The Prevalence of Gast roesophageal Reflux in Ast hm a
Pat ient s w it hout Reflux Sym pt om s
SUSAN M . HARDING, M ELANY R. GUZZO, and JOEL E. RICHTER
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama;
and Department of Gastroenterology, The Cleveland Clinic Foundation, Cleveland, Ohio
Gastroesophageal reflux is a potential trigger of asthma that may
be clinically silent. This study examines the prevalence of gastro-
esophageal reflux in asthma patients without reflux symptoms. This
prospective cohort study evaluated 26 patients with stable asthma
without reflux symptoms using esophageal manometry and 24-h
esophageal pH testing. Gastroesophageal reflux was considered
present if esophageal acid contact times were abnormal. Demo-
graphic variables were analyzed to determine if they predicted the
presence of gastroesophageal reflux. Asthma patients with asymp-
tomatic gastroesophageal reflux were compared with 30 age-
matched asthma patients with symptomatic gastroesophageal re-
flux. The prevalence of abnormal 24-h esophageal pH tests in
asthma patients without reflux symptoms was 62% (16 of 26). De-
mographic variables did not predict abnormal 24-h esophageal pH
tests in asthma patients with asymptomatic gastroesophageal re-
flux. Asthma patients with asymptomatic gastroesophageal reflux
had higher amounts of proximal esophageal acid exposure (p ,
0.05) compared with asthma patients with symptomatic gastroe-
sophageal reflux. Because demographic variables do not predict
abnormal 24-h esophageal pH tests in asthma patients without re-
flux symptoms, 24-h esophageal pH testing is required. This study
suggests that gastroesophageal reflux is present in asthma pa-
tients, even in the absence of esophageal symptoms.
G astroesophageal reflux is common in adult asthma patients
and is a potential trigger of asthma (1). In a questionnaire sur-
vey, Field and coworkers reported that 77% of asthma pa-
tients experienced heartburn, 55% complained of regurgita-
tion, and in the week prior to completing the questionnaire,
41% of the asthma patients reported reflux-associated respira-
tory symptoms (2). Twenty-four hour esophageal pH testing
accurately diagnoses gastroesophageal reflux with a sensitivity
and specificity of approximately 90% (3). The frequency of
false-negative results of 24-h esophageal pH testing ranges be-
tween 10% and 25% (4). E valuating 104 consecutive asthma
patients, Sontag and coworkers observed that 82% of asthma
patients had abnormal amounts of acid reflux on 24-h esoph-
ageal pH testing (5). Identifying gastroesophageal reflux in
asthma patients is important because aggressive treatment of
gastroesophageal reflux may result in improvement of respira-
tory symptoms in selected patients (68). A double-blind, pla-
cebo-controlled, multicentered trial evaluating asthma out-
come with aggressive medical therapy using a proton pump
inhibitor has not been reported to date.
(Received in original form July 16, 1999 and in revised form December 8, 1999)
Presented at Digestive Disease Week, American Gastroenterological Association,
Washington, DC, May 11, 1997.
Supported in part by a grant from Glaxo Wellcome, Inc. Dr. Harding is sup-
ported by a Sleep Academic Award, National Heart, Lung, and Blood Institute,
National Institutes of Health, Grant HL03633.
Correspondence and requests for reprints should be addressed to Susan M. Har-
ding, M.D., Division of Pulmonary, Allergy, and Critical Care Medicine, 215 Tins-
ley Harrison Tower, 1900 University Boulevard, University of Alabama at Birming-
ham, Birmingham, AL 35294. E-mail: sharding@uab.edu
Am J Respir Crit Care M ed Vol 162. pp 3439, 2000
Internet address: www.atsjournals.org
Patients with asthma aggravated by gastroesophageal re-
flux may not have classic reflux symptoms of heartburn or re-
gurgitation, leaving the clinician unaware that gastroesoph-
ageal reflux may be a trigger for the asthma. A mbulatory 24-h
esophageal pH testing plays a key diagnostic role in asthma
patients without reflux symptoms. U sing this test, Irwin and
coworkers studied a group of difficult-to-control asthma pa-
tients and found that gastroesophageal reflux was clinically
silent in 24% (9). They observed that vigorous treatment of
gastroesophageal reflux was helpful in converting difficult-to-
control asthma patients into ones who were no longer difficult
to control (9). More recently, in a retrospective review of 199
asthma patients undergoing esophageal pH testing, we found
that 35 (18% ) did not have reflux symptoms, of which 10
(29% ) had abnormal esophageal acid contact times. Twenty-
four hour esophageal pH testing was well tolerated without
untoward effects in these 199 asthma patients (10). The preva-
lence and severity of gastroesophageal reflux in asthma pa-
tients without reflux symptoms has not been carefully studied
in a prospective manner. Thus, the aims of this study are to
prospectively determine the prevalence and severity of gas-
troesophageal reflux in stable asthma patients of all severities
without reflux symptoms using 24-h esophageal pH testing
and to compare this group with asthma patients with reflux
symptoms undergoing similar testing.
