ASTHMA AND GASTROESOPHAGEAL REFLUX IN INFANTS AND CHILDREN

THE DIFFICULT ASTHMATIC

0889-8561/01 $15.00

+ .OO

ASTHMA AND GASTROESOPHAGEAL REFLUX IN INFANTS AND CHILDREN Margaret J. Goldenhersh, MD, and Marvin Ament, MD

Gastroesophageal reflux (GER) is a term that describes the intermittent regurgitation of stomach contents into the esophagus. This term has been applied to physiologic or functional reflux and GER disease (GERD). GERD includes the spectrum of associated signs and symptoms associated with this condition, some of which have been recognized because of improved technologic and diagnostic ~apabi1ities.l~ PATHOPHYSIOLOGY

The esophagus essentially is composed of involuntary smooth muscle in its distal two thirds that functions to propel food from the mouth to the stomach by peristaltic contractions. There is a specialized tonically contracted region of the distal esophagus, the so-called “physiologic high pressure zone” or lower esophageal sphincter, that works as a functioning gateway at the gastroesophageal junction. The lower esophageal sphincter is primarily under neural hormonal control. It relaxes in response to swallowing and with esophageal distension or contractions in the absence of swallowing. In the lower esophageal sphincter (LES), spontaneous transient LES relaxations (TLESRs) not associated with the corresponding esophageal event also may occur and are related to the physiologic functioning of venting swallowed air through eructation.

From the Department of Pediatrics, Division of Gastroenterology and Nutrition, University of California at Los Angeles School of Medicine (MJG, MA); and the Department of Pediatrics, Division of Allergy Immunology, Brentwood Allergy and Asthma Medical Corporation (MJG), Los Angeles, California IMMUNOLOGY A N D ALLERGY CLINICS OF NORTH AMERICA VOLUME 21 * NUMBER 3 * AUGUST 2001

439

440

GOLDENHERSH & W E N T

Gastroesophageal reflux occurs when there is loss of an esophagogastric pressure gradient maintained by the LES. Many patients who are recognized to have gastroesophageal reflux disease have the condition because they have a low basal LES pressure. Many other patients have a normal basal sphincter pressure but have an increased number of 'ILESRs. These events may be caused by transient increases in gastric pressure mediating the reflux events.16 CLINICAL PRESENTATION

GERD in infants and children may be classified into four categories: 1. Physiologic GERD 2. Functional GERD 3. Pathologic GERD 4. Secondary GERD A certain degree of GERD is normal or physiologic in infants and children. Such episodes of reflux typically occur during the immediate postprandial period, are of short duration, and are usually clinically insignificant, although episodic regurgitation may be apparent. Infants and children with functional GERD are otherwise healthy, without conditions that predispose to reflux, and exhibit frequent emesis or regurgitation with no sequelae. When GERD results in disease, it becomes pathologic GERD. Examples of pathologic GERD are (1) esophagitis, (2) chronic pulmonary disease, (3) apnea, (4)failure to thrive, and (5) neurobehavioral manifestations. Secondary GERD may be associated with neurologic impairment, hiatal hernia, or esophageal atresia. Some patients with pathologic GERD manifest it by showing compromise in respiratory function, esophageal barrier function, or nutrition that can be characterized as neurobehavioral.

Functional GERD Functional GERD is the form of reflux most commonly found in the general care of infants and young children. It is a common finding with daily emesis occurring in up to 50% of well infants by 3 months of age. Unlike reflux in adults, which tends to persist, complete resolution of functional GERD usually occurs by 6 months of age? There is no question that most patients with functional GERD have complete resolution by 6 months of age. A smaller group may continue to have intermittent reflux episodes that can occur up to 2 years of age. Early in infancy reflux is manifested primarily by effortless, painless regurgitation. At times the regurgitation may be more forceful or projectile in nature and other times silent as in oral regurgitation. The episodes of regurgitation tend to occur most frequently during the hours following feedings, but some infants seem to manifest reflux almost constantly

ASTHMA AND GASTROESOPHAGEALREFLUX IN INFANTS AND CHILDREN

441

through the day. Regurgitation during quiet sleep is uncommon, and when it does occur it is during periods of wakefulness or active sleep. The volume of emesis may be variable and seems to be inversely related to the frequency of episodes. Episodes in functional reflux may vary from 1 to 10 times per day.19 Pathologic GERD When there is delayed clearance or increased noxiousness of the reflux, when respiratory function is compromised, or if regurgitation results in significant caloric loss, there is pathologic GERD. Pathologic GERD may evolve in patients with frequent overt vomiting or in situations in which reflux is occult or physiologic. This emphasizes the finding that increased frequency or volume of reflux may not always correlate.I6 Esophagitis

Symptoms that may suggest underlying pain from reflux esophagitis in infants are crying, generalized irritability or fussiness, 'colicky' behavior, or sleep disturbance. Feeding difficulties such as outright refusal or pulling away from the bottle also may indicate esophageal pain with swallowing. Older children often complain of frank heartburn, epigastric, abdominal or substernal chest pain, or swallowing difficulties similar to complaints of adults with reflux disease.lg Odynophagia or painful swallowing suggests irritation of the esophagus, sometimes attributed to reflux esophagitis. Sometimes the pain is so severe the individual feels as if his or her chest is being crushed. The symptom of dysphagia or difficulty in swallowing is less specific for esophagitis, but it also may represent a complication of a long-standing reflux esophagitis or peptic stricture. Gastrointestinal bleeding, evidenced by hematemesis, guaiac positive stools, iron deficiency, or melena, may further suggest esophagitis. It is important to recognize that on occasion patients with significant reflux esophagitis may not experience any pain or symptoms referable to the esophageal inflammation. Long-standing severe reflux esophagitis rarely may culminate in metaplastic changes to a columnar epithelium, known as Barrett's esophagitis, which has a subsequent risk of esophageal adenocarcinoma. This problem has become recognized less frequently in children as diagnosis of GERD has been made earlier and treated more aggressively. Children with occult pathologic reflux may present with dysphagia caused by stricture formation. Chronic Pulmonary Disease

One of the most important sequelae of GERD is chronic pulmonary disease. The association between GERD and recurrent aspiration pneu-

442

GOLDENHERSH & AMENT

monia is obvious. It was not until esophageal pH monitoring was developed that the link to reflux could be recognized clearly between other chronic respiratory disorders, including cough, bronchospasm, bronchitis, laryngospasm, and hoarseness. The ability to monitor intraesophageal pH for prolonged periods of time has allowed the demonstration of the frequency and quantity of subclinical episodes of acid reflux that may occur in patients with pulmonary symptoms. Mechanisms that may account for a causal relation of GERD and chronic pulmonary disease include microaspiration and neurally mediated reflux bronchospasm. Microaspiration involves contamination of the upper airway by amounts of reflux insufficient to produce pneumonia. Pulmonary sequelae result from the effects of direct irritation, triggering of local neuropathways to control airway tone, and stimulation of an inflammatory cascade. Reflux responses (bronchospasm or laryngospasm) involving acid stimulation of esophageal afferent nerves are known to occur. Although GERD should not be viewed as a primary cause for the vast majority of cases involving asthma or chronic cough, it is important to consider it in certain clinical situations. Patients whose asthma symptoms occur primarily at night often have problematic reflux. Likewise, GERD should be suspected when chronic cough or wheezing is apparent during infancy or in the absence of a family history of asthma. The presence of subclinical GERD should be sought actively in any patient with wheezing that is difficult to control medically. Reflux is the likely cause of chronic hoarseness or laryngitis in selected cases. A careful history to elicit signs and symptoms of GERD should be taken in any child with chronic respiratory symptoms. Apnea

Although infant apnea, generally of the obstructive type, has been documented following acid reflux into the esophagus, the premise that GERD is etiologic in sudden infant death syndrome remains controversial. It may be that acid reflux with obstructive apnea includes laryngospasm, which is induced by laryngo- or nasopharyngeal microaspiration or reflux laryngospasm mediated by stimulation of acid-sensitive esophageal receptors. Failure to Thrive

Caloric deprivation occurs with GERD in pediatrics. The first and most obvious is attributed to the frequent and voluminous emesis occasionally observed in infants and toddlers with functional GERD. Food refusal or inadequate intake also may develop in complicated GERD as an expression of pain from esophagitis or as a conditioned behavior.

