Value of tests for evaluation of gastroesophageal reflux in children

Value of Tests for Evaluation of G a s t r o e s o p h a g e a l R e f l u x in Children By William F. Meyers, Charles C. Roberts, Dale G. Johnson, and John J. Herbst Salt Lake City, Utah 9 T h e accuracy of five tests for the diagnosis of gastroesophageal reflux in children w a s p e r f o r m e d in 9 3 sympt o m a t i c children w i t h gastroesophageal reflux and 16 nonreflux patients. These tests include the barium esophagram, the T u t t l e test, e x t e n d e d esophageal pH monitoring, esophagoscopy, and esophageal biopsy. Esophagoscopy w a s less sensitive in detecting reflux in patients than any o t h e r t e s t (P = < 0 . 0 0 1 ) , and biopsy w a s m o r e likely to identify reflux patients than the barium swallow (P = < 0 . 0 2 ) , but t h e r e w a s no t e s t superior t o others. T h e severity of esophagitis noted at endoscopy or t h e presence of eosinophils or neutrophils in the mucosa w a s not associated w i t h a decreased possibility t h a t one o t h e r t e s t would be normal or t h a t surgical repair of t h e reflux would be p e r f o r m e d . Patients w i t h e x t e n d e d esophageal pH t e s t scores m a r k e d l y elevated w e r e less likely to have a n o t h e r negative t e s t (P = < 0 . 0 1 ) and more likely to have surgical repair of gastroesophageal reflux (P = < 0 . 0 0 1 ). Obtaining t w o t e s t s of esophageal function t h a t agree increases t h e c e r t a i n t y of diagnosis, and use of several t e s t s are indicated if t h e results of a single t e s t do not support the clinical impression. 9 1 9 8 5 by Grune & S t r a t t o n , Inc. I N D E X W O R D S : Gastroesophageal reflux.

report our experience with the diagnostic accuracy of extended esophageal pH monitoring, esophageal biopsy, endoscopy, barium esophagography, and the Tuttle test, in the evaluation of 109 children for the presence or absence of GER. CASE REPORTS Between July 1978 and July 1982, 109 patients were referred for evaluation of symptoms suggesting GER. Their age varied from 1.5 months to 16 years with a mean age of 23.9 months. All five tests of esophageal function were obtained in 77 patients and four tests were obtained in the other 32 patients. There were no significant differences in age or symptoms of those having only four tests. O f those with four tests, results of esophagoscopy were not available in three and esophageal biopsies were not obtained in 29. At the time of evaluation, the presence of failure to thrive, respiratory or gastrointestinal symptoms, or other significant medical problems, were noted. The main gastrointestinal symptom was vomiting, but occasionally extreme irritability or, on a rare occasion, heartburn was associated with esophagitis. The main respiratory problems were those of recurrent pneumonia, apnea, choking spells, wheezing, or chronic cough. Behar et al noted in adults that two positive tests for G E R resulted in a diagnosis of G E R with a 95% accuracy while a cumulative 30% false positive rate was experienced using a single test. TM Our patients were defined as having significant G E R if they had compatible symptoms and three or more tests of esophageal function that were positive. Nonreflux patients bad at least three negative tests of esophageal function to provide confirmation that significant reflux was not present.

E V E R A L TESTS HAVE BEEN used to evaluate patients for gastroesophageal reflux (GER). The most commonly used tests include the barium esophagram, the Tuttle test, gastric scintiscan, manometry, extended esophageal pH monitoring, esophagoscopy and esophageal biopsy. 1-8 In two adult studies comparing some of these tests, the Tuttle test was shown to be the most accurate in confirming the presence of r e f l u x . 7'9 Both of these studies included esophageal manometry and the acid perfusion test. The acid perfusion test is of limited usefulness in small children because it requires that the patients be able to describe symptoms, and several centers have shown the insensitivity of esophageal m a n o m e t r y in diagnosing GER. 4'1~ Benz et al noted that the barium swallow identified 83% of reflux patients but was also positive in 52% of an asymptomatic group? In a recent study of pediatric patients with severe symptoms of reflux, 17 of 30 being neurologically impaired, the scintiscan and barium studies were positive in approximately 50% of cases while the Tuttle test was positive in all but one patient. There were essentially no false positive studies in the control patients. ~2 The relative accuracy of several studies was reported by Berquist et al in a select group of children with chronic lung disease and suspected GER.13 This study reported that positive results for the tests varied from 37% to 79%. In this study, we