M ETHODS
Subjects
This prospective cohort study was approved by the H uman U se Com-
mittee at the U niversity of A labama at Birmingham on March 9, 1995.
Subjects were recruited from the outpatient pulmonary clinic at the
U niversity of A labama at Birmingham. Potential subjects were
screened over the telephone for the presence of reflux symptoms in-
cluding heartburn, regurgitation, water brash, dysphagia, and epigas-
tric pain. If they denied symptoms, they were informed about the
study and called back after 7 d to see if they were still interested in en-
rolling, and requestioned as to the presence of esophageal symptoms.
Consecutive asthma patients without reflux symptoms who met the
entrance criteria and had asthma stability for at least 2 wk, and gave
informed consent participated. Stable asthma was defined as stable
asthma symptoms and no change in asthma medications during the
2 wk before study entry. The subject population met the A merican
Thoracic Societys definition of asthma, including: a 200-ml and a
12% improvement in FE V 1 with bronchodilators, or a 20% decrease
in FE V 1 after methacholine challenge, performed in accordance with
the guidelines of the Lung H ealth Study; subjects were nonsmokers
and had no symptoms consistent with chronic bronchitis nor other
forms of chronic lung disease (1113). A sthma patients without reflux
symptoms had rare heartburn or regurgitation (once a month or less),
no dysphagia, no history of esophageal, gastric surgery, or sclero-
derma, and no previous treatment with antireflux medications includ-
ing H 2 antagonists, proton pump inhibitors, prokinetic agents, or reg-
ular use of antacids.
To assess the severity of gastroesophageal reflux in asthma pa-
tients with asymptomatic gastroesophageal reflux ( 2Sx 1pH ), com-
parisons were made with asthma patients with symptomatic gastro-
esophageal reflux ( 1Sx 1pH ). This symptomatic gastroesophageal
Harding, Guzzo, and Richter: Asymptomatic Reflux in Asthmatics
reflux group is a previously described cohort group which participated
in a reflux treatment trial in which subjects had asthma criteria as pre-
viously defined, reflux symptoms including the presence of heartburn
and/or regurgitation at least twice monthly, had abnormal 24-h esoph-
ageal pH tests, and were not on antireflux medication such as antac-
ids, H 2 antagonists, proton pump inhibitors, or prokinetic agents (7).
Esophageal M anometry and Ambulatory 24-h
Esophageal pH Testing
Standardized methods of esophageal manometry and ambulatory 24-h
esophageal pH testing were performed on all subjects. A fter an over-
night fast, esophageal manometry was done in the supine position us-
ing a round polyvinyl catheter (diameter 4.5 mm) (A ndorfer Medical
Specialties, G reendale, WI) continuously perfused with distilled wa-
ter at a rate of 0.5 ml/min by a low-compliance pneumohydraulic cap-
illary infusion system (A ndorfer Medical Specialties). The location
and mean resting pressure at midexpiration of the lower and upper
esophageal sphincters, mean esophageal contraction amplitude in the
distal esophagus, and percentage of peristaltic contractions in re-
sponse to ten 5-ml swallows of water were obtained and measured by
previously described techniques (14).
