formulas contain processed rice, corn or potato starch, guar gum or locust bean gum and for the most part are available in Europe, Asia and the United States. These formulas decrease overt regurgitation and vomiting frequencies compared with unthickened formulas or formulas thickened with rice cereal. A potential advantage of AR formulas over formula with added cereal or starch is that the former are designed to contain a caloric density, osmolarity, protein, calcium, and fatty acid content appropriate to an infant’s nutritional needs when taken in normal volume.
The use of AR-formulas and formulas with added thickener results in a decrease of observed regurgitation, although the difference may be small. Although the actual number of reflux episodes detected by pH-metry of MII may not decrease, the reduction in regurgitation is often welcomed as an improvement in quality of life for caregivers and possibly the infant. The impact of thickened formula on the natural history of physiologic GER or GERD has not been studied. The allergenicity of commercial thickening agents is uncertain and the possible nutritional risks of long-term use require further study.
A largely untested potential advantage of AR formulas is that, because they thicken in the stomach, they do not require a large bore nipple hole and do not substantially increase sucking effort. In vitro studies have suggested a decrease in the absorption of minerals and micronutrients from formulas commercially thickened with indigestible carbohydrates. The clinical significance of this is unclear.
There are rare infants with GERD who are unable to gain weight despite conservative measures in whom nasogastric or nasojejunal feeding may be beneficial. Similarly, naso-jejunal feeding is occasionally useful in infants with recurrent GER-related pneumonia to prevent recurrent aspiration. Although these approaches to therapy are widely utilized, there are no controlled studies comparing them to pharmacologic or surgical treatments.
Enteral continuous feeds can often be used as a bridge until the regurgitant predominat portion of GERD resolves in the infant, allowing weight gain and growth to continue and potentially avoiding surgical management.
Positioning therapy for infants
Several studies in infants have demonstrated significantly decreased acid reflux in the flat prone compared to flat supine position. There is conflicting evidence, as to whether infants placed prone with the head elevated have less reflux than those kept prone but flat. The amount of reflux in supine infants with head elevated is equal or greater than in infants supine and flat. The semi-supine positioning attained in an infant car-seat actually has been shown by some studies to exacerbate GER in infants.
Although the full upright position appears to decrease measured reflux, studies have shown that using formula thickened with rice cereal is more effective in decreasing the frequency of regurgitation than upright positioning after all feeds.
In the 1980s, prone positioning was recommended for the treatment of GERD in infants because studies showed less reflux in this position. Interestingly, prone sleep positioning is associated with longer uninterrupted sleep periods, and supine sleep positioning with more frequent arousals and crying. However, concerns regarding the association between prone positioning and sudden infant death syndrome (SIDS) required a reassessment of the benefits and risks of prone positioning for GERD treatment.
A Scandanavian study (i.e. Nordic epidemiological SIDS study) demonstrated that the mortality from SIDS was >10 times higher in prone-sleeping infants and 3 times higher in side-sleeping infants than in supine infants.
Therefore, prone positioning is acceptable if the infant is observed and awake, particularly in the postprandial period, but prone positioning during sleep can only be considered in infants with certain upper airway disorders where the risk of death from GERD outweighs the risk of SIDS. Prone positioning may be beneficial in children over 1 year of age with GER or GERD whose risk of SIDS is negligible.
Lifestyle changes in children and adolescents
Lifestyle changes often recommended for children and adolescents with GER and GERD include dietary modification, avoidance of alcohol, weight loss, positioning changes, and cessation of smoking. Most studies investigating these recommendations have been performed in adults, thus their applicability to children of all ages is uncertain.
A review of lifestyle changes in adults with GERD concluded that only weight loss improved pH profiles and symptoms. Although alcohol, chocolate, and high-fat meals reduce LES pressure, only a few studies have evaluated the impact of these factors on symptoms.
Tobacco smoke exposure is associated with increased GER symptoms, yet neither tobacco nor alcohol cessation has been shown to improve esophageal pH profiles or symptoms.
Current evidence generally does not support (or refute) the use of dietary changes to treat GER beyond infancy.
Expert opinion suggests that children and adolescents with GERD should avoid caffeine, chocolate, alcohol and spicy foods if they provoke symptoms.
Based on the current epidemic of obesity in the United States, and the concordant increase in GERD, at least in adults, it is logical that reducing or eliminating obesity likely decreases GER. Exposure to tobacco should be avoided because, among many reasons, it has been linked to adenocarcinoma of the esophagus in adults, and more importantly, to esophagitis development in children.
Although it is recommended that life style changes should be implemented, irrespective of additional therapeutic interventions (i.e. medication) is not known whether any lifestyle changes have an additive benefit in pediatric patients receiving pharmacological therapy.
The major pharmacologic agents currently used for treating GERD in children are gastric acid buffers, mucosal surface barriers and gastric anti-secretory agents.
Since the withdrawal of cisapride from commercial availability in most countries, prokinetic agents have been less frequently used, though domperidone is commercially available in Canada and Europe.