From the Department o f Pediatrics, Scott and White Memorial Hospital, Temple, Tex; University o f Missouri, Kansas City; University o f Utah School o f Medicine and Primary Children's Medical Center, Salt Lake City, UT; Louisiana State University Medical Center, Shreveport, La. Supported in part by the Cystic Fibrosis Foundation and the Thrasher Research Fund. Address reprint requests to John J. Herbst, MD, Department o f Pediatrics, Louisiana State University, P.O. Box 33932, Shreveport, LA 33932. 9 1985 by Grune & Stratton, Inc. 0022-3468/85/2005~9011503.00/0

Journal of Pediatric Surgery, Vo120, No 5 (October), 1985: pp 515-520

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S

ESOPHAGEAL TESTS

Barium Esophagram In a manner similar to that reported by MacCauley et al, 1 a quantity of barium suspension that approximated that of a normal meal was administered. If the necessary volume was not taken by mouth, it was given via gavage and the tube removed. The infants were rolled from left to supine to right side, and intermittently fluoroscoped over five minutes. Two episodes of

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spontaneous reflux in five minutes was a positive study. No Valsalva maneuver or abdominal compression was used to initiate reflux. Tuttle Test A pH microelectrode, 1.4 mm in diameter, was placed into the distal one-third of the esophagus after assuring a gastric pH of less than 3. 6 Final probe placement corresponded to 4 cm less than the esophageal l e n g t h as e s t i m a t e d by S t r o b e l et al (EL = .252 • height (CM) + 5)) 5 A radiograph for confirmation of probe placement was done only if warranted because of skeletal deformities or hiatal hernia. Following instillation into the stomach of 300 cc/1.7 m 2 of 0.1 N HC1 by gavage, esophageal pH was monitored for 30 minutes in a supine position. Reflux was defined as an esophageal pH of less than 4 for greater than 15 seconds. An abnormal test consisted of two or more episodes of reflux in 30 minutes or a single episode lasting longer than 10 minutes. The same technique was followed using unfiltered apple juice (pH = 3.9) as a separate second Tuttle test or as the only test in some of the patients. This material was eagerly swallowed by all patients, and maneuvers to encourage burping were performed prior to monitoring esophageal pH for 30 minutes. Abdominal compression and leg maneuvers were not applied. Extended Esophageal pH Monitoring Monitoring of esophageal pH for 18 to 24 hours was performed as previously described by Jolley et al. 6 Usually this study was done at the same time as the Turtle test and placement of the pH probe was the same for both tests. A score was developed by looking at four determinants of reflux greater than two hours after eating while the patients were awake, asleep, upright, and supine. The four determinants were frequency of reflux, number of episodes greater than four minutes duration, time of the longest episode, and the percent of time in reflux. A score of less than 64 was considered a normal test. Esophagoscopy A pediatric fiberoptic endoscope was used in all cases. The esophageal mucosa was graded as normal, mucosal erythema, or mucosal erythema plus. This included redness plus any combination of linear erosions, friability, ulcers, or exudates.

MEYERS ET AL

phageal junction visualized at esophagoscopy as recommended by Weinstein et al. 16 Biopsies were oriented and sectioned perpendicularly to the mucosal surface. The presence of hyperplastic epithelial changes were considered the minimal criterion on biopsy for a positive test: These changes consisted of a germinative layer greater than l/lo the thickness of the squamous epithelium and dermal pegs longer than 2/3 the thickness of the epithelium. The presence of intraepithelial neutrophils or eosinophils was also considered an abnormal finding indicative of esophagitis) 7 The infiltrate was described as rare, mild, moderate or severe corresponding with two to three cells per section, one cell per two to three high power field. All slides were coded and interpreted without knowledge of clinical course or other test results. Statistical testing was performed using the Chi Square Test. RESULTS Of the 109 patients, 93 patients had three or more tests positive for reflux: 27 had five positive tests, 43 had four positive tests, and 22 had three positive tests. Eighty-nine patients had one or no negative tests and the four patients with two negative tests did not have erythema at esophagoscopy and one additional negative test. These 93 patients were classified as having GER. Vomiting was present in 83, respiratory symptoms in 48, and failure to thrive (weight less than 3rd percentile for age) in 34 (Table 1). In 40 patients, vomiting and respiratory symptoms were noted in the same patients. The male to female incidence was 1.2:1. Associated congenital problems were noted in 27 patients. Central nervous system disorders including mental retardation, meningomyelocoele, and Down's Syndrome, were present in 12 patients. Congenital heart disease was present in four patients, 12 patients had repaired tracheoesophageal fistula, and one patient had tracheoamalacia. Thirteen patients had four negative tests and three had three negative tests; none had more than one positive test. These 16 patients were classified as nonreflux patients; five had repaired tracheoesophageal fistula. In patients with reflux, the barium esophagram Table 1. Clinical Status o f P a t i e n t s Reflux Patients N