Immediately after esophageal manometry, a 2.5-mm-diameter mono-
crystalline catheter with two antimony pH electrodes (Medtronic U p-
per A irway, Minneapolis, MN) was passed nasally and positioned
with the distal electrode 5 cm above the proximal border of the lower
esophageal sphincter and the proximal electrode just below the upper
esophageal sphincter. The proximal probe was placed within 3 cm of
the upper esophageal sphincter using both commercially available
and custom-made probes (Medtronic U pper A irway) with interprobe
distances of 10, 12, 15, and 18 cm. The electrodes were calibrated at
pH 7 and 1, using a buffer solution (Fisher Scientific, Fairlawn, NJ)
before and at the completion of each study. A reference electrode was
placed on the anterior chest. Both electrodes were connected to a dig-
ital recorder which stored pH data every 4 s. Subjects were sent home
with instructions to record meal times, time of assuming the supine
position for sleep, and time of arising in the morning. Subjects were
encouraged to perform normal daily activities and asked to avoid
foods and beverages with a pH , 4. They were also instructed to re-
port respiratory symptoms in a diary and to push the event button on
the digital recorder.
A fter at least 18 h of recording, data were downloaded into an
IBM A T personal computer and analyzed separately for the proximal
and distal esophageal pH electrodes. Based on 110 healthy control
subjects using 95th percentile data in our laboratory, abnormal
amounts of acid reflux were present in the distal esophagus if the total
percent time pH , 4 exceeded 5.8% during the 24-h study period, or
upright acid exposure exceeded 8.2% , or supine acid exposure ex-
ceeded 3.5% (15). Based on studies in 20 healthy volunteers, abnor-
mal amounts of proximal reflux occurred if the total percent time pH
, 4 exceeded 1.1% , or upright acid exposure exceeded 1.7% , or su-
pine acid exposure exceeded 0.6% (16). Subjects were considered to
have reflux present if one or more of these six pH parameters was not
in the normal range. The 24-h esophageal pH test also allows correla-
tion of respiratory symptoms with esophageal acid events. Subjects
were instructed to record respiratory symptoms and esophageal symp-
toms. R espiratory symptom and esophageal acid correlation were as-
sessed by reviewing patient diaries, digital recording event markers,
and esophageal pH tracings. R espiratory symptoms monitored in-
cluded wheezing, chest tightness, shortness of breath, and cough.
O ther symptoms monitored included chest pain, heartburn, regurgita-
tion, and nausea. A respiratory or esophageal symptom was associ-
ated with a reflux event if the esophageal pH was , 4 simultaneously
with the symptom or within 5 min before its onset. There are minimal
data evaluating the symptomreflux correlation on a temporal basis
(17). Investigators have used temporal relationships as long as 10 min
and as restrictive as 2 min (18, 19). In our pH laboratory, 5 min has
been used routinely for symptom correlation (10, 20).
Data Collection
A ll patients completed a standardized asthma and reflux question-
naire before esophageal testing. A sthma-specific questions included
age of onset, exacerbating triggers, atopy, seasonal variation, noctur-
35
nal symptoms, and a family history of asthma. A sthma symptoms,
medication usage, and health care utilization determined asthma se-
verity in accordance with the National A sthma E ducation Program
E xpert Panel R eport (21). G astroesophageal reflux questions in-
cluded the presence and frequency of heartburn, regurgitation, chest
pain, dysphagia, hoarseness, and sore throat.
Analysis
Chi-square analysis or the Fisher exact tests were performed to deter-
mine if specific asthma demographic variables were associated with
abnormal esophageal acid contact times in asthma patients without
reflux symptoms. A sthma patients with asymptomatic gastroesoph-
ageal reflux ( 2Sx 1pH ) were compared with 30 previously character-
ized age-matched asthma patients with symptomatic gastroesophageal
reflux ( 1Sx 1pH ), to evaluate the severity of gastroesophageal reflux
in asthma patients with asymptomatic gastroesophageal reflux (7).
E sophageal manometry and pH values from these two groups were
compared using the Mann-Whitney rank sum test. D emographic vari-
ables, asthma severity, and asthma medications used in asthma pa-
tients with asymptomatic gastroesophageal reflux ( 2Sx 1pH ) were
compared with asthma patients with symptomatic gastroesophageal
reflux ( 1Sx 1pH ) using chi-square analysis or the Fisher exact tests.
D ata are expressed as mean 6 SD (22).
