GERD Asthma (2)

Original Paper

Digestion 2008;77:218–224

DOI:10.1159/000146083 A

sthma and Gastroesophageal Reflux: Clinical Evaluation of Esophago-Bronchial

Reflex and Proximal Reflux András Rosztóczy a László Makk b Ferenc Izbéki a Richárd Róka a Attila Somfay b

Tibor Wittmann a

a

F irst Department of Medicine and b D epartment of Pulmonology, Albert Szent-Gy?rgyi Medical Centre,

University of Szeged, S zeged , Hungary

acid perfusion is able to establish the presence of EBR, how-

ever prospective therapeutic trials are needed to confirm its

clinical value. The increased amount of acid reflux during the

supine period in patients with EBR may indicate a role for ap-

propriate nighttime acid suppressive therapy.

C opyright ? 2008 S. Karger AG, Basel Introduction G astroesophageal reflux disease (GERD) is a common disorder, with approximately 20% of the general popula-tion suffering from its classical symptoms at least once a week [1, 2] . Among patients with asthma GER

D has been shown to be more prevalent, especially nighttime symp-toms [3] . Furthermore, not only the prevalence of symp-tomatic GERD is increased in patients with asthma, but a similarly high proportion of patients have abnormal gas-troesophageal reflux without the typical reflux symptoms (heartburn, regurgitation) as well, thus gastroesophageal reflux is considered to play an important role in the patho-genesis of the disease [4–6] . Gastroesophageal reflux can trigger bronchial hyperresponsiveness (BHR) in two ma-K ey Words G astroesophageal reflux disease ?Bronchial hyperresponsiveness ? Asthma ?Esophago-bronchial reflex Abstract

A ims: To evaluate the prevalence of proximal reflux and esophago-bronchial reflex (EBR) in patients with asthma,

and to compare the symptom spectrum, esophageal acid

sensitivity, pH monitoring, and the endoscopic and mano-

metric parameters of EBR-positive and -negative patients

with asthma. P atients and Methods: Forty-three consecu-

tive patients with recent diagnoses of asthma and 20 pa-

tients with chronic cough but without asthma were prospec-

tively submitted to detailed reflux and respiratory symptom

analysis, upper gastrointestinal endoscopy, esophageal ma-

nometry, Bernstein test and double-channel intra-esopha-

geal pH monitoring. The presence of EBR was studied by

combined esophageal acid (0.1

N HCl) perfusion and metha-choline test. R esults: Patients with asthma had significantly

more proximal acid reflux than controls. Patients with EBR

positivity were more likely to have an acid-sensitive esopha-

gus and had more acid reflux especially in the supine period

at the distal measurement point. Other parameters were

similar. C onclusions: Patients with asthma had significantly

more proximal acid reflux than those with chronic cough.

The combination of the methacholine test with esophageal R eceived: January 28, 2008

A ccepted: June 16, 2008

P ublished online: July 19, 2008 András Rosztóczy,MD F irst Department of Medicine, Albert Szent-Gy?rgyi Medical Centre U niversity of Szeged, Korányi fasor 8 HU–6720Szeged (Hungary)

T el./Fax +36 62 54 59 97, E-Mail air@in1st.szote.u-szeged.hu ?

2008 S. Karger AG, Basel 0012–2823/08/0774–0218$24.50/0

Accessible online at:

https://www.360docs.net/doc/725717453.html,/dig F.I. was supported by a grant from the National Office for Research

and Technology (RET-08/2004).

jor pathways. The first is microaspiration which will occur when the regurgitated gastric acid reaches the pharynx and drops into the airways of patients. The second in-volves reflex mechanisms when acid triggers the sensory nerve endings of the distal esophagus. This may cause ei-ther a typical vagal response (involving esophageal affer-ents, the nucleus of the solitary tract in the midbrain, and efferents projecting to the tracheobronchial tree) or an axon reflex with neuroinflammatory consequences [7] .

A lthough these pathways are well established, human studies – evaluating their role in gastrosophageal reflux-induced BHR – are still not available [8, 9] .

F urthermore, the controversial results of anti-reflux therapeutic modalities in patients with asthma may sug-gest a role for patient selection on this basis [10–12] .

T herefore, in the present study we aimed to evaluate the prevalence of proximal reflux and esophago-bronchi-al reflex (EBR) in patients with asthma, and secondly, to compare the symptom spectrum, esophageal acid sensi-tivity, pH monitoring, and the endoscopic and manomet-ric parameters of E BR-positive and -negative patients with asthma.

Patients and Meth ods

S ixty-five consecutive patients with a recent diagnosis of bron-chial asthma were prospectively invited for evaluation of GERD. Twenty-two of the 65 patients refused to participate and 43 pa-tients (male/female 12/31, mean age 46, (range 27–76) years) signed the consent form and took part in the study. A group of 20 patients with chronic cough but without BHR and matched for age, sex and body mass index (BMI) was studied as control.

A ll patients with asthma met the criteria of the American Tho-racic Society [13] and the diagnosis was confirmed by methacho-line provocation test. Patients with inhalative allergy (pollinosis, house dust, etc.), autonomic neuropathy (diabetics, chronic alco-hol consumers, etc.) or regular smokers (more than 1 cigarette/ week) were not enrolled. Patients with impaired baseline respira-tory function (FE V 1!70%) were also excluded. Patients were screened for GERD by means of symptom analysis, upper gastro-intestinal endoscopy, esophageal manometry, 24-hour double-channel pH monitoring, and esophageal acid sensitivity (Bern-stein) testing. The presence of EBR was evaluated by combined methacholine and Bernstein test. The results of the diagnostic tests performed were not disclosed to the investigators. Proton pump inhibitors were stopped 7 days before testing. Other drugs affecting gastrointestinal motility, acid secretion, visceral sensi-tivity and anti-asthmatic treatments – such as long-acting ?-ago-nists and inhalative steroids – were suspended 72 h before the studies. During this period patients were allowed to use short-act-ing ?-agonists in case of asthmatic wheezing, but tests were post-poned if the patient needed such treatment during the last 12 h. The study protocol was approved by the Medical Ethics Commit-tee of the University of Szeged.

Lung Function Tests

F or lung function tests, a Lung test 1,000 spirometer (MES, Krakow, Poland) equipped with the ISPA provocation system was used. Lung function tests were carried out each day between 10 a.m. and 1 p.m. in a room with controlled temperature and hu-midity.

E sophageal Acid Sensitivity (Bernstein Test)

P atients were fasted overnight before the study. A baseline spi-rometry was carried out and FEV 1was measured. For the Bern-stein test a naso-esophageal perfusion catheter was positioned 10 cm above the lower esophageal sphincter and the spirometry was repeated. During the acid stimulation test 0.9% saline and 0.1 N HCl was perfused (12 ml/min for 10 min) in a double-blinded manner with repeated spirometries after each session. Esophageal and respiratory symptoms were monitored during the proce-dure.

Establishment of BHR and EBR

P atients with a normal baseline lung function test (FEV 1170% of the predicted value) were submitted to the following provoca-tion: a naso-esophageal catheter was placed 10 cm above the low-er esophageal sphincter and either 0.9% saline or 0.1 N HCl was perfused (12 ml/min) in a double-blinded manner during the methacholine test. Increased concentrations of methacholine (0.03–8.0 mg/ml; Metacolina Lofarma 1% Polvere per inalazione, Lofarma, Italy) were inhaled at 3-min intervals. The methacho-line dose was doubled at each step of the procedure. The proce-dure was stopped if FEV 1decreased by 20% compared to the base-line value.

P atients were considered to have EBR, if the 20% FEV 1de-crease was reached by an at least one-step ( 61 doubling concen-tration) lower dose of methacholine than during NaCl perfu-sion.

Esophag eal and Respiratory Symptom Analysis

P atients were asked to complete a standardized questionnaire regarding their symptoms related to GERD (such as heartburn, chest pain and gastroesophageal acid regurgitation) and bronchi-al asthma (wheezing, cough).

Upper Gastrointestinal Endoscopy

T he presence and severity of esophagitis were assessed by up-per gastrointestinal endoscopy (Olympus Q130) on the basis of the Los Angeles classification [14] .

T he severity of esophagitis was scored as: no erosions = 0; grade LA-A = 1; grade LA-B = 2; grade LA-C = 3, and grade LA-D = 4.