ASTHMA AND GASTROESOPHAGEAL REFLUX IN INFANTS AND CHLDREN

443

Neurobehavioral Manifestations

Sandifer syndrome is the most well known of the neurobehavioral complexes that manifest as pediatric GERD. In this condition there is a complex of maneuvers involving head tilting, neck cocking, and apisthotonic posturing which is a specific response to the child to reflux. Secondary GERD A variety of underlying conditions have been recognized associated with GERD. Nearly one third of children with sigruficant neurologic impairment have GERD. Reflux in these patients involves different mechanisms than those in patients with functional GERD. These mechanisms include frequent supine positioning, muscle spasticity, kyphoscoliosis, altered feeding patterns through nasogastric or gastrostomy tubes, or altered central and enteric neural Controls of gastrointestinal (GI) motility. The natural history of GERD in neurologically impaired children is characterized by protracted episodes of vomiting, coughing and choking during and after feedings, and recurrent bronchitis and pneumonia. Other conditions that predispose to secondary GERD are trachoesophageal atresia and large hiatal hernias. DIAGNOSTIC STUDIES FOR GERD

Diagnostic studies used in establishing the diagnosis of GERD include the following: 1. Upper GI series 2. Scintigraphy 3. pH probe studies 4. Upper intestinal endoscopy 5. Esophageal manometry Diagnosis In healthy infants in whom there is effortless regurgitation that begins before 6 months of age, no further diagnostic testing should be required to establish the diagnosis of functional GERD. The infants who gain weight, grow normally, and have no overt pathologic signs and symptoms should have no further testing. These infants are thriving. If on the other hand the infant is vomiting sufficiently to impair weight gain or if vomiting consistently requires effort, further evaluation should be considered. Infants who have the onset of vomiting that begins beyond 6 months of age, or who fail conservative management should have testing per-

444

GOLDENHERSH & AMENT

formed.lg Testing also should be performed when the parents are not reassured by the physician. Upper GI Series

The barium upper GI series always should be the first test ordered in the evaluation of complicated GERD. The primary role of this study is to exclude obstructive conditions in the differential diagnosis, such as pyloric stenosis, malrotation, antral web, intestinal atresia, peptic ulcer, and eosinophilic gastroenteropathy, rather than diagnose reflux. The complications of GERD, including peptic stricture, esophagitis, and aspiration to the airway, also may be detected by an upper GI series. For children with feeding difficulties or in whom recurrent respiratory problems result in aspiration, video fluoroscopic barium swallow should be given. Scintigraphy

Gastroesophageal scintigraphy, also referred to as a "milk" scan, is a radionuclide imaging technique that offers advantages over standard esophagrams in evaluating GERD. This study is conducted using a radio-labeled liquid meal providing a more functional or physiologic assessment for reflux. Imaging usually is performed for 1 hour (rather than a few minutes during an upper GI series), notes the frequency of reflux episodes, and quantifies the gastic emptying process. Scintigraphy continues to be the best choice when attempting to document pulmonary aspiration attributed to GERD, although its sensitivity is very low. pH Probe Studies