RESULTS
Demographic and Esophageal pH Values of Asthma
Patients Without Reflux Symptoms
O f 220 asthma patients screened, 80 (36% ) denied reflux
symptoms of whom 58 met entrance criteria with 26 agreeing
to participate. A sthma patients without reflux symptoms had a
mean age of 43 6 16 yr, 18 (69% ) were women, and 20 (77% )
were white. A t the time of testing, nine (35% ) had mild
asthma, 16 (61% ) had moderate asthma, and one (4% ) had se-
vere asthma as defined by the National A sthma E ducation
Program (21). The esophageal pH probe was well tolerated in
all subjects, with none reporting worsening of respiratory
symptoms during testing. A sthma medication use included in-
haled b2-agonists on an as-needed basis only in five (19% ),
regular use of inhaled b2-agonists in 19 (73% ), inhaled corti-
costeroid use in 15 (58% ), inhaled nedocromil in three (12% )
subjects, inhaled anticholinergics in two (8% ), and oral theo-
phylline in three (12% ) subjects. None of the subjects used
oral b2-agonists, oral corticosteroids, or leukotriene antago-
nists. The mean number of medications used per day by each
subject was 1.9 6 1.3. Pulmonary function data show a mean
FE V 1 of 85 ( 6 14) percent predicted, FE V 1/FVC ratio of 68%
( 6 10), FE F 2575% of 51 ( 6 23) percent predicted, and peak ex-
piratory flow rate of 89% ( 6 20) percent predicted. Metha-
choline challenge testing was performed in one patient who
had a provocative dose causing a 20% fall in FE V 1 (PD 20) us-
ing normal saline alone.
Table 1 reviews esophageal manometry and pH variables
of the 26 asthma patients without reflux symptoms ( 2Sx),
consisting of the subset of 10 asthma patients without reflux
symptoms with negative 24-h esophageal pH tests ( 2Sx 2pH )
and the subset of 16 asthma patients without reflux symptoms
with positive 24-h esophageal pH tests ( 2Sx 1pH or asymp-
tomatic gastroesophageal reflux); and the cohort of 30 asthma
patients with reflux symptoms with positive 24-h esophageal
pH tests ( 1Sx 1pH or symptomatic gastroesophageal reflux).
Note that all mean esophageal acid contact times in the 2Sx
group are in the abnormal range. Sixteen (62% ) asthma pa-
tients without reflux symptoms had at least one abnormal
esophageal pH parameter. This 62% prevalence has a wide
confidence interval (42% to 80% ). In asthma patients with
asymptomatic gastroesophageal reflux, 14 (88% ) had abnor-
mal esophageal acid contact times at the distal probe during
36 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000

the total period, with five (28% ) having supine reflux. Proxi-
mal reflux was frequent in the asthma patients with asymp-
tomatic gastroesophageal reflux with 12 (75% ) having abnor-
mal total amounts of esophageal acid and five (28% ) having
supine proximal reflux. E leven (69% ) asthma patients with as-
ymptomatic gastroesophageal reflux had abnormal esoph-
ageal acid contact times at both the distal and proximal esoph-
ageal pH probes, whereas one (6% ) had abnormal values at
the proximal probe only. D ata at the distal and proximal
esophageal pH probes of the asymptomatic gastroesophageal
reflux group ( 2Sx 1pH ) show that 15 of 16 (94% ) subjects
had more than one abnormal esophageal pH parameter. Two
subjects had two, three subjects had three, eight subjects had
four, one subject had five, and one subject had six out of six
abnormal esophageal pH parameters.
R espiratory symptom correlation showed that 6 of 74 (8% )
reported cough episodes, 2 of 2 (100% ) reported shortness of
breath episodes, 0 of 1 (0% ) indicated sputum production epi-
sodes, and 1 of 1 (100% ) had chest pain episodes associated
with esophageal acid exposure. Wheezing or chest tightness
was not reported during 24-h esophageal pH testing.
There were no differences in age, asthma duration, body
mass index, lower esophageal sphincter pressure, percent peri-
staltic esophageal contractions, or upper esophageal sphincter
pressure between the asymptomatic reflux group ( 2Sx 1pH )
and the group without gastroesophageal reflux ( 2Sx 2pH )
(Table 1). A sthma patients with asymptomatic gastroesoph-
ageal reflux had higher amplitude of esophageal contractions
than those without gastroesophageal reflux (p , 0.005). A s ex-
pected, the group with gastroesophageal reflux had signifi-
cantly higher amounts of esophageal acid exposure at both the
proximal and distal esophageal pH probes than those with
normal esophageal acid contact times (p , 0.01 in all esoph-
ageal pH variables shown in Table 1 except proximal supine
acid exposure [p 5 0.13] and the number of episodes lasting
greater than 5 min at the proximal probe [p 5 0.14]).