F'n'*

Symptoms

Emesis

5 Tests

2 3 . 6 mo

13

64

25

36

42

4 Tests

2 4 . 8 mo

3

29

9

12

21

2 3 . 9 mo

16

93

34

48

83

EsophagealBiopsy Esophageal biopsies using a Rubin multipurpose suction biopsy tube (Quinton Instrument Co, Seattle, Wash) were obtained 3 cm to 4 cm from the gastroeso-

Respiratory

Age

Normal N

* Failure To Thrive

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Table 2. Results of Tests for Reflux

Reflux Patient + Test - Test Non Reflux Patients +Test -- Test

Barium Esophagram

Tuttle

Extended pH

80/93; 86% 13/93; 14%

116/126; 92% 10/126; 8%

82/93; 88% 11/93; 12%

49/90; 54% 41/90; 46%

64/66; 97% 2/66; 3%

5/16; 31% 11/16; 69%

9/29; 31% 20/29; 69%

1/16; 6% 15/16; 94%

0/11; 0% 11/11; 100%

2/15; 13% 13/15; 87%

demonstrated reflux in 86.0% of 93 patients. Among nonreflux patients, the barium esophagram incorrectly demonstrated reflux in 5/16 patients (31.3% false positive results). The Tuttle test was performed using 0.1N HC1 in 46 patients and using apple juice in all 109 patients. The test correctly indicated if the patients had G E R or not in 90.8% of cases when apple juice was used and 80.6% of cases when 0.1N HC1 was used. There was no significant difference in accuracy between the two tests and results were combined for further studies. The results of the two tests agreed in 30 patients and 28 (93%) had GER. In reflux patients, 10/126 Tuttle tests were negative (8% false negative) while nine of 29 tests were positive in nonreflux patients for a false positive rate of 31% (Table 2). Extended pH monitoring was obtained in all 109 patients and predicted occurrence of reflux in 87.0% of patients. There were 11 false negative results in 93 reflux patients (11.8% false negative) and one false positive result in 16 nonreflux patients (6.3% false positive). Esophagoscopy was done in 90 reflux patients: 41 had normal mucosa, 32 had erythema of esophageal mucosa, and 17 had more severe gross esophagitis. Of 25 patients in whom reflux was severe enough that surgical repair was required, 7 had normal esophagoscopy, 9 had erythema of the esophagus, and 9 had more severe esophagitis. There were no false positive results among the 11 nonreflux patients having endoscopy. Of the 17 patients with more severe esophagitis, only 9 eventually required surgery for control of symptoms of GER. The overall accuracy of the esophageal biopsy in predicting presence or absence of reflux was 95.1% in 81 patients with biopsies. There were two false positive results in 15 nonreflux patients (13.3%) and two false negative results in 66 reflux patients (3.0%). The two nonreflux children had an increased germinative layer and tall papillae only. Both esophagoscopy and biopsy were performed in 64 patients with GER. Table 3 compares these two methods of detecting esophagitis. An abnormal biopsy was noted in 62 of the 64 patients (97%) while an abnormal esophagoscopy was noted in only 37 of the 64 patients (51.8%). An abnormal