24-Hour Double-Channel Intra-Esophageal pH Monitoring

T he 24-hour intra-esophageal pH monitoring studies were carried out on an inpatient basis using the classical criteria of De-Meester et al. [15, 16] . Proximal pH results were considered abnor-mal in accordance to the criteria of Cool et al. [17] . A double-chan-nel, naso-esophageal, antimony pH probe (Synectics Medical, Sweden) was positioned. E lectrodes were located 5 and 20 cm above the lower esophageal sphincter (LES), and were connected to a portable data logger (Digitrapper pH, Synectics Medical, Swe-den). Computer-assisted data analysis was carried out with the Polygram for Windows 98 software supplied by Synectics Medical,

Asthma and GE RD Digestion 2008;77:218–224219

R osztóczy /Makk /Izbéki /Róka /Somfay /

Wittmann Digestion 2008;77:218–224220Sweden. The following parameters, e.g. the number of episodes

with pH ! 4, the percentage of the time with pH ! 4, the number of

episodes with pH ! 4 lasting for longer than 5 min, and the longest

episode with pH ! 4, were recorded during the full length of the

study, and separately in the upright, supine and postprandial (120

min) periods. The DeMeester score was also calculated.

Esophag eal Manometry

E sophageal motility was studied by standard, water perfusion,

stationary manometry (Polygraph HR, Synectics Medical, Swe-

den) with computer-assisted analysis of the tracings (Polygram

5.06C2, Synectics Medical, Sweden) according to our previously

published protocol. Briefly, a station pull-through technique was

applied, and measurements were made at the levels of the lower

esophageal sphincter, the esophageal body, the upper esophageal

sphincter and the pharynx, on the basis of Castell’s criteria [18,

19] .

Statistical Analysis

F or statistical analysis the Graphpad Prism 4.0 software was

used. Frequency distribution analysis was carried out by Fischer’s

test; group means were compared by Student’s unpaired t test, with Welch’s correction if the variances were different. The level of significance was set at p !0.05. R esults E valuation of Gastroesophageal Reflux in Patients with Asthma and Chronic Cough T able 1 summarizes the demographic data of the 43 patients enrolled. All 22 patients (34%) who did not par-ticipate marked ‘lack of any gastrointestinal symptoms’ as the cause of refusal. T he symptomatic evaluation of patients with asthma (n = 43) and chronic cough (n = 20) showed that the prev-alence of either typical reflux symptoms (heartburn, acid regurgitation) or respiratory symptoms (chronic cough, wheezing) were similar. Both groups included a similar number of patients with no typical reflux symptoms, but who had respiratory symptoms only. The patient groups were also similar in terms of Bernstein test positivity and the endoscopic severity of esophagitis ( t able 1 ). The re-sults obtained by esophageal manometry, such as lower esophageal sphincter pressure, relaxation time, esopha-geal body peristaltic wave amplitude, duration, propaga-tion velocity, rate of simultaneous contractions were not different (data not shown). T he parameters of respiratory function (FEV 1,peak expiratory flow) did not change significantly in either pa-tient group during the acid perfusion test. The FEV 1val-ues are shown in f igure 1 . Furthermore, the acid perfu-sion test alone was not able to provoke a significant ( 1 20%) reduction of FEV 1 in any patient. T he 24-hour double-channel esophageal pH monitor-ing showed that patients with asthma have significantly higher acidic reflux parameters with the exception of postprandial values at 20 cm above the LES than those without BHR. On the other hand pH parameters ob-tained at 5 cm above the LE S were not different ( t a-ble 2 ). E valuation of Gastroesophageal Reflux in Patients with and without EBR I n 22/43 (51%) patients with asthma, esophageal acid perfusion enhanced methacholine sensitivity. These pa-tients were considered to have EBR. This subgroup of pa-tients reached the limit of a 20% FEV 1 decrease at 2 (range 1–4) steps lower cumulative methacholine dose than dur-ing the baseline challenge. The mean methacholine con-centrations were 3.6 8 0.6 and 1.4 8 0.3 mg/ml, respec-Table 1. Demographic data, clinical symptom spectrum and en-doscopic results of patients with asthma (BHR+) and patients

with chronic cough (BHR–)

Demographic data

n 4320

Male/female 12/315/15n.s.

Age, years 46824983n.s.

BMI 28.680.830.681.3n.s.

Clinical symptoms

Heartburn 30 (70%)12 (60%)n.s.