A lthough 24-h esophageal pH monitoring is the best test
available to assess gastroesophageal reflux, normal values vary
from center to center and values near the definition of abnor-
mal may not be reproducible (15). Figures 1 and 2 examine in-
dividual esophageal acid contact times in the 26 asthma pa-
tients without reflux symptoms ( 2Sx) at the distal probe
(Figure 1) and the proximal probe (Figure 2). Normal values
are represented below the line on each variable. O pen circles
represent values from asthma patients with normal esophageal
acid contact times ( 2Sx 2pH ), and filled circles represent val-
ues from asthma patients with abnormal esophageal acid con-
tact times ( 2Sx 1pH ). There is a large range of values.
Predictors of Gastroesophageal Reflux in Asthma
Patients without Reflux Symptoms
Chi-square and the Fisher exact test analyses showed that no de-
mographic variable (including childhood onset asthma, family
history of asthma, asthma severity, seasonal variation, history of
atopy, nocturnal symptoms, sore throat, hoarseness, nocturnal
awakenings associated with dyspnea, wheezing with eating or al-
cohol use) predicted abnormal esophageal acid contact times.
Demographic Variables of Asthma Patients with
Symptomatic Gastroesophageal Reflux
Tables 1 and 2 review demographic and esophageal variables
of the 30 asthma patients with symptomatic gastroesophageal
reflux ( 1Sx 1pH ). Pulmonary function data show a mean
FE V 1 of 72 ( 6 25) percent predicted, FE V 1/FVC of 65 ( 6 13),
FE F 2575% of 44 ( 6 35) percent predicted, and peak expiratory
flow rate of 80 ( 6 25) percent predicted. Methacholine chal-
lenge testing was not required for the diagnosis of asthma in
these 30 patients. R espiratory symptom correlation showed

TABLE 1
ASTHM A PATIENTS WITHOUT REFLUX SYM PTOM S ( 2Sx), ASTHM A PATIENTS WITHOUT
REFLUX SYM PTOM S OR GASTROESOPHAGEAL REFLUX ( 2Sx 2pH), ASTHM A PATIENTS WITH
ASYM PTOM ATIC GASTROESOPHAGEAL REFLUX ( 2Sx 1pH), AND ASTHM A PATIENTS WITH
SYM PTOM ATIC GASTROESOPHAGEAL REFLUX ( 1Sx 1pH)*

2Sx 2Sx 2pH 2Sx 1pH 1Sx 1pH

(n 5 26) (n 5 10) (n 5 16) (n 5 30) p Value

Age, yr 42.9 6 16.1 37.6 6 14.7 44.5 6 17.6 46.4 6 12.8 0.63
Asthma duration, yr 13.3 6 13.0 10.7 6 9.1 14.9 6 14.9 17.4 6 14.8 0.43
Body mass index, kg/ m 2 28.4 6 6.1 27.7 6 6.6 28.8 6 6.0 29.5 6 6.9 0.72
Esophageal manometry
LES pressure, mm Hg, nl . 10 mm Hg 13.4 6 5.8 12.2 6 4.9 14.2 6 6.3 9.4 6 5.4 0.01
Mean amplitude contractions, mm Hg 7.8 6 39.4 55.6 6 18.8 94.3 6 42.0 78.1 6 34.5 0.23
Peristaltic contractions, % 88.4 6 26.3 91.0 6 20.3 86.7 6 30.2 90.3 6 21.0 0.77
UES pressure, mm Hg 52.4 6 23.0 56.0 6 24.2 50.0 6 22.7 45.0 6 22.9 0.49
Esophageal pH, distal probe
Total, nl , 5.8% 7.3 6 7.0 2.2 6 1.3 10.4 6 7.3 12.1 6 6.9 0.22
Upright, nl , 8.2% 8.6 6 9.0 3.2 6 1.7 11.9 6 10.1 12.6 6 6.5 0.14
Supine, nl , 3.5% 4.8 6 9.5 0.7 6 1.3 7.4 6 11.4 10.1 6 10.8 0.43
No. of episodes . 5 min, nl , 4 2.6 6 3.4 0.4 6 0.5 3.9 6 3.7 5.2 6 4.5 0.40
Longest episode, min, nl , 18.5 16.3 6 17.1 5.6 6 5.2 23.0 6 18.6 24.5 6 19.6 0.98
Esphageal pH proximal probe
Total, nl , 1.1% 2.5 6 6.1 0.5 6 0.3 3.8 6 7.6 1.4 6 1.6 0.03
Upright, nl , 1.7% 3.1 6 8.2 0.8 6 0.4 4.6 6 10.3 1.3 6 1.6 0.09
Supine, nl , 0.6% 1.0 6 2.2 0.0 6 0.1 1.5 6 2.6 1.3 6 3.2 0.61
No. of episodes . 5 min, nl 5 0 0.8 6 2.4 0.1 6 0.3 1.3 6 3.0 0.5 6 0.8 0.63
Longest episode, min, nl , 3 6.9 6 12.6 1.5 6 1.0 10.3 6 15.2 5.3 6 8.0 0.08

Definition of abbreviations: LES 5 lower esopphageal sphincter; nl 5 normal value; UES 5 upper esophageal sphincter.