Comparisons between pharmacologic agents for GERD in children have been impaired by small sample size, absence of controls, and use of unreliable endpoints such as esophageal histology.
Antacids directly buffer gastric contents, thereby reducing heartburn and potentially healing esophagitis.
On-demand use of antacids may provide rapid symptom relief in some children and adolescents with non-erosive reflux disease. Although this commonly used practice appears to carry little risk, it has not been formally studied in children.
Intensive, high-dose antacid regimens (e.g., magnesium hydroxide and aluminum hydroxide; 700 mmol / 1.73 m2/day) are as effective as cimetidine for treating peptic esophagitis in children aged 2-42 months. No studies of antacids to date have employed combined esophageal pH/MII to assess outcome.
Surface protective agents containing either alginate or sucralfate:
Alginates are insoluble salts of alginic acid, a component of algal cell walls. In older studies of alginic acid therapy in pediatric patients with GERD, the liquid preparations used also contained buffering agents, making it difficult to isolate the effect of the surface protective agent itself. Alginate is also available as tablets, and is useful for on-demand treatment of symptoms.
Sucralfate is a compound of sucrose, sulfate and aluminum which, in an acid environment, forms a gel that binds to the exposed mucosa of peptic erosions. In adults, sucralfate (1 g po QID) decreased symptoms and promoted healing of non-erosive esophagitis.
None of the surface agents is recommended as sole treatment for severe symptoms or erosive esophagitis. Moreover, the long-term or prolonged use of the surface agents, even as adjunctive therapy for GERD-related symptoms and esophageal disease, is not advised.
Histamine-2 receptor antagonists H2RAs
Histamine-2 receptor antagonists (H2RAs) decrease acid secretion by inhibiting histamine-2 receptors on gastric parietal cells.
One dose of ranitidine (5 mg/kg) has been shown to increase gastric pH for 9-10 hours in infants. Pharmacokinetic studies in 4-11 year old children suggest that peak plasma ranitidine concentration occurs 2.5 hours after dosing with a half life of 2 hours. Gastric pH begins to increase within 30 minutes of administration and the effect lasts for 6 hours. In an infant study, ranitidine (2 mg per kg per dose orally) reduced the time that gastric pH was below 4.0 by 44% when given twice daily and by 90% when given three times per day. Tachyphylaxis to intravenous ranitidine have been observed after 6 weeks, and tolerance to oral H2RAs in adults is well recognized. The efficacy of H2RAs in achieving mucosal healing is much greater in mild esophagitis than in severe esophagitis.
In infants and children with erosive esophagitis, significant improvement in clinical and histopathology scores was demonstrated in cimetidine-treated patients compared to those given placebo. Extrapolation of the results of a large number of adult studies to older children and adolescents suggests that H-2 receptor antagonists may be used in these patients for the treatment of GERD symptoms and for healing esophagitis, although H2RAs are less effective than PPI for both symptom relief and healing of esophagitis.
Proton pump inhibitors (PPIs)
PPIs inhibit acid secretion by blocking Na+, K+ ATP-ase, the final common pathway of parietal cell acid secretion, often called the proton pump. Studies in adults have shown that PPI therapy produces higher and faster healing rates for erosive esophagitis than H2RAs. Although there have been no head-to-head clinical trials in children comparing the H2RAs to PPIs, data strongly suggests that PPIs are superior.
The superior efficacy of PPIs is largely due to their ability to maintain intragastric pH at or above 4 for longer periods and to inhibit meal-induced acid secretion, a characteristic not shared by H2RAs. In contrast with H2RAs, the effect of PPIs does decrease with chronic or long-term use. The potent suppression of acid secretion by PPIs also results in decrease of 24-hour intragastric volumes, thereby facilitating gastric emptying and decreasing the volume of reflux.
PPIs currently approved for use in children in North America are omeprazole, lansoprazole, esomeprazole, pantoprazole, and rabeprazole. In Europe, omeprazole, lansoprazole and esomeprazole are approved. To date, the only PPI that has been approved for use in infants < 1 year of age either in North America or Europe is esomeprazole.
Children 1-10 yrs of age appear to have a greater capacity to metabolize some PPIs compared to adolescents and adults. Studies demonstrated that pediatric patients less than 10 years of agerequire higher per kilogram doses to attain the same acid blocking effect, or area-under-the-curve. However, these observations may not apply to each of the PPIs. There are few pharmacokinetic data for PPIs in infants, but studies indicate that infants < 6 months may have a lower per kilogram dose requirement than older children and adolescents.
Interestingly, there is a great debate amongst pediatric gastroenterologists, and pediatricians about the pros and cons of pharmacological management in the less than 12 month old population with suspected GERD.
The number of PPI prescriptions written for infants has increased many-fold in recent years despite the absence of evidence for acid-related disorders in the great majority. Four placebo controlled trials with different PPIs have been performed in the under 12 month population and none of have demonstrated a significant benefit in the treatment group compared to the placebo based on symptom assessment. The Global Consensus Committee wrestled with this area enthusiastically but without final definitive decisions due to the lack of data. Infant responses to many stimuli, including GER, are nonspecific and need to be characterized with careful, thoughtful and sensitive questioning by the healthcare provider.