Acid regurgitation 26 (60%)13 (65%)n.s.

No reflux symptom 12 (28%) 6 (30%)n.s.

Cough 37 (86%)20 (100%)n.s.

Wheeze 37 (86%)14 (70%)n.s.

Bernstein test positivity 18 (42%)9 (45%)n.s.

Endoscopy

Hiatal hernia 23 (55%)10 (50%)n.s.

NERD/ERD 29/1410/10n.s.

LA-A 74

LA-B 56

LA-C 20

LA-D 00

Mean esophagitis score 1.6480.20 1.6080.16n.s.

NERD = Patients without esophageal erosions; ERD = patients

with esophageal erosions; LA-A, -B, -C, -D = Los Angeles grade

A, B, C, D esophagitis, n.s. = not significant.

Unless otherwise indicated the data are presented the num-

bers of patients with percentages in parentheses or mean 8

SEM.

Asthma and GE RD Digestion 2008;77:218–224221

tively. Considering that esophageal acid perfusion is able

to induce chest discomfort and it may consequently im-

pair respiratory function, forced vital capacity (FVC) and

FEV 1 /FVC values were also recorded ( t able 3 ).

I n the remaining 21 patients esophageal HCl perfu-

sion did not change the methacholine concentration (3.7

8 0.7 vs. 3.8 8 0.7 mg/ml) necessary for a 20% FEV 1de-

crease. EBR-positive and -negative subgroups showed no

difference in demographic parameters, symptom spec-

trum and endoscopic results ( t able 4 ). Manometric pa-

rameters were also similar (data not shown).

I n patients with EBR (n = 22) the baseline Bernstein

test reproduced the typical symptoms significantly more

often than in subjects without E BR (n = 21, p !0.03),

however the esophageal acid perfusion test was not able

to provoke a significant FEV 1 decrease in itself (data not

shown).

T he 24-hour double-channel pH monitoring revealed

significantly higher esophageal acid exposure times at

5 cm above the LES in patients with EBR in the supine

period (p ! 0.04) and during the course of the whole study

(p ! 0.05). On the contrary, no differences were seen be-

tween values at the proximal point (20 cm above the LES;

t able 5 ).

C oncerning the two major pathways involved in the

development of gastroesophageal acid reflux-induced

BHR, the prevalence of abnormal proximal reflux was 12

of 43 patients, and EBR was present in 22 of 43 cases. Sev-

enteen patients had neither an abnormal proximal reflux

nor a positive EBR test ( f ig. 2 ).

F ig. 1. Changes of FEV 1 during the esophageal acid perfusion test.

a In patients with bronchial hyperresponsiveness (BHR+, n = 43, I ) and in patients with chronic cough (BHR–, n = 20, y ).

b In

patients with esophago-bronchial reflex positivity (EBR+, n = 22,

I ) and negativity (EBR–, n = 21, y ). Baseline = After perfusion tube insertion; NaCl = after 0.9% NaCl perfusion; HCl = after 0.1 N HCl perfusion. Data expressed as mean 8SE M. Table 2. Results of double-channel esophageal pH monitoring in patients with asthma (BHR+; n = 43), and in patients with chron-ic cough (BHR–; n = 20) at 5 and 20 cm above the LES (mean 8 SEM)20 cm above the LOS pH <4 episodes in 24 h, n 18865820.04Upright 15845820.03Supine 3.181.30.280.10.03Postprandial 1184482n.s.>5 min, 24 h 0.480.10.180.10.04Fraction time pH <4, 24 h, %0.980.30.280.10.03Upright, % 1.480.60.280.10.05Supine, %0.380.10.080.10.04Postprandial, % 1.980.80.680.3n.s.5 cm above the LOS pH <4 episodes in 24 h, n 768973815n.s.Upright 67884988n.s.Supine 108224812n.s.Postprandial 44863586n.s.>5 min, 24 h 1.180.3 1.780.7n.s.Fraction time pH < 4, 24 h, % 3.480.5 4.281.3n.s.Upright, % 5.080.8 5.081.6n.s.Supine, % 1.180.3 3.181.1n.s.Postprandial, %7.981.18.682.8n.s.DeMeester score 14.582.018.384.9n.s.n.s. = Not significant.