* Data are expressed as mean 6 SD.

The 2Sx 2pH and the 2Sx 1pH groups are subsets of the 2Sx group.

p value comparing the 2Sx 1pH group with the 1Sx 1pH group.
Harding, Guzzo, and Richter: Asymptomatic Reflux in Asthmatics
that 1 of 1 (100% ) of reported shortness of breath episodes, 15
of 32 (47% ) of wheezing, 14 of 36 (39% ) of cough episodes,
and 4 of 7 (57% ) episodes of chest pain were associated with
esophageal acid events. Seventy-one of 86 (83% ) heartburn
symptoms and 24 of 28 (86% ) regurgitation episodes were as-
sociated with esophageal acid events.
Comparing Asthma Patients with Asymptomatic
Gastroesophageal Reflux with Asthma Patients
with Symptomatic Gastroesophageal Reflux
Table 2 reviews demographic characteristics and Table 1 re-
views esophageal manometry and acid contact times in 16
asthma patients with asymptomatic gastroesophageal reflux
(2Sx 1pH ) and 30 age-matched asthma patients with symp-
tomatic gastroesophageal reflux (1Sx 1pH ). A sthma patients
with asymptomatic gastroesophageal reflux had less severe
asthma, and were not using theophylline or oral corticosteroids.
A sthma patients with asymptomatic gastroesophageal reflux
had higher lower esophageal sphincter pressures and higher
amounts of total proximal esophageal acid exposure compared
with asthma patients with symptomatic gastroesophageal reflux.
There were no significant differences between groups in asthma
duration, body mass index, mean amplitude of esophageal con-
tractions, percent of peristaltic contractions, upper esophageal
sphincter pressure, or distal esophageal acid exposure.
DISCUSSION
This prospective cohort study examines the prevalence of gas-
troesophageal reflux, defined as abnormal amounts of esoph-
ageal acid on 24-h esophageal pH tests, in asthma patients
without reflux symptoms. The high prevalence rate of 62% (16
of 26) of asthma patients with clinically silent reflux illus-
trates that gastroesophageal reflux may be commonly associ-
Figure 1. Esophageal acid contact times at the distal esophageal probe
in 26 asthma patients without reflux symptoms. Esophageal acid con-
tact times are represented as the percent time in which the esophageal
pH was less than 4 at the distal esophageal pH probe located 5 cm
above the lower esophageal sphincter. Total values represent the en-
tire recording period, upright values represent time when awake, and
supine values represent time of bedtime to morning arising. Open cir-
cles represent asthma patients considered to have normal esophageal
acid contact times, and solid circles represent asthma patients consid-
ered to have abnormal esophageal acid contact times. The solid line
represents the point at which values under the line are considered to
be in the normal range. Note that asthma patients were considered to
have abnormal esophageal acid contact times if one of the six esoph-
ageal pH values was in the abnormal range.
37
Figure 2. Esophageal acid contact times at the proximal esophageal
probe in 26 asthma patients without reflux symptoms. Esophageal
acid contact times are represented as the percent time in which the
esophageal pH was less than 4 at the proximal esophageal pH probe
located within 3 cm below the upper esophageal sphincter. Open cir-
cles represent asthma patients considered to have normal esophageal
acid contact times, and solid circles represent asthma patients consid-
ered to have abnormal esophageal acid contact times. The solid line
represents the point at which values under the line are considered to
be in the normal range. Note that asthma patients were considered to
have abnormal esophageal acid contact times if one of the six esoph-
ageal pH values was in the abnormal range.
ated with asthma, even in the absence of reflux symptoms.