Esophageal pH probe testing is the most useful method for documenting pathologic reflux. It is also the best means of establishing a temporal relationship between acid reflux and a particular symptom. In uncomplicated functional GERD or in patients with documented reflux episodes, it provides little useful additional information. It has to be considered the gold standard of all the examinations performed for determining pathologic reflux? Because it is a study that is carried on for at least 24 hours, it has a much greater chance of picking up patients who have pathologic reflux that occurs intermittently. Some individuals show pathologic reflux only during sleep, others only when awake, or at all times. Thirty percent of individuals with pathologic GERD have reflux intermittently rather than on a daily basis. For this reason, individuals who are suspected to have pathologic reflux, and in whom the first 24-

ASTHMA AND GASTROESOPHAGEAL REFLUX IN INFANTS AND CHnDREN

445

hour intraesophageal pH monitoring study is normal, should have a second day of monitoring.'* Well-established standards exist for the evaluation of reflux based on intraesophageal pH monitoring, which is why this test is so valuable in the diagnosis of the condition. Furthermore, the intraesophageal pH can be monitored in response to therapies that are used for treatment. Upper Intestinal Endoscopy

Upper intestinal endoscopy is the most sensitive means for detecting mucosal disease with clinical GERD. The indications for this technique are overt evidence suggesting esophagitis such as hematemesis or guaiac-positive stools, dysphagia, odynophagia, or failure to thrive, failure or relapse after empirical acid suppression trial, or (in the older child) symptoms such as heartburn, odynophagia, or dysphagia. Pediatric endoscopy is safe if performed by individuals who monitor their patients carefully through the procedures. Blind suction esophageal biopsies also can be performed to look for e~ophagitis,2~ but this technique does not give a visual inspection of the condition of the entire esophagus. Esophageal Manometry

Esophageal manometry is a technique that may be used in the diagnosis and management of reflux in which one is trying to determine if the individual has a pathologically low lower esophageal sphincter pressure and if there is dysfunction in the emptymg of the esophagus. These studies are important in patients who have esophageal atresia to determine the degree of peristaltic abnormality in the esophagus. This may be important in the surgical management of these patients. THERAPY OF GERD

The therapeutic approach to gastroesophageal reflux is based on a limited number of modalities: 1. Positional therapy: In infants less than 3 months of age, the infant should be placed in the prone upright position with the head elevated 20" to 30". After 3 months of age this therapy often proves difficult as the infant begins to turn over and move about in his or her bed. 2. Dietary management: Frequent, smaller volume feedings may result in less frequent overt episodes of reflux, but this approach may fatigue caretakers. Thickening the feedings with Vz to 1 tablespoon of cereal per ounce of formula also can be considered

446

GOLDENHERSH & AMENT

as another means of trying to reduce reflux by increasing the viscosity of formula. In infants with impaired emptying, symptoms may become worse.15 3. Prokinetic agents: Bethanecol at a dosage of 0.1 to 0.2 mg/kg/d given in three or four divided doses should be considered as a possible therapy. The only other therapy available is metoclopramide at a dosage of 0.1 to 0.15 mg/kg given 15 to 30 minutes before feedings six times per day. These agents increase the lower esophageal sphincter pressure and improve the rate of gastric emptying. Acid-blocking agents such as cimetidine, ranitidine, and famotidine may be used to block acid production, which occurs with these agents 70% of the time. A sodium-potassium proton pump inhibitor at a dosage of 0.7 to 1.0 mg/kg per day accomplishes the same thing. Examples of these agents are Prevacid and Prilosec.

If symptoms persist or do not improve with the .use of these medications, the patient can be considered for surgical correction of the defect.1,3,4,12, Surgery is successful in totally relieving symptoms in 95% of patients with reflux. Only 5% of pediatric patients who have correction of their reflux with surgery have a recurrence secondary to breakdown of the fundoplication within the first 2 to 3 years. After this time, it is uncommon for such an event to occur. ASTHMA AND GERD

The prevalence of GERD among asthmatics is high, ranging from 34% to 89%.",13, 24 Though the association between the two conditions remains firm, many studies have shed confounding light on a true causal relationship. Dispute exists over whether GERD initiates an asthmatic airway response, bronchial asthma (BA) and its treatment initiates a GERD response, or a noncausal coexistence occurs between the two conditions. The present body of literature, which tends to separate out evidence according to proposed pathophysiologic GERD/BA mechanism, is confusing. Support for the microaspiration theory (gastric acid in respiratory airways following GERD) includes: demonstration of transient increased total-lung resistance following intratracheal acid infusion (in cats) with later prevention by complete cervical vagotomy26;and pH probe detection of GERD coinciding with decrease in tracheal pH and demonstrable improvement in tracheal pH and BA symptoms following GERD surg e r ~ . *Contradictory ~ data reveal abnormal proximal GERD to be a highly variable and inconsistent marker for microaspiration.2sEvidence for another commonly proposed GERD/BA mechanism, vagal-induced airway hyper-responsiveness, includes peak expiratory flow studies which reveal decreases in peak expiratory flow with esophageal acid infusion. Incomplete peak expiratory flow recovery has been shown to occur only in patients with combined GERD/BA di~ease.2~ A third

ASTHMA AND GASTROESOPHAGEAL REFLUX IN INFANTS A N D CHILDREN

447

popularly proposed mechanism of GERD-induced BA, a vagally mediated reflex that induces bronchoconstriction, is supported by the demonstrable atropine-induced abolition of an important esophageal-bronchial reflex. The direct relationship between the lowering of airway flow, heart rate, and arterial blood-oxygen saturation and the increase of intraesophageal acid instillation can be abolished by atropine in the absence of respiratory findings? Other studies reveal conflicting data of the effects of spontaneous GERD or acid perfusion of the esophagus on pulmonary function in humans." 23,25 Despite ongoing controversy, there is a body of evidence that strongly suggests that antireflux therapy improves BA symptoms and reduces BA medication requirement^.^, 14,20 Though critical review weighs heavily on the side of GERD induction of BA symptoms, there is not much evidence for sigruficant GERD impact on objective pulmonary function.'O The available data does not seem to support a relationship between GERD-induced bronchospasm and worsening pulmonary function; however, several study groups have found that GERD can cause breathlessness in patients with normal pulmonary function and normal methacholine challenge." 21 One plausable explanation of GERD-induced respiratory symptoms without accompanying pulmonary function changes involves pain-stimulated increases in minute ventilation. The greater respiratory effort may result in patient sensation of breathlessness. Acid perfusion and manometric studies that evaluate minute ventilation and respiratory sensation support discomfort-induced ventilatory changes in the absence of pulmonary function change^.^ GERD is a common occurrence in the asthmatic population. Despite the strong association between the two clinical conditions, causality remains inconclusive. Clearly BA symptoms and medication requirement improve with medical or surgical antireflux therapy. Paradoxically, there is little convincing evidence that GERD adversely affects pulmonary function. Other issues such as patient discomfort, coexistent esophagitis, and the role of local inflammatory mediators may be contributory. Future clarification will depend on properly controlled studies investigating the historically evasive relationship between these two important disease entities.

References 1. Ahrens P, et a1 Antireflux surgery in children suffering from reflux associated respiratory diseases. Pediatr Pulmonol28:89-93, 1999 2. Anderson LI, Sdunidt A, Bundgaard A Pulmonary function and acid application in the esophagus. Chest 90:358, 1986 3. Axelrod FR, et al: Fundoplicationand gastrostomy in familial dysantonomia. J Pediatr 118:38&394, 1991 4. Ceriati E, et al: Gastroesophageal reflux in neurologically impaired children: Partial or total fundoplication?Langenbocks Arch Chir 383:317-319,1998 5. Choy D, Leung R Gastroesophageal reflux disease and asthma. Respirology 2163,1997 6. DePas WJ, Winterbaue RH, Lusk JA, et al: Chronic dyspnea unexplained by history, chest roentgenogram and spirometry: Analysis of a seven year experience. Chest 1001293, 1991