R osztóczy /Makk /Izbéki /Róka /Somfay /

Wittmann Digestion 2008;77:218–224

222

F ig. 2. The prevalence of esophago-bronchial reflex (E BR) and

pathological proximal reflux (ppGER) in patients with asthma.

Table 4. Demographic data, clinical symptom spectrum and en-

doscopic results of patients with esophago-bronchial reflex posi-

tivity (E BR+) and patients without esophago-bronchial reflex

(EBR–)

Demographic data

n 2221

Male/female 4/188/13n.s.

Age, years 49834283n.s.

BMI 29.581.027.681.3n.s.

Clinical symptoms

Heartburn 13 (59%)17 (81%)n.s.

Acid regurgitation 12 (55%)14 (67%)n.s.

No reflux symptoms 8 (36%) 4 (19%)n.s.

Cough 20 (91%)17 (81%)n.s.

Wheeze 19 (86%)18 (86%)n.s.

Bernstein test positivity 13 (59%) 5 (24%)0.03

Endoscopy

Hiatal hernia 12 (55%)12 (57%)n.s.

NERD/ERD 14/815/6n.s.

LA-A 52

LA-B 14

LA-C 20

LA-D 00

Mean esophagitis score 1.6380.32 1.6780.21n.s.

NERD = Patients without esophageal erosions; ERD = patients

with esophageal erosions; LA-A, -B, -C, -D = Los Angeles grade

A, B, C, D esophagitis; n.s. = not significant.

Unless otherwise indicated the data are presented as the num-

bers of patients with percentages in parentheses or mean 8 SEM.

Table 3. Parameters of respiratory function during methacholine test combined with esophageal perfusion of NaCl and HCl in pa-tients with esophago-bronchial reflex (mean 8 SEM)Table 5. Results of double-channel esophageal pH monitoring in patients with esophago-bronchial reflex positivity (EBR+; n = 22) and in patients without esophago-bronchial reflex (EBR–; n = 21) at 5 and 20 cm above the lower esophageal sphincter (LES; mean 8 SEM)20 cm above the LES pH <4 episodes in 24 h, n 188418811n.s.Upright 14841689n.s.Supine 481382n.s.Postprandial 10831187n.s.>5 min, 24 h 0.380.10.480.3n.s.Fraction time pH <4, 24 h, %0.780.2 1.180.7n.s.Upright, % 1.080.3 1.881.3n.s.Supine, %0.380.10.380.3n.s.Postprandial, % 1.780.5 2.281.5n.s.5 cm above the LES pH <4 episodes in 24 h, n 9481658870.05Upright 808155387n.s.Supine 14845810.04Postprandial 528103686n.s.>5 min, 24 h 1.480.50.880.3n.s.Fraction time pH <4, 24 h, % 4.380.8 2.480.40.04Upright, % 6.381.4 3.780.7n.s.Supine, % 1.680.50.580.10.04Postprandial, %9.782.3 6.081.5n.s.DeMeester score 18.183.310.781.50.05n.s. = Not significant.

Discussion

A lthough several studies have been carried out to eval-uate the relationship between asthma and GERD [3–12, 20, 21] , our study is the first to evaluate the prevalence of the two major pathogenetic pathways involved in a paral-lel fashion. Experimental studies in cats showed that mi-croaspiration of acid – caused by proximal gastroesopha-geal reflux –impaired the respiratory function ten times more potently than esophageal acid perfusion. Although similar studies were not carried out in conscious humans, the presence of microaspiration may be considered a more severe pathological condition [20, 22] .

I n our study, an abnormal proximal acid reflux was established in 28% of the patients with BHR, while 51% had positive results on the EBR test. Our results provide evidence for the coexistence of the two pathophysiologi-cal pathways, as a significant overlap (8 patients, 19%) was observed between the groups with pathological prox-imal reflux and EBR positivity. Although 9 of the 17 pa-tients who had neither pathological proximal acid reflux nor a positive EBR test had at least 1 proximal acid reflux episode, GERD seems unlikely to play a role in the devel-opment of their asthma. This hypothesis should be fur-ther tested by the evaluation of non-acidic or weak acidic reflux in this subset of the patients [21] .

O ur patients with asthma (BHR+) had significantly more acid exposure in the proximal esophagus compared to the control group with chronic cough (BHR–), how-ever their clinical symptom spectrum was similar. This may suggest that patients with asthma have a different, more acidic reflux composition than those with chronic cough and other proximal respiratory disorders. In these latter patient groups recent studies provided data for the important pathogenetic role of weak and non-acidic re-flux [23–25] .

W e were not able to make a distinction between pa-tient groups by stationary esophageal manometry in any of the studied parameters of LE S and esophageal body motility. This confirms the previous observation of Zer-bib et al. [26] who found similar resting LES pressures in patients with and without BHR. They evaluated the num-ber of transient LES relaxations as well, and found no dif-ference at rest, but an increase after methacholine chal-lenge. Since they observed an increased number of reflux episodes in this period, they proposed that bronchial ob-struction may trigger or aggravate gastroesophageal re-flux through this mechanism.

I n our patients with asthma, the baseline esophageal acid perfusion test has failed to change the respiratory function significantly, similar to the results of Wu et al.

[8] and Hervé et al. [9] . Furthermore, our results support their other observation as esophageal acid perfusion is able to enhance the effect of methacholine stimulation in such patients.

W e have been able to demonstrate that esophageal acid perfusion enhanced the effect of methacholine challenge in 50% of the patients with BHR, while none of the pa-tients with normal baseline methacholine test had sig-nificant FEV 1reduction when esophageal acid perfusion was added. This suggests that the studied reflex is not present in patients without BHR. On the other hand, the esophagus of patients with EBR positivity appeared to be more sensitive to acid as their typical reflux symptom had more likely been reproduced by the standard Bernstein test. The 24-hour pH monitoring results of these patients showed significantly higher values for acidic reflux in the distal esophagus, especially in the sleeping period, com-pared to those without EBR positivity. The data that Zer-bib et al. [26] provided as bronchial obstruction can in-crease the number of transient LES relaxations may lead us to consider that patients with asthma and EBR may be at a higher risk as their reflux episodes may trigger/ag-gravate the bronchial obstruction, which would further trigger/aggravate reflux by promoting transient LES re-laxations. Controlled therapeutic trials are needed to confirm the hypothesis as more potent anti-reflux thera-py – not only the elimination of pathological proximal reflux and microaspiration, but distal acidic gastroesoph-ageal reflux episodes as well – might be important for the better control of asthma in this subset of patients.

A further important observation was that all other parameters studied, such as the prevalence of hiatal her-nia, erosive esophagitis, or the symptom spectrum, were similar in patients groups with and without BHR. At en-doscopy, a macroscopically intact esophageal mucosa was observed at a similar rate to other studies conducted in patients with extra-esophageal reflux disease [2].Con-cerning the symptom spectrum of the patients studied approximately one third of the enrolled patients had no typical reflux symptoms at all. It is known that patients with respiratory disorders may have silent GE RD [6], which means that they lack typical reflux symptoms in spite of the presence of abnormal acid reflux. Conse-quently these patients are invisible for the epidemiologi-cal studies based on typical reflux symptoms, and only detailed clinical evaluation may reveal their reflux. We observed that the enrollment of patients without typical reflux symptoms for esophageal function analysis is more difficult. While we were able to enroll all patients

Asthma and GE RD Digestion 2008;77:218–224223

R osztóczy /Makk /Izbéki /Róka /Somfay

/

Wittmann

Digestion 2008;77:218–224224with typical reflux symptoms, approximately two thirds

(22/34) of the patients with BHR and without reflux

symptoms refused participation. Reviewing the litera-

ture, the available studies have not evaluated this prob-

lem. The small number of subjects studied without typi-

cal reflux symptoms did not allow us to compare their

esophageal function parameters to those of patients with

reflux symptoms. Further prospective analysis of the

esophageal function in patients with BHR with and

without reflux symptoms may be useful to clarify this

question.Conclusions P atients with BHR had significantly more proximal acid reflux than those with chronic cough. The combina-tion of methacholine test with esophageal acid perfusion is able to establish EBR, however prospective therapeutic trials are needed to confirm its clinical value. The in-creased amount of acid reflux during the supine period in patients with EBR positivity may indicate that the ef-fectiveness of nighttime acid suppressive therapy can be important for the attenuation of the reflex. Since the re-

sults of anti-reflux treatments are controversial in pa-

tients with asthma, it might be useful to test such a subset

of patients in further trials.

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