Identifying clinically silent gastroesophageal reflux in asthma
patients requires 24-h esophageal pH testing. D emographic
asthma variables including nocturnal asthma symptoms were
not helpful in identifying asthma patients with asymptomatic
gastroesophageal reflux. H owever, this study has limited power
to identify characteristics associated with reflux among asymp-
tomatic patients because of the small patient population, in-
cluding whether asthma medications predispose to the devel-
opment of reflux. Furthermore, this prevalence rate of 62% is
associated with wide confidence levels. A lso, this is a prelimi-
nary report, performed in a university-based clinic setting, and
may not represent the general asthma population.
The severity of reflux in asthma patients with asympto-
matic gastroesophageal reflux is not less than asthma patients
with symptomatic gastroesophageal reflux. Compared with
asthma patients with symptomatic gastroesophageal reflux,
asthma patients with asymptomatic gastroesophageal reflux
had higher lower esophageal sphincter pressures, but similar
esophageal acid contact times at the distal esophageal pH
probe (5 cm above the manometrically defined lower esoph-
ageal sphincter). This finding may be partially explained by
two factors. First, asthma patients with symptomatic gastro-
esophageal reflux were more likely to be on theophylline (p ,
0.005) and theophylline may decrease lower esophageal sphinc-
ter pressure (23). Second, asthma patients with symptomatic
gastroesophageal reflux had more severe asthma as character-
ized by the National A sthma E ducation Program than did
asthma patients with asymptomatic gastroesophageal reflux.
The diaphragmatic crura participates in lower esophageal
sphincter pressure generation (24, 25). H yperinflation associ-
ated with bronchospasm may place the diaphragmatic crura at
a functional disadvantage because of geometric flattening (26,
27). A lthough no studies to date have examined asthma pa-
38 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 162 2000

TABLE 2 It is unlikely that this study overestimated the prevalence

DEM OGRAPHIC CHARACTERISTICS OF ASTHM A PATIENTS of gastroesophageal reflux because false-positive tests are rare
WITH ASYM PTOM ATIC GASTROESOPHAGEAL REFLUX (2Sx 1pH) (, 5% ), and in fact, false-negative results are much more com-
AND ASTHM A PATIENTS WITH SYM PTOM ATIC mon (range 10 to 25% ) (4). A lso, all but one (6% ) of the asthma
GASTROESOPHAGEAL REFLUX (1Sx 1pH) patients with asymptomatic gastroesophageal reflux had more
2Sx 1pH 1Sx 1pH than one abnormal esophageal pH parameter with 13 (81% )
(n 5 16) (n 5 30) p Value having three or more abnormal esophageal pH parameters.
Women, n (%) 10 (63%) 18 (60%) 0.88
Irwin and coworkers showed in difficult-to-control asthma
White, n (%) 13 (81%) 27 (90%) 0.41 patients that identifying and treating gastroesophageal reflux,
Asthma severity,* n (%) regardless of the presence of reflux symptoms, improved
Mild 5 (31%) 7 (23%) 0.73 asthma control (9). The association between asthma and gas-
Moderate 10 (63%) 5 (17%) 0.005 troesophageal reflux is complex. For instance, esophageal acid
Severe 1 (6%) 18 (60%) 0.001 caused a decrease in peak expiratory flow rates in asthma pa-
Asthma medications, n (%)
Inhaled as needed basis b2-agonists, only 2 (13%) 1 (3%) 0.27
tients with gastroesophageal reflux. In a guinea pig model,
Inhaled b2-agonists 12 (75%) 26 (87%) 0.42 H amamoto and coworkers found that esophageal acid infusion
Inhaled corticosteroids 11 (69%) 16 (53%) 0.49 results in the release of airway substance P and that this release
Inhaled cromolyn 3 (19%) 4 (13%) 0.68 of substance P was coupled with airway edema (30). H owever,
Inhaled anticholinergics 2 (13%) 6 (20%) 0.69 there are conflicting data. Likewise, therapeutic trials using a
Oral corticosteroids 2 (13%) 15 (50%) 0.03 cross-over design have not shown significant improvement in
Oral b2-agonists 1 (6%) 8 (27%) 0.13
Oral theophylline 2 (13%) 18 (60%) 0.005
asthma outcomes (31, 32). For example, a double-blind, pla-
No. of medications used per day, cebo-controlled cross-over study of 107 asthma patients using
Mean 6 SD 2.1 6 1.5 3.0 6 1.6 0.07 omeprazole 40 mg daily or placebo for 8 wk showed an im-
provement in nocturnal asthma symptoms during the omepra-
* Defined by National Asthma Education Program (21).