The combined NASPGHAN and ESPGHAN committee suggested that there is currently insufficient evidence to justify the routine use of prokinetic agents such as domperidone, baclofen, cisapride, metoclopramide, erythromycin, or bethanechol for GERD in pediatric patients. Nevertheless, despite the lack of definitive evidence for efficacy, certain prokinetic agents continue to be used for pediatric GERD continues.
Cisapride is a mixed serotonergic agent that facilitates the release of acetylcholine at synapses in the myenteric plexus, thus increasing gastric emptying and improving esophageal and intestinal peristalsis. After cisapride was found to produce prolongation of the QTc interval on electrocardiogram, a finding increasing the risk for sudden death, its use was restricted to limited-access programs supervised by a pediatric gastroenterologist and to patients in clinical trials, safety studies or registries.
Domperidone and metoclopramide are anti-dopaminergic agents that facilitate gastric emptying. A recent systematic review of studies on domperidone identified only four RCTs in children, none providing “robust evidence” for efficacy of domperidone in pediatric GERD. Domperidone occasionally causes extrapyramidal central nervous system side effects and rarely produces QTc prolongation on electrocardiogram.
Metoclopramide has cholinergic and mixed serotonergic effects. A meta-analysis of 7 randomized controlled trials of metoclopramide in developmentally normal children 1 month to 2 years of age with symptoms of GER found that metoclopramide reduced daily symptoms and the RI in children 1 month to 2 years of age but was associated with significant side effects. Another study found that metoclopramide and placebo equally reduced symptom scores of infants with GER.
Bethanechol, a direct cholinergic agonist, studied in a few controlled trials has uncertain efficacy and a high incidence of side effects in children with GERD.
Erythromycin, a dopamine receptor antagonist, is sometimes used in patients with gastroparesis to hasten gastric emptying. Its role in therapy of GER and GERD has not been investigated.
Baclofen is a gamma-amino-butyric-acid receptor agonist that reduces both acid and non-acid reflux in healthy adults and in adults with GERD. In children, it was shown to accelerate gastric emptying for 2 hours after dosing, without any deleterious effect on LES resting pressure or esophageal peristalsis.
Fundoplication prevents GER by increasing the LES baseline pressure, decreasing the number of TLESRs and the nadir pressure during swallow induced relaxation, increasing the length of the esophagus that is intra-abdominal, accentuating the angle of His and reducing a hiatal hernia if present. Fundoplication usually eliminates GER, including physiologic reflux. However, surgery does not correct poor esophageal clearance or improve gastric emptying.
Most of the literature on surgical therapy in children with GERD consists of retrospective case series in which documentation of the diagnosis of GERD and details of previous medical therapy are deficient, making it difficult to assess the indications for and responses to surgery. Children with underlying conditions predisposing to the most severe GERD comprise a large percentage of most surgical series, further confounding efforts to determine the benefits versus risks of surgical anti-reflux procedures in specific patient populations. The absence of systematic post-operative evaluation, including objective testing with pH or impedance studies and endoscopy, further complicates the assessment of surgical outcomes in most series.
In chlidren who have undergone fundoplication, those with neurologic impairment (NI) have more than twice the complication rate, 3 times the morbidity and 4 times the re-operation rate of children without neurologic impairment. One case series with a follow-up period of 3.5 years reported that over 30% of NI children had major complications or died within 30 days of anti-reflux surgery. 25% of those patients had operative failure and 71% had a return of one or more pre-operative symptoms within a year of surgery. Children with repaired esophageal atresia also have a high rate of operative failure, though not as high as those with NI.
Recurrence of GER after anti-reflux surgery in children with NI or EA may not be obvious and detection often requires a high index of suspicion, repeated evaluation over time and use of more than one test. In a recent retrospective review of 198 children, 74% of whom had underlying disorders, two thirds had GERD symptoms or required medical treatment for GERD within 2 months of anti-reflux surgery.
Fundoplication in early infancy has a higher failure rate than fundoplication performed later in childhood and appears to be more frequent in children with associated anomalies.
Children who are at increased risk for severe, chronic GERD and esophagitis sequelae:
Children with certain underlying disorders are at high risk of developing severe, chronic GERD, compared to those who are otherwise healthy. These children are at risk for both acute, more complicated GERD and for long-term sequelae thereby requiring ongoing therapy.
While the latter do develop GERD, which on occasion may be severe, the prevalence of severe, chronic GERD is much higher in those with certain underlying conditions, such as 1) neurologic impairment (NI) or
2) anatomic abnormalities, such as repaired esophageal atresia (EA) or hiatal hernia (HH). These children are more likely to require long-term treatment for healing and maintenance.
Complications of severe GERD occur with greatest frequency in children with underlying GERD-provoking conditions.
