advances in gerd...gerd. therefore, if an asthma patient who has severe gerd continues to have gerd...

Gastroenterology & Hepatology Volume 8, Issue 6 June 2012 401

GE

RD

AdvAnces in GeRd

section editor: Joel e. Richter, Md

C u r r e n t D e v e l o p m e n t s i n t h e M a n a g e m e n t o f A c i d - R e l a t e d G I D i s o r d e r s

Is There a Relationship Between GERD and Asthma?

John G. Mastronarde, MDProfessor of Internal MedicineDirector, The Ohio State University Asthma CenterThe Wexner Medical Center at The Ohio State UniversityColumbus, Ohio

G&H How prevalent is gastroesophageal reflux disease in asthma patients?

JGM Approximately25millionAmericanshaveasthma.How many of these individuals have gastroesophagealrefluxdisease(GERD)dependsonhowGERDisdefined.TheprevalenceofGERDcertainlyappearstobehigherinasthmapatientsthaninthegeneralpopulation,butstud-ieshaveuseddifferentdefinitions ofGERD,making itdifficulttocomparetheirfindingsandcompiledata.TheprevalenceofGERDinasthmapatientshasrangedfrom25%to80%instudies,manyofwhichuseself-reportedGERD. In a study conducted by the American LungAssociation Asthma Clinical Research Centers (ACRC)Network,38%ofasthmapatientshadGERD(asdefinedbyapositivepHprobe).

G&H Do all patients with asthma and GERD exhibit classic symptoms of GERD?

JGM There is certainly a populationof asthmapatientswho have classic symptoms of GERD, including heart-burn. AmongthesesymptomaticGERDpatients,pulmo-narysymptoms,notablycough,mayalsooccur.However,asignificantnumberofasthmapatientshavesilentGERD(ie,GERDonlydetectedbypHprobes).InthepreviouslymentionedACRCstudy,noneofthe38%ofpatientswhohadapositivepHprobehadclassicsymptomsofGERD.

G&H What has been the historical understanding of the relationship between GERD and asthma?

JGM Ithas longbeenthoughtthat treatmentofrefluxin asthma patients improves their asthma. This belief

was even reflected in the last setofguidelines from theNational Institutes of Health (NIH) for the treatmentof asthma. These guidelines recommended that physi-ciansconsideradministeringanempirictrialofantirefluxtherapytopatientswithpoorlycontrolledasthma,evenintheabsenceofGERDsymptoms.Theseguidelineswerebasedonbothanimalstudies,whereacidinstilledintheesophagus resulted in airway hyperresponsiveness, andpreviousclinicaltrialsthatallhadsignificantlimitationssuchassmallsamplesize,poorlydefinedasthma,poorlydefinedGERD,andinadequatetreatmenttime.

G&H What is the current understanding of the relationship between GERD and asthma?

JGM The answer to this question is a bit controver-sial.Again,itdependsonhowGERDisdefinedandifGERDissymptomaticornot.Intermsofacidreflux,thereappearstobe2differentgroupsofpatientswithasthma and GERD, as previously mentioned. OnegrouphasasthmaandclassicGERDsymptoms.Somedata suggest that GERD treatment in these patientsimprovestheirqualityoflifeandmayimproveasthmaexacerbations.Inaddition,GERDtreatmentmaycausesmallincreasesinlungfunctionthatarestatisticallysig-nificantbutofquestionableclinicalsignificance.Thus,atthistime,itappearsthattheremaybesomerelation-shipbetween symptomaticGERDandasthma-relatedquality of life and, possibly, exacerbations in thesepatients,andtreatmentofGERDinthesepatientsmayhavesomeimpactontheirasthma.