zole phase; however, there may have been an order effect from
the cross-over (33). Furthermore, Boeree and coworkers evalu-
ated 30 asthma patients with gastroesophageal reflux using
tients, they may be more prone to developing functional im- omeprazole 40 mg twice daily for 3 mo in a randomized, dou-
pairment of the diaphragmatic crura resulting in alterations in ble-blind, placebo-controlled parallel manner trial, and found
lower esophageal sphincter pressure generation. no difference in spirometry, asthma symptoms scores, medica-
A sthma patients with asymptomatic reflux had higher tion use, peak expiratory flow rates, or methacholine PD 20 (34).
amounts of proximal esophageal acid compared with gastric U nfortunately, there was difficulty with patient compliance
patients with symptomatic reflux. Interestingly, in two previ- with 13 (43% ) of the subjects taking less than 75% of the study
ously reported studies, proximal esophageal acid predicted drug (34). R ecently, Field and Sutherland reviewed all E nglish
asthma improvement with antireflux therapy (7, 28). studies in the ME D LINE database with 326 medically treated
Four studies prior to our own investigation have noted that asthma patients with gastroesophageal reflux, noting that
asthma patients may have asymptomatic gastroesophageal re- asthma symptoms improved in 69% of subjects, asthma medica-
flux (7, 9, 28, 29). Larrain and coworkers prospectively exam- tions were reduced in 62% , and evening peak expiratory flow
ined adult onset nonallergic asthma patients and found that 21 rates improved in 26% of patients without pulmonary function
of 81 (26% ) subjects had gastroesophageal reflux without ever test improvement (8). Likewise, antireflux surgery performed
experiencing heartburn (29). O ur study differs from Larrain on 417 asthma patients improved asthma symptoms, asthma
and coworkers study in two ways: the patient population se- medications use, and pulmonary function in 79% , 88% , and
lected (nonallergic asthma without a family history of asthma), 27% , respectively (35). Clearly, the association between asthma
and, most importantly, the technique by which gastroesoph- and gastroesophageal reflux needs further investigation. A dou-
ageal reflux was diagnosed (an esophagram after a 300-ml ble-blind, placebo-controlled, multicentered trial evaluating
barium meal which had an 8% false-positive rate and a 56% asthma outcomes with aggressive medical antireflux therapy us-
false-negative rate in their patient population) (29). Irwin and ing a proton pump inhibitor has not been reported to date.
coworkers also noted prospectively that 24% of difficult-to- This report suggests that gastroesophageal reflux is present
control asthma patients with gastroesophageal reflux had no in patients with stable asthma, even in the absence of esoph-
reflux symptoms (9). O ur study differs from Irwin and cowork- ageal symptoms with a prevalence rate of 62% , and it shows
ers study in that their patient population included only asthma the value of esophageal pH monitoring because demographic
patients who required more than 10 mg of prednisone every variables did not identify this asthma population. The severity
other day for at least three consecutive months per year. In a of gastroesophageal reflux in asthma patients with clinically si-
retrospective study, H arding and coworkers reviewed 24-h lent reflux is not less severe than in asthma patients with reflux
esophageal pH test results in 35 asthma patients without reflux symptoms. In fact, asthma patients with asymptomatic gas-
symptoms, of whom 10 (29% ) had abnormal esophageal acid troesophageal reflux had higher amounts of proximal esoph-
contact times. These asthma patients were referred to the ageal acid exposure. A sthma patients with asymptomatic gas-
esophageal pH laboratory, thus selection bias may have been troesophageal reflux should be included in future studies
introduced (10). Finally, Schnatz and coworkers, in a retro- evaluating asthma outcome with aggressive antireflux therapy
spective review of asthma patients and patients with chronic in asthma patients with gastroesophageal reflux.
cough, found that eight of 35 (23% ) with gastroesophageal re-
flux presented without esophageal symptoms (28). Schnatz and Acknowledgment : The authors thank Martin Robbins, Christy F. Austin, and
Arren Graf for their editorial assistance.
coworkers study included a mixed population of patients with
pulmonary disease (asthma and chronic cough) and examined
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