Performing studies of various GERD therapies in these groups has inherent difficulties, because the populations are heterogeneous; many are unable to report symptoms, some have more than one condition, and some require drug to be given by feeding tube. This limits the data available to allow evidence-based recommendations on therapy. However, some studies with quantitative endpoints, e.g., endoscopic healing, are available.
What are the adverse effects associated with each treatment option?
1) Prolonged treatment with aluminum-containing antacids significantly increases plasma aluminum in infants, and some studies report plasma aluminum concentrations close to those that have been associated with osteopenia, microcytic anemia and neurotoxicity.
2) Milk-alkali syndrome, a triad of hypercalcemia, alkalosis and renal failure can occur due to chronic or high-dose ingestion of calcium carbonate.
3) Although this is much less common than it was in the era before acid suppressive drugs, all antacid buffering agents should be used with particular caution in infants and young children.
4) Because safe, convenient alternatives are available that are more acceptable to patients, chronic antacid therapy is generally not recommended for patients with GERD
H2 Receptor Antagonists:
1) The fairly rapid tachyphylaxis that develops with H2RAs is a drawback to chronic use.
2) In some infants, H2RA therapy causes a number of side effects including; irritability, head banging, headache, and somnolence.
3) These symptoms often can be interpreted as ongoing symptoms of GERD and could result in an inappropriate increase in dosage.
4) Other side effects include liver disease and gynecomastia.
5) Other adverse effects of suppression of gastric acid are discussed in the section on proton pump inhibitors.
Proton pump inhibitors:
1) Side effects occur in up to 14% of children taking PPIs.
2) The most common are headache, diarrhea, constipation and nausea, each occurring in 2-7%.
3) These often resolve with decreased dose or change to a different PPI.
4) Parietal cell hyperplasia and occasional fundic gland polyps are benign changes that result from PPI-induced acid suppression and hypergastrinemia.
5) Enterochromaffin-like cell hyperplasia also occurs as a function of acid suppression.
6) A prospective study monitoring treated patients for up to 2 years, and retrospective studies of patients treated for up to 11 yrs, have found only milder grades of enterochromaffin-like cell hyperplasia.
7) A more recent retrospective study using more sensitive staining techniques showed ECL hyperplasia in the gastric body in almost half of children receiving long-term PPI continuously for a median of 2.84 yrs (up to 10.8 yrs); the hyperplasia was of the lowest 2 grades (not clinically significant), and no patient developed atrophic gastritis, or carcinoid tumors.
8) Increasing evidence suggests that acid suppression by H2RA or PPI may increase rates of community-acquired pneumonia in adults and children, gastroenteritis in children, and candidemia and necrotizing enterocolitis in preterm infants.
9) In one study, PPI use was associated with bacterial enterocolitis in adults; doubling of the PPI dose increased the risk.
10) PPIs have been shown to alter the gastric and intestinal bacterial flora of adults, but this has only rarely been shown to cause clinical disease.
11) The effect of PPI therapy on the gastrointestinal flora of infants and childen, or the consequences of any alteration in flora have not been evaluated fully and critically require studies to address this potential risk.
12) Deficiency of vitamin B12 has been found in adults over 65 years chronically treated with PPI, probably as a result of gastric achlorhydria.
13) A recent study of adults in the UK showed a significantly increased incidence of hip fractures that was related to dose and duration of acid suppression.
14) It is important to note that this observation, or for that matter, any evidence of bone demineralization has not yet been documented in pediatric patients.
15) In retrospective case review, 18 cases of biopsy proven PPI-induced acute interstitial nephritis causing acute renal failure were reported, and the authors suggest this entity may go unrecognized as 'unclassified acute renal failure.
16) Despite the small sizes of the studies, and lack of prospective data, PPIs are considered one of the most common causes of acute interstitial nephritis in adults.
17) This adverse effect is considered to be an idiosyncratic reaction, more frequent in the elderly, for unclear reasons.
18) Animal studies suggest that acid suppression may predispose to the development of food allergy, but this remains to be confirmed by human studies.
19) As mentioned, none of these adverse events have been demonstrated in pediatric patients receiving PPIs.
What are the possible outcomes of GERD and esophagitis?
Possible outcomes of GERD and esophagitis
Although we do know risk factors, we are not very clear about how to predict overall prognosis; i.e. the severity of the symptoms are not correlated with the severity of the inflammation and there are no biological markers for severity of disease and/or disease progression. The figure which depicts signs of complicated GERD is one of those that describes the type of patients that the clinician should consider having a lower threshold to monitor long-term and more frequently.
In adults, the frequency and severity of symptoms of GERD have a moderate correlation with the severity of mucosal injury. In a study of 129 patients (1-17 years of age) with GERD who underwent endoscopy and symptom evaluation, the prevalence and severity of anorexia/feed refusal was significantly greater in children with erosive esophagitis than those with NERD. In contrast, for infants, symptoms do not reliably predict the presence of esophagitis. Currently, there is no way to accurately predict the severity of mucosal injury in pediatric patients based on symptoms alone. Of importance is that mucosal injury was defined endoscopically in one study and by histology in the others. This discrepancy illustrates the need for greater precision in the definition of GERD in pediatric practice.
Esophagitis, hemorrhage, stricture, Barrett's esophagus and esophageal adenocarcinoma are well-recognized complications in children, as they are in adults. Erosive esophagitis occurs in more than one-third of pediatric-age patients with underlying GERD-promoting disorders, such as neurologic impairment or esophageal atresia. Erosive esophagitis is more prevalent and severe in these latter groups, as are stricture, Barrett's esophagus and adenocarcinoma.
In a double-blind, randomized placebo-controlled trial in 48 otherwise healthy children with erosive esophagitis healed by PPI, the investigators found that relapse of reflux esophagitis up to 3 months after discontinuation of maintenance treatment occurred in just one child. Recurrence of relevant symptoms was also uncommon (< 15%) during the 30-month follow-up period. Other than this study, there are limited data available regarding relapse rates in otherwise healthy children. In contrast, children with underlying disorders that predispose to severe GERD have higher grades of erosive esophagitis than in the study, and are more likely to have chronic, relapsing erosive esophagitis.
In a minority of pediatric patients, GERD leads to the narrowing of the esophageal lumen. This narrowing, due to edema or fibrosis, impedes the passage of food causing persistent dysphagia. Persistent, progressive or troublesome dysphagia is, therefore, a warning symptom for stricture of the esophagus and warrants additional investigation. It must be distinguished from the other causes of esophageal narrowing in pediatric patients, which are age-related. Pediatric patients with eosinophilic esophagitis also present with dysphagia, so endoscopy with esophageal biopsies is indicated to determine the cause of the narrowing.
The different treatment regimens are outlined above and in particular the potential adverse events and outcomes of such treatments. The overall risk of the majority of the pharmacological treatment regimens as well as that of surgery are for the most part also outlined. The potential outcome of the disease left untreated has also been alluded to in this piece but a "quantitative" outcome that can be offered to parents is not yet characterized. In the end, the age of the child, the severity of the GERD manifestations and mucosal disease are all taken into account when discussing risks/benefits of available treatment options.
What causes this disease and how frequent is it?
The incidence of reflux esophagitis in children with GERD increases with age (See
Estimated Incidence Rates of GERD in Children and Adolescents
The overall true population-based prevalence, and even more, incidence of GERD in childhood remains not well characterized. There is some evidence that GERD either is "over diagnosed" in the infant population with indirect data from pharmacy databases evaluating acid suppression agent prescriptions, and/or, underdiagnosed in some populations. A survey of primary care givers recently demonstrated that over 50% of children ages 1-5 years had to wait 3 months or more after the onset of symptoms before the condition was diagnosed, and 78% visited two or more physicians before receiving the diagnosis.
At the present time there have been no studies performed to date that have described, observed or documented an infectious cause of GERD. Infectious causes of esophagitis have been described, ranging from fungal infections (e.g., Candida) to viral infections which are most common; i.e. EBV, Herpes. The mode of transmission is typically fecal-oral and oral-oral with some being transmitted via respiratory routes. Treatment is based upon the infectious etiology involved as the etiology of the esophagitis.
As described, there are no specific predisposing exposures leading to GERD including zoonoses, environmental, toxin and activities.
Certain underlying disorders predispose pediatric patients to the most severe and chronic GERD, and its complications. These include significant neurological impairment, such as cerebral palsy, genetic disorders such as Cornelia de Lange syndrome and Down's syndrome, congenital esophageal abnormalities, such as repaired esophageal atresia or congenital diaphragmatic hernia, and chronic lung disease, such as cystic fibrosis.
Otherwise healthy children and adults with hiatal hernia or with a strong family history of GERD, Barrett's esophagus or esophageal adenocarcinoma also have a higher prevalence of chronic GERD with complications. While pediatric data are scarce, in adults, obesity and incremental weight gain are also associated with a significantly higher prevalence and increased severity of GERD, Barrett’s esophagus and esophageal adenocarcinoma.
Genetics and GERD
Significant clustering of reflux symptoms, hiatal hernia, erosive esophagitis, Barrett esophagus, and esophageal adenocarcinoma can occur in families, suggesting heritability of GERD and its complications. A large Swedish Twin Registry study found increased concordance for reflux in monozygotic, compared to dizygotic, twins. In another more recent study, collagen type III alpha I was determined to be a GERD susceptibility gene and a male risk factor for hiatus hernia in adults.
Therefore, it is important for the clinician who is evaluating the child with suspected GERD to obtain a detailed family history of gastroesophageal reflux disease, upper gastrointestinal disease or esophageal disorders.
Several other pediatric patient populations appear to be at higher risk of GERD symptoms; these patient populations have also been listed.
In a Mayo clinic study of 986 twin pairs (from an initial mail-out questionnaire), 481 monozygotic and 505 dyzygotic twins, the prevalence of irritable bowel syndrome, dyspepsia and GERD was 12%, 10% and 20%, respectively. Genetic modeling revealed that genetic factors influenced development of IBS in 22% and 13% for GERD, but none for dyspepsia, and it was felt that the genetic contribution to GERD and IBS may be mediated by anxiety and depression hereditability.
Untreated, long-term GERD is a known risk factor for Barrett's esophagus and more importantly esophageal adenocarcinoma. However only a small fraction of people with GERD develop esophageal cancer and the reasons for this observations remain unclear. A study from the University of Toronto identified a mutation in the epidermal growth factor gene that when present in individuals with persistent GERD resulted in a 10-fold increased risk for development of esophageal adenocarcinoma. Thus, there are likely yet-to-be identified genetic factors which when combined with the right host factors result in an increased risk of severe GERD and long-term sequelae.
How do these pathogens/genes/exposures cause the disease?
As mentioned previously, there are no specific pathogens which are directly related to GERD and the genetic risk has been discussed but as with many complex gastrointestinal diseases, genes likely play an indirect role in the development of GERD and esophagitis.
Chemical exposures can cause esophagitis, but are not linked to the development of GERD and environmental exposures which are a risk factor for eosinophilic esophagitis are discussed elsewhere.
What complications might you expect from the disease or treatment of the disease?
A recently published review aimed to assess evidence of whether GERD in children or adolescents persists into adulthood.
PubMed searches (1966-2010) identified longitudinal studies of GERD extending from childhood/infancy into adulthood, as well as longitudinal studies within pediatric age groups.
1) In one study, heartburn during childhood was more often recalled by adults with reflux symptoms than by those without (30% versus 9%; p < 0.001), as was medication or surgery for GERD (both p < 0.01).
2) Another study found that GERD symptoms were more common in adults diagnosed with reflux esophagitis during childhood/adolescence than in those who were not (46% versus 30%).
3) Regurgitation during infancy increased the risk of feeding problems after 1 year (odds ratio 4.2 (95% confidence interval: 1.4-12.0)) and of reflux symptoms at 9 years of age (relative risk 2.3 [95% confidence interval: 1.3-4.0]).
4) In one study, abnormal esophageal histology persisted in infants after 12 months without reflux symptoms.
5) A proportion (59-100%: three studies) of patients with reflux symptoms and/or reflux esophagitis during the pediatric years still required treatment after 1-8 years.
6) In another study, however, just 7% of patients with healed reflux esophagitis relapsed after 9 months without treatment.
7) The limited available evidence suggests that some infants, children, and adolescents with GERD are more likely than those without GERD to have symptoms later in life.
How can GERD and esophagitis be prevented?
There are no specific drugs and/or vaccines yet that can change the course of history.
Behavior factors which might mediate against the development of GERD are those which decrease risk for obesity and stress in the environment.
However, there are no longitudinal studies published which evaluate specific behavior change as an intervention method to prevent GERD development.
There are nutritional/genetic factors that should be taken into account and if there is a strong family history of upper GI disease and in particular, GERD, esophagitis, Barrett's esophagus and esophageal adenocarcinoma, the clinicial should be highly suspicious of GERD in the patient in their office when presenting with signs and symptoms consistent with the disease. Use of family history or GERD inheritability in prevention of GERD has not yet been done in any controlled clinical study.
The nutritional factors are outlined above, and in particular, the following foods/food groups have been implicated as increasing GERD symptom risk, but the avoidance or restriction thereof has not been evaluated in the pediatric patient as a preventative measure:
1) Acidic foods, liquids; e.g., citrus fruits
2) Spicy and greasy foods
3) Caffeinated and carbonated liquids, foods
4) High fat containing foods resulting in delayed gastric emptying
5) Tomato containing foods
What is the evidence?
Sarbin Ranjitkar, S, Kaidonis, JA, Smales, RJ. "Gastroesophageal reflux disease and tooth erosion". Int J Dent. 2012. pp. 479-850.
Morera, C, Nurko, S.. "Heterogeneity of lower esophageal sphincter function in children with achalasia". J Pediatr Gastroenterol Nutr,. vol. 54. 2012. pp. 34-40.
Winter, HS, Illueca, M, Henderson, C, Vaezi, M. "Review of the persistence of gastroesophageal reflux disease in children, adolescents and adults: does gastroesophageal reflux disease in adults sometimes begin in childhood?". Scand J Gastroenterol,. vol. 46. 2012. pp. 1157-1168.
Tack, J, Blondeau, K, Boecxstaens, V, Rommel, N. "Review article: the pathophysiology, differential diagnosis and management of rumination syndrome". Aliment Pharmacol Ther,. vol. 33. 2012. pp. 782-788.
Siddiqui, MR, Abdulaal, Y, Nisar, A, Ali, H, Hasan, F. "A meta-analysis of outcomes after open and laparoscopic Nissen's fundoplication for gastro-oesophageal reflux disease in children". Pediatr Surg Int,. vol. 27. 2011. pp. 359-366.