ThesecondgroupofpatientshaveasthmaandsilentGERD. Several large studies, including a recent pedi-atric study conducted by the American Lung Associa-tionACRCNetworkthatwasrecentlypublishedinThe

402 Gastroenterology & Hepatology Volume 8, Issue 6 June 2012

GE

RD

Journal of the American Medical Association,haveprettyconvincingly demonstrated that asthma patients (bothadults and children) who have asymptomatic GERDdemonstrated by pH probe testing do not have anyimprovementsintheirasthmacontrolorlungfunctionwhentreatedwithprotonpumpinhibitors.

Theserecent,largeclinicaltrialshavefocusedonthetreatmentofacidreflux.Atheoryhasbeenputforththatalkali GERD may worsen asthma control; however, todate,thistheoryhasbeenlargelyunproven,asonlyafewsmallstudieshaveevaluatedthistypeofGERD.Alargerandomized controlled trial with well-defined asthmapatientsandobjectivedocumentationofalkaliGERDisrequiredtoanswerthisimportantclinicalquestion.

Thus, to date, although GERD treatment mayresult in nonspecific improvements in quality of lifein patients with symptomatic GERD and asthma, bynowIthinktherehavebeenenoughstudies,includingthe ACRC study, to conclude that treatment of silentGERDdoesnotimproveasthmaatall.Thisconclusionisasignificantchangefromwhatdoctorshavebelievedfor a long time. I amnot certain thatGERD-inducedasthmaexists.Clearly, somepatientswithGERDhaverespiratory symptoms, primarily cough, but the exactmechanism for this relationship is unclear, which, Ithink, is part of the confusion in this area. However,I do not believe that the presence of these respiratorysymptoms isequivalentor sufficient tomakethediag-nosisofchronicinflammatoryasthma.IwonderifthereareothereffectsofGERD,suchasworseningofvocalcorddysfunction,thatmaymimicasthmaandhaveledusinthepasttoerroneouslyconcludethatGERDwasworseningasthma.

G&H Why then is GERD more common in asthma patients than in the general population?

JGM ItisnotentirelyclearwhyGERDismorecommoninasthmapatients.Severaltheorieshavebeenadvanced,withthemostcommononebeingthatpressureswingsin the thorax of asthmatics allow more acid to refluxinto the esophagus.There are animal studies that sug-gestthatinstillationofacidintheesophagusstimulatesvagal tone and may increase respiratory resistance and“prime”theairwaysforbronchoconstriction.Theseandother animal studies suggest that chronic microaspira-tion from GERD may trigger bronchoconstrictionandalsopossiblyincreaseinflammationintheairways.However,thishypothesishasnotbeenadequatelytestedin humans. In addition, some asthma medications,specificallyb-agonistsandtheophylline,mayreducetheloweresophagealsphinctertoneand,thus,promoteacid

refluxinasthmatics;however,againtheclinicalimpactof these changes does not appear to be significant, atleastinpatientswithasymptomaticGERD.

G&H Why does GERD treatment improve (albeit only by a little) quality of life in patients with symptomatic GERD?

JGM Iamnotcertainthat there isagoodanswertothis question. It may be that effective treatment ofGERDresultsinanimprovementinoverallwell-beingandis,thus,reflectedinimprovedqualityofliferelatedtoasthma.

G&H Have any studies examined the impact of nonmedical GERD treatment on asthma?

JGM Most studies looking at GERD treatment andasthmahaveevaluatedeitherH2blockersorprotonpumpinhibitors,which,asisknown,donotcurereflux.SomeresearchershavestartedtowonderwhetherotherGERDtreatments,suchasNissenfundoplication,wouldimprovepatients’ asthma. Thus far, all of the studies evaluatingwhetherNissen fundoplication(orother surgicalproce-dures that eliminate reflux) improves asthma outcomeshave been case reports or very small cohort studies; norandomizedtrialshaveyetbeenconductedonthisissue.Asthefindingshavebeenvariable,definitivelyansweringthis question would require a large randomized trial ofNissenfundoplicationversusshamNissenfundoplicationin well-defined asthma patients with objective evidenceofGERD.However, thