DOI 10.1378/chest.126.5.1398 2004;126;1398-1399Chest

 Susan M. Harding Trigger : Acid StressGastroesophageal Reflux as an Asthma

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9 Goodwin JL, Enright PL, Kaemingk KL, et al. Feasibility ofusing unattended polysomnography in children for research:report of the Tucson Children’s Assessment of Sleep Apneastudy (TuCASA). Sleep 2001; 24:937–944

10 Serebrisky D, Cordero R, Mandeli J, et al. Assessment ofinspiratory flow limitation in children with sleep disorderedbreathing by a nasal cannula pressure transducer system.Pediatr Pulmonol 2002; 33:380–387

Gastroesophageal Reflux as anAsthma Trigger

Acid Stress

S ince Sir William Osler recognized that gastro-esophageal reflux (GER) is a potential asthma

trigger more than a century ago, multiple investiga-tions have shown a potential interaction between theesophagus and the lung. Despite this, there are stillmany unanswered questions as to how these twoorgans interact. To substantiate this interaction andto begin to examine causality, three criteria shouldbe met. First, GER prevalence should be higher inasthmatic patients than in control subjects. Second,GER should alter airway reactivity and inflammatorymarkers. And third, GER therapy should improveasthma outcomes. So where do we stand concerningacid stress?1,2

GER symptom prevalence is higher in asthmaticpatients compared to control subjects. Field et al3examined 109 asthmatic patients and 135 controlsubjects in two control groups, finding that heart-burn was present in 77% of asthmatic patientscompared to 48% of control subjects. Furthermore,41% of asthmatic patients noted reflux-associatedrespiratory symptoms, and 28% of them utilizedinhalers while experiencing GER symptoms. So, notonly do asthmatic patients have a higher prevalenceof GER symptoms than control subjects, they alsoassociate GER symptoms with asthma symptoms.Our laboratory noted4 that of 151 respiratory symp-toms reported in 199 asthmatic patients during 24-hesophageal pH testing, 79% of respiratory symptomswere temporally related to esophageal acid.

In this issue of CHEST (see page 1490), Kiljanderand Laitinen provide further insight into GER prev-alence in asthmatic patients. In randomly selectedasthmatic patients undergoing 24-h esophageal pHtesting, 36% of asthmatic patients had abnormalesophageal acid contact times and 25% of asthmaticpatients with abnormal esophageal acid contacttimes were free of typical GER symptoms includingheartburn. Furthermore, heartburn was not alwaysassociated with abnormal esophageal acid contact

times. So, should esophageal pH testing be per-formed in asthmatic patients to identify GER inclinical practice? My answer is, no! Although esoph-ageal pH testing is considered to be the “goldstandard” for identifying GER, it has a sensitivity andspecificity of approximately 90% and is not a perfecttest.5 Day-to-day esophageal acid contact times varywith activity and diet. Recently, a wireless esopha-geal pH system has been developed that allowsmonitoring up to 48 h without the use of an intra-nasal catheter, so that patients are less likely to altertheir daily activities and/or diet.6 Also, a nonacidrefluxate, undetectable with pH monitoring, mayhave an impact. Currently, minimal data exist onnonacid reflux and its effect on the lung. NonacidGER can be measured by esophageal impedancemonitoring, which was not performed in this study.7Despite these issues, Drs. Kiljander and Laitinenverify for us again that the prevalence of GER isindeed high in asthmatic patients.

So, why is GER so prevalent in asthmatic patients?Predisposing factors include an increased pressuregradient between the thorax and abdomen, leadingto more frequent reflux episodes. Asthmatic patientswith GER also have a higher prevalence of hiatalhernia (64%) compared to control subjects (19%),predisposing them to GER development.1 Finally,asthma medications may potentiate GER. For in-stance, theophylline increases gastric acid secretionand decreases lower esophageal sphincter pressure,inhaled �2-adrenergic agonists decrease loweresophageal sphincter pressure in a dose-dependentmanner, and oral corticosteroids increase esophagealacid contact times.1,8

If GER is an important asthma trigger, thenmechanisms should explain how GER alters airwayreactivity and inflammatory markers. The potentialmechanisms include a vagally mediated reflex, a localaxonal reflex, heightened bronchial reactivity, andmicroaspiration.1 Furthermore, neurogenic inflam-mation appears to play a key role in esophagealacid-induced bronchoconstriction. Elegant morpho-logic studies identified a direct connection betweenthe esophagus and the lung with nitric oxide-contain-ing neurons. In animal models, esophageal afferentnerve stimulation results in action potentials andtachykinin release (substance P and neurokinin-A) inthe lung.8 Aspiration may damage the airway epithe-lium, resulting in the release of cytokines and adhe-sion molecules leading to neurogenic inflammationand the initiation of other inflammatory pathways.9These mechanisms are dependent on the activationof capsaicin-sensitive sensory nerves, with the sub-sequent release of tachykinins that, in conjunctionwith kinins, nitric oxide, oxygen radicals, and pro-teases, modulate diverse aspects of airway inflamma-

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tion.2 Thus, excessive acidification leading to “acidstress” has many potential adverse effects on thelung.

So, with this in mind, does antireflux therapyimprove asthma outcomes? Previous trials haveshown that antireflux therapy improves asthmasymptoms in approximately 70% of asthmatic pa-tients with GER.10,11 However, these trials hadmajor design flaws, including small patient popula-tions, inadequate asthma outcome analyses, and theuse of a placebo crossover design in many of theproton pump inhibitor trials. Another importantfinding is that pulmonary function improvementdoes not always follow asthma symptom improve-ment.10,11 The Cochrane Airways Group Registry12

examined randomized controlled trials of childrenand adults who had been treated with medical orsurgical antireflux therapy, identifying 328 subjectsand finding that seven of nine studies had at leastone significantly improved asthma outcome. Thereare hints in large cohort studies that GER mayimpact asthma. GER was noted to be a risk factor forasthma hospitalization in asthmatic patients over theage of 19.13 Also, in a retrospective cross-sectionalanalysis of 10,959 asthmatic patients,14 GER waspredictive for higher numbers of oral steroid burstsand asthma hospitalizations. So GER may be animportant asthma trigger in selected asthmatic pa-tients, however, a definitive outcomes study has notbeen published to date.

A problem with our current state of knowledge isthat we do not know which asthmatic patients wouldbenefit from GER therapy. Many asthmatic patientshave GER without GER actually being a trigger oftheir asthma. Potential predictors of asthma re-sponse include the presence of regurgitation, noc-turnal asthma, nonallergic asthma, difficult-to-control asthma, a history of reflux-associatedrespiratory symptoms, and a high body mass index.1These predictors have not been validated in largerstudies, so currently it is up to the clinician todetermine whether GER is indeed a trigger of theirindividual patient’s asthma. A 3-month empiric trialof aggressive acid suppression utilizing a protonpump inhibitor could be used to identify theseasthmatic patients.1 Hopefully, future investigationswill allow clinicians to target those asthmatic patientswho have acid stress.

Susan M. Harding, MD, FCCPBirmingham, AL

Dr. Harding is Associate Professor of Medicine, the Division ofPulmonary, Allergy & Critical Care Medicine, University ofAlabama at Birmingham.This research was funded by National Institutes of Health-

National Heart, Lung, and Blood Institute grant RO1 HL75614–01.Dr. Harding has been a Consultant to and has received Clinical TrialFunding from AstraZeneca LP.Reproduction of this article is prohibited without written permis-sion from the American College of Chest Physicians (e-mail:permissions@chestnet.org).Correspondence to: Susan M. Harding, MD, FCCP, Division ofPulmonary, Allergy & Critical Care Medicine, 1900 UniversityBlvd, THT Rm 215, University of Alabama at Birmingham,Birmingham, AL 35294; e-mail: sharding@uab.edu

References1 Harding SM. Gastroesophageal reflux and asthma: insight

into the association. J Allergy Clin Immunol 1999; 104:251–259

2 Ricciardolo FL, Gaston B, Hunt J. Acid stress in the pathol-ogy of asthma. J Allergy Clin Immunol 2004; 113:610–619

3 Field SK, Underwood H, Brant R, et al. Prevalence ofgastroesophageal reflux symptoms in asthma. Chest 1996;1009:316–322

4 Harding SM, Guzzo MR, Richter JE. 24-h esophageal pHtesting in asthmatics: respiratory symptoms correlation withesophageal acid events. Chest 1999; 115:654–659

5 Kahrilas PJ, Quigley EM. Clinical esophageal pH recording: atechnical review for practice guideline development. Gastro-enterology 1996; 110:1982–1996

6 Pandolfino JE, Richter JE, Ours T, et al. Ambulatory esoph-ageal pH monitoring using a wireless system. Am J Gastro-enterol 2003; 98:740–749

7 Shay S, Tutuian R, Sifrim D, et al. Twenty-four hourambulatory simultaneous impedance and pH monitoring: amulticenter report of normal values from 60 healthy volun-teers. Am J Gastroenterol 2004; 99:1037–1043

8 Harding SM. Recent clinical investigations of asthma andgastroesophageal reflux. Am J Med 2003; 115(suppl):39S–44S

9 Stein MR. Advances in the approach to gastroesophagealreflux (GER) and asthma. J Asthma 1999; 35:309–314

10 Field SK, Sutherland LR. Does medical antirefux therapyimprove asthma in asthmatics with gastroesophageal reflux?Chest 1998; 114:275–283

11 Field SK, Gelfand GA, McFadden SD. The effects of surgeryon asthmatics with gastroesophageal reflux. Chest 1999;116:766–774

12 Gibson PG, Henry RL, Coughlan JL. The effect of treatmentfor gastro-oesophageal reflux on asthma in adults and chil-dren. Cochrane Database Syst Rev (database online) Issue 2,2002

13 Diette GB, Krishnan JA, Dominici F, et al. Asthma in olderpatients: factors associated with hospitalization. Arch InternMed 2002; 121:8–10

14 Shireman TI, Heaton PC, Gay WE, et al. Relationshipbetween asthma drug therapy patterns and healthcare utili-zation. Ann Pharmacother 2002; 36:557–564

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T he patient needed to undergo a closed reductionof a dislocated shoulder in the emergency de-

partment where I was training. And, because thepatient had been “fall-down drunk” at the time, the

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DOI 10.1378/chest.126.5.1398 2004;126; 1398-1399Chest

Susan M. HardingGastroesophageal Reflux as an Asthma Trigger : Acid Stress

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