Romano, C, Chiaro, A, Comito, D, Loddo, I, Ferrau, V. "Proton pump inhibitors in pediatrics: evaluation of efficacy in GERD therapy". Curr Clin Pharmacol,. vol. 6. 2011. pp. 41-47.
Othman, S. "Gastroesophageal reflux studies using milk in infants and children - the need for multiple views". Nucl Med Commun,. vol. 32. 2011. pp. 967-971.
Omari, T. I., Schwarzer, A., vanWijk, MP. "Optimisation of the reflux-symptom association statistics for use in infants being investigated by 24-hour pH impedance". J Pediatr Gastroenterol Nutr,. vol. 52. 2011. pp. 408-413.
May, JG, Shah, P, Lemonnier, L, Bhatti, G, Koscica, J, Coticchia, JM. "Systematic review of endoscopic airway findings in children with gastroesophageal reflux disease". Ann Otol Rhinol Laryngol,. vol. 120. 2011. pp. 116-122.
Lee, JH, Kim, MJ, Lee, JS, Choe, YH. "The effects of three alternative treatment strategies after 8 weeks of proton pump inhibitor therapy for GERD in children". Arch Dis Child,. vol. 96. 2011. pp. 9-13.
Lazorick, S., Peaker, B., Perrin, EM. "Prevention and treatment of childhood obesity: care received by a state medicaid population". Clin Pediatr (Phila),. vol. 50. 2011. pp. 816-826.
Kubiak, R, Andrews, J, Grant, HW. "Long-term outcome of laparoscopic nissen fundoplication compared with laparoscopic thal fundoplication in children: a prospective, randomized study". Ann Surg,. vol. 253. 2011. pp. 44-49.
Ghezzi, M., Silvestri, M., Guida, E. "Acid and weakly acid gastroesophageal refluxes and type of respiratory symptoms in children". Respir Med,. vol. 105. 2011. pp. 972-978.
Di Pace, MR, Caruso, AM, Catalano, P, Casuccio, A, De Grazia, E. "Evaluation of esophageal motility using multichannel intraluminal impedance in healthy children and children with gastroesophageal reflux". J Pediatr Gastroenterol Nutr,. vol. 52. 2011. pp. 26-30.
Chiou, E, Rosen, R, Nurko, S. "Effect of different pH criteria on dual-sensor pH monitoring in the evaluation of supraesophageal gastric reflux in children". J Pediatr Gastroenterol Nutr,. vol. 52. 2011. pp. 399-403.
Chang, AB, Lasserson, TJ, Gaffney, J, Connor, FL, Garske, LA. "Gastro-oesophageal reflux treatment for prolonged non-specific cough in children and adults". Cochrane Database Syst Rev. 2011.
Winter, H., Kum-Nji, P., Mahomedy, SH. "Efficacy and safety of pantoprazole delayed-release granules for oral suspension in a placebo-controlled treatment-withdrawal study in infants 1-11 months old with symptomatic GERD". J Pediatr Gastroenterol Nutr,. vol. 50. 2010. pp. 609-618.
Tolia, V., Gilger, MA, Barker, PN, Illueca, M. "Healing of erosive esophagitis and improvement of symptoms of gastroesophageal reflux disease after esomeprazole treatment in children 12 to 36 months old". J Pediatr Gastroenterol Nutr,. vol. 51. 2010. pp. 593-598.
Sistonen, S. J., Koivusalo, A., Nieminen, U. "Esophageal morbidity and function in adults with repaired esophageal atresia with tracheoesophageal fistula: a population-based long-term follow-up". Ann Surg,. vol. 251. 2010. pp. 1167-1173.
Ruigomez, A., Lundborg, P., Johansson, S. "Follow-up of a cohort of children and adolescents with gastro-esophageal reflux disease who were free of reflux esophagitis at initial diagnosis". Scand J Gastroenterol,. vol. 45. 2010. pp. 814-821.
Rosen, R, Levine, P, Lewis, J, Mitchell, P, Nurko, S. "Reflux events detected by pH-MII do not determine fundoplication outcome". J Pediatr Gastroenterol Nutr,. vol. 50. 2010. pp. 251-255.
Pearson, EG, Downey, EC, Barnhart, DC. "Reflux esophageal stricture - a review of 30 years' experience in children". J Pediatr Surg,. vol. 45. 2010. pp. 2356-2360.
Macchini, F, Fava, G, Selicorni, A, Torricelli, M, Leva, E, Valadè, A. "Barrett's esophagus and Cornelia de Lange Syndrome". Acta Paediatr,. vol. 99. 2010. pp. 1407-1410.
Koebnick, C, Getahun, D, Smith, N, Porter, AH, Der-Sarkissian, JK, Jacobsen, SJ. "Extreme childhood obesity is associated with increased risk for gastroesophageal reflux disease in a large population-based study". Int J Pediatr Obes. vol. 6. 2011 Jun. pp. e257-63.
Higginbotham, T. W. "Effectiveness and safety of proton pump inhibitors in infantile gastroesophageal reflux disease". Ann Pharmacother,. vol. 44(3). 2010. pp. 572-576.
Garza, J. M, Kaul, A.. " Gastroesophageal reflux, eosinophilic esophagitis, and foreign body". Pediatr Clin North Am,. vol. 57. 2010. pp. 1331-1345.
Francavilla, RA, Magista, AM, Bucci, N. "Comparison of esophageal pH and multichannel intraluminal impedance testing in pediatric patients with suspected gastroesophageal reflux". J Pediatr Gastroenterol Nutr,. vol. 50. 2010. pp. 154-160.
Castilloux, J, Bouron-Dal, SD, Christophe, F. "Endoscopic assessment of children with esophageal atresia: Lack of relationship of esophagitis and esophageal metaplasia to symptomatology". Can J Gastroenterol,. vol. 24. 2010. pp. 312-316.
Vandenplas, Y, Rudolph, CD, Di Lorenzo, C. "Pediatric Gastroesophageal Reflux Clinical Practice Guidelines: Joint Recommendations of the North American Society of Pediatric Gastroenterology, Hepatology, and Nutrition and the European Society of Pediatric Gastroenterology, Hepatology, and Nutrition". J Pediatr Gastroenterol Nutr. vol. 49. 2009 Oct. pp. 498-547.
Tolia, V, Vandenplas, Y. "Systematic review: the extra-oesophageal symptoms of gastro-oesophageal reflux disease in children". Aliment Pharmacol Ther,. vol. 29. 2009. pp. 258-272.
Sherman, PM, Hassall, E, Fagundes-Neto, U. "A global, evidence-based consensus on the definition of gastroesophageal reflux disease in the pediatric population". Am J Gastroenterol,. vol. 104. 2009. pp. 1278-1295.
Salvatore, S, Hauser, B, Devreker, T. "Esophageal impedance and esophagitis in children: any correlation?". J Pediatr Gastroenterol Nutr,. vol. 49. 2009. pp. 566-570.
Orenstein, SR, Hassall, E, Furmaga-Jablonska, W, Atkinson, S, Raanan, M. "Multicenter, double-blind, randomized, placebo-controlled trial assessing the efficacy and safety of proton pump inhibitor lansoprazole in infants with symptoms of gastroesophageal reflux disease". J Pediatr,. vol. 154. 2009. pp. 514-520 e514.
Omari, T, Davidson, G, Bondarov, P, Nauclér, E, Nilsson, C, Lundborg, P. "Pharmacokinetics and acid-suppressive effects of esomeprazole in infants 1-24 months old with symptoms of gastroesophageal reflux disease". J Pediatr Gastroenterol Nutr,. vol. 45. 2007. pp. 530-537.
Ongoing controversies regarding etiology, diagnosis, treatment
1) What does inflammation in the esophagus really mean?
-Does esophageal disease progress?
-Can newer diagnostic modalities be used to better characterize upper GI disease in children?
2) GERD and extraesophageal GERD definitions in children:
-Lack of biological markers/surrogates for pediatric GERD
-Potential target population for novel promotility approaches
-Newer diagnostic modalities
-pH-impedance; high resolution manometry; Video Pill cam
3) Many acid suppression options are available, but how do we handle the proton pump inhibitor (PPI) “failures”?
-Does the clinician address children differently than adults?
-Another target population for promotility approaches
-Acid versus nonacid - what role does nonacid reflux play in the propagation of GERD
-Is the fundoplication, “played out" - do they really last?
-Reflux inhibitors: the new frontier…or is there something else?
Copyright © 2017, 2013 Decision Support in Medicine, LLC. All rights reserved.
No sponsor or advertiser has participated in, approved or paid for the content provided by Decision Support in Medicine LLC. The Licensed Content is the property of and copyrighted by DSM.
Sign Up for Free e-newsletters
Psychiatry Advisor Articles
- Characteristics of Unipolar Mania, Distinct from Bipolar Disorder, Described
- Aspirin, N-Acetylcysteine Effective Adjunctive Treatments in Bipolar Depression
- Higher Neuroticism Linked to Anxiety, Anhedonia in Depression
- Subthreshold Pediatric Bipolar Disorder Is a Significant Psychiatric Burden
- Interview-Only Version of Yale-Brown Obsessive-Compulsive Scale Effective for OCD Monitoring in Youth
- Part 1: Adolescent Tech Use and Mental Health: Expert Roundtable
- Challenging Stigma: Should Psychiatrists Disclose Their Own Mental Illness?
- Social Anxiety in Schizophrenia: An Overlooked Problem
- Inflammation: Is It the Link Between Rheumatoid Arthritis and Depression?
- The Robot Will See You Now: The Increasing Role of Robotics in Psychiatric Care
- Childhood Physical Violence Associated With Decreased Total Cholesterol
- How the Government Shutdown Affects FDA Activities
- The Robot Will See You Now: The Increasing Role of Robotics in Psychiatric Care
- Extended-Release Naltrexone Improves Psychiatric Disorders During Addiction Therapy
- Infections, Antibiotics Associated With Subsequent Increased Risk for Mental Disorders in Youth