Esophagoscopy

Biopsy

biopsy was a highly sensitive test for the presence of documented acid reflux even when the endoscopic appearance of the mucosa was normal, since only two G E R patients had normal biopsies. In addition to an increase in the germinative layer and height of the papillae, an intraepithelial cellular infiltrate with at least rare eosinophils or neutrophils were noted in 13 of 27 patients with normal endoscopy, 11 of 26 with erythema, and eight of 20 with erythema plus other more severe endoscopy findings. The presence and quantity of polymorphonuclear infiltrate did not correspond with severity of endoscopic findings (P > 0.05), but was a sensitive indicator of the presence of GER. Besides the above histologic findings in the reflux patients, Barrett's columnar esophageal mucosa was noted in three children with G E R one of whom had a tracheo esophageal fistula. Normal criterea for hyperplastic stratified squamous epithelium cannot be applied to this columnar epithelium, but for purposes of determining diagnostic accuracy, these biopsies were considered abnormal./8 All of the tests of esophageal function are subject to false negative and false positive results. Among nonreflux patients no test had significantly fewer false positive results than another test. Among reflux patients, esophagoscopy was significantly less sensitive (P < 0.001) than any other test, since it will detect only those patients whose reflux is severe enough to cause visible esophagitis. Among the other tests, biopsy is more sensitive than barium swallow (P < 0.02) but there is no significant superiority among all other tests. In reflux patients the degree of esophagitis noted at endoscopy did not affect the chances that one of the other tests might be negative. In patients with normal esophagoscopy, 24% (10/41) had one or another normal test, 22% (7/32) of the patients had one normal Table 3. Esophagoacopy and Biopsy in GER Patients

Esophsgo6copy Normal Erythema Erythema plus Total

N 27 26 11 64

Presenceof Polym(~phonuclearCe~ls + Papillaeand + Germsnitive Layer Abnormal Heavy Moderate Mild Rare

26 25 11 62

2 2 1 5

2 4 2 8

7 3 3 13

2 2 2 6

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MEYERS ET AL

test if only erythema was noted, and if more severe esophagitis was noted, 30% (5/17) had another negative test. Those with eosinophils or neutrophils in mucosal biopsies were as likely as the endoscopic groups to have other tests falsely negative for reflux. There was some correlation between an abnormal score on extended pH monitoring and the occurrence of falsely negative tests. Among reflux patients with scores less than 200, 14/54 (26%) had either a normal barium swallow, Tuttle test or biopsy. Among those with scores over 200, only 2/39 (5%) had a normal result in one of the tests (P < 0.01). The degree of abnormality of the extended pH test, esophagoscopy or the biopsy did not precisely predict the patients who would require antireflux surgery although only 6/53 patients (11%) with pH scores less than 150 came to surgery while 20/40 patients (50%) with scores greater than 150 had surgical repair of G E R (P < 0.001). In patients with normal esophagoscopy, 8/41 (20%) eventually had antireflux surgery while 8/32 (25%) with only erythema and 6/17 (35%) of those with more severe esophagitis eventually had surgery for GER (P > 0.05). DISCUSSION

This study demonstrates that none of the esophageal function tests have complete diagnostic accuracy. All give false positive and negative results that require careful interpretation and correlation with other data. Esophagoscopy was the least sensitive test since 46% of 90 reflux patients had a normal exam. The biopsy was significantly more sensitive in detecting reflux than the barium esophagram, but excepting esophagoscopy, no other comparison of tests demonstrated superiority of one test over another. For the purposes of this study, reflux patients were defined as patients with compatible symptoms and at least three tests indicating reflux. When children with normal esophagoscopy are excluded, no reflux patient had more than one negative test. In a similar manner, all nonreflux patients had at least three negative tests and no more than one positive test. Categorizing the patients using this rigid criteria as having G E R or not allows clinically useful comparisons among the various tests. The excess of males in the G E R group has been noted by other authors) 9 The high incidence of other abnormalities, especiallyof the central nervous system in pediatric G E R patients, has also been noted. 2~ The barium esophagram correctly detected reflux in 86% of patients, but its usefulness is compromised by a high rate of positive examinations in nonreflux patients (31% of 16 patients). These results compare very favorably with other studies) 2'21 Euler et al, for example, reported only 26% accuracy. 22 Reasons for the