448

GOLDENHERSH & AMENT

7. Donnely RJ, Berrisford RG, Jack CIA, et al: Simultaneous tracheal and esophageal pH monitoring: Investigating reflux-associated asthma. Ann Thorac Surg 56:1029-1034, 1993 8. Euler AR, Ament ME: Detection of gastroesophageal reflux by simultaneous measurement of intraluminal pH probe measurement (Tuttle test). Pediatrics 60:6548, 1977 9. Field SK, Evans JA, Price LM The effects of acid perfusion of the esophagus on ventilation and respiratory sensation. Am J Respir Crit Care Med 1571058, 1998 10. Field SK, Sutherland LR Does medical antireflux therapy improve asthma in asthmatics with gastroesophageal reflux? A critical review of the literature. Chest 114:275,1998 11. Field SK, Underwood M, Brant R, et a1 Prevalence of gastroesophageal reflux symptoms in asthma. Chest 9931G322, 1996 12. Fonkalsrud EW, et al: Surgical treatments of the gastroesophageal reflux syndrome in infants and children. Am J Surg 154:ll-18, 1987 13. Goldman J, Bennet J R Gastroesophageal reflux and respiratory disorders in adults. Lancet 494495, 1988 14. Harding SM, Richter JE, Guzzo M, et al: Asthma and gastroesophageal reflux: Acid suppressive therapy improves asthma outcome. Am J Med 100395, 1996 15. Hillemeir C, et al: Delayed gastric emptying in infants with gastroesophageal reflux. J Pediatric 98:190-193, 1981 16. Kawahara H, Dent J, Davidson G: Mechanisms responsible for gastroesophageal reflux reflux. Gastroenterology 113:399408,1997 17. Kubiak R, et al: Effectiveness of fundoplication in early infancy. J Pediatr Surg M295299, 1999 18. Mahajari L, et al: Reproducibility of 24-hour intraesophageal p H monitoring in pediatric patients. Pediatrics 101:260-263, 1998 19. Nelson SP, Chen EH, Syniar GM, et a 1 One-year follow-up of symptoms of gastroesophageal reflux during infancy: Pediatric Practice Research Group. Pediatrics 102:E67, 1998 20. Perrin-Fayolle M, Gormand F, Braillon G, et al: Long term results of surgical treatment in asthmatic patients. Chest 9640, 1989 21. Pratter MR, Curley FJ, Dubois J, et a1 Cause and evaluation of chronic dyspnea in pulm0~1-ydisease clinic. Arch Intern Med 1492277, 1989 22. Sampson LK, Georgeson KE, Royal SA: Laparoscopic gastric antroplasty in children with delayed gastric emptying and gastroesophageal reflux. J Pediatr Surg 33282285, 1998 23. Schan CA, Harding SM, Haile JM, et a1 Gastroesophageal reflux-induced bronchoconstriction: An intranesophageal acid infusion study using state-of-the-art technology. Chest 106:731-737,1994 24. Sontag SJ, OComel S, Khandelwal S, et al: Most asthmatics have gastroesophageal reflux with or without bronchodilator therapy. Gastroenterology 99:613420, 1990 25. Spaulding HS, Mansfield LE, Stein MR, et al: Further investigation of the association between gastroesophageal reflux and bronchoconstriction. J Allergy Clin Immunol 69:516, 1982 26. Tuchman DN, Boyle JT, Pack AI, et al: Comparison of airway responses following tracheal or esophageal acidification in the cat. Gastroenterology 878724381, 1984 27. Winter HS, et al: Intraepithelial eosinophils: A new diagnostic criterion for reflux esophagitis. Gastroenterology 83:818-823, 1982 28. Wright RA, Miller SA, Comello BF Acid-induced esophago-bronchial-cardiac reflux in humans. Gastroenterology 9971-323, 1990

Address reprint requests to Margaret J. Goldenhersh, MD UCLA School of Medicine Brentwood Allergy and Medical Corporation 11645 Wilshire Boulevard, Suite 800 Los Angeles, CA 90025