high accuracy in this study may include the severity of reflux patients studied, and the fact that a specific protocol specifying a volume of contrast material that approximates a routine feeding is used. 1 The barium esophagram is a simple, reasonably accurate, initial screening test and is an excellent procedure to rule out distal anatomic obstructions that may mimic gastroesophageal reflux. The Tuttle test is a useful test that requires only a short period of pH monitoring. Our studies indicate no significant difference in results if either apple juice or 0.1 N HC1 is used. The risks of aspirating the HC1 or the discomfort of passing a nasogastric tube to administer the HC1 are a significant drawback to its use. Since results are the same and apple juice is readily swallowed by infants, it is recommended for routine use. The detection of reflux in 92% of reflux patients with this test confirms previous studies that it is a very sensitive test for GER. The finding is tempered by the finding that nine of 29 tests (31%) were positive in nonreflux patients. This high rate of false positive results has not previously been noted. The results of the two Tuttle tests agreed in only 68% of cases. However, if the results agreed, the accuracy of diagnosis improved to 93%. This is in agreement with the observation of Behar et al that two positive tests in adults give 95% accuracy. 14Where there is clinical doubt and there are conflicting test results, it is reasonable to do a second Tuttle exam. Many groups have used extended esophageal pH studies to identify GER, but the accuracy of the test as compared to others has not been documented in children. 23-25The tests accurately predict significant reflux in 87% of 93 reflux patients. These results are not notably better than results of barium swallow or the Tuttle test, but there was only one false positive test among 16 nonreflux patients (6%). Esophagoscopy and biopsy are important in the evaluation of esophagitis, dysphagia, and stricture. All of the 32 patients with erythema and the 17 patients with more severe esophagitis at esophagoscopy had reflux; erythema of the mucosa was not noted in nonreflux patients. An abnormal esophagoscopy is a very specific finding in children with reflux but is not very sensitive since 46% of the 90 reflux patients had normal mucosa at esophagoscopy. These results are much better than those of Biller and co-workers who diagnosed esophagitis at endoscopy in 44 of 64 patients who had normal mucosal biopsies) 6 The esophageal biopsy was a sensitive and specific test of G E R in our experience, and correctly indicated presence or absence of reflux in 95% of the 81 patients who had biopsies. False negative results occurred in 2/66 reflux patients (3%) and there were two false

TESTS FOR GASTROESOPHAGEAL REFLUX

519

positive results (13%). These results c o m p a r e well with those of Behar et al in a d u l t patients. ~4 T h e severity or presence of an i n f l a m m a t o r y infilt r a t e on biopsy did not correlate well with severity of esophagitis noted at biopsy. This has previously been noted by L e a p e and co-workers, s Except with m a r k e d l y a b n o r m a l e x t e n d e d p H monitoring, a single positive test for G E R did not c h a n g e the likelihood a n o t h e r test would be positive. W i t h extended p H monitoring, patients with the most abnorm a l scores (over 200) had only a 5% c h a n c e of having a n o r m a l b a r i u m swallow, T u t t l e test, or biopsy, while 26% of patients with scores under 200 had one of the above tests normal. A m o n g the tests t h a t a r e quantifiable, (esophagoscopy, biopsy, and extended p H monitoring) patients with the most a b n o r m a l results were only slightly m o r e likely to come to surgery. Fifty percent of patients with p H scores over 150 eventually had s u r g e r y while only 14% of patients with scores under 150 h a d surgery ( P < 0.01). In a similar m a n n e r , 24% of patients with normal esophagoscopy h a d antireflux surgery while 33% of patients with e r y t h e m a and 35% of patients with more severe esophagitis had surgery ( N S ) . Finally the presence of an i n f l a m m a t o r y cell

infiltrate in the esophageal m u c o s a did not i n c r e a s e the likelihood the p a t i e n t would u n d e r g o surgery. G E R is a c o m m o n p e d i a t r i c diagnosis but no single test consistently s e p a r a t e s reflux f r o m nonreflux patients. A c o m b i n a t i o n of tests increases d i a g n o s t i c a c c u r a c y , and if two tests a r e positive, others a r e likely to be positive as well. T h e b a r i u m swallow is easily a v a i l a b l e for a first test a n d excellent for ruling out m a n y a n a t o m i c g a s t r o i n t e s t i n a l disorders which cause similar s y m p t o m s . T h e choice of a c o n f i r m a t o r y test m a y be d i c t a t e d by local a v a i l a b i l i t y of testing procedures. T h e T u t t l e test is of b r i e f d u r a t i o n a n d m a y be p e r f o r m e d as an o u t p a t i e n t procedure, b u t the incidence of false positive tests is quite high. A prolonged e s o p h a g e a l p H study is m o r e c u m b e r s o m e b u t there a r e few false positive results a n d the test will d e t e c t night t i m e or i n t e r m i t t e n t reflux. R e c e n t studies have shown t h a t an increased m e a n d u r a t i o n o f reflux while asleep correlates well with G E R i n d u c e d p u l m o n a r y disease. 27 T h e e s o p h a g e a l biopsy is a sensitive test t h a t m a y be done i n d e p e n d e n t l y of esophagoscopy which helps e v a l u a t e the presence of esophagitis. Esophagoscopy provides a visual index of the severity of esophagitis but is less sensitive at d e m o n s t r a t i n g m i n o r a b n o r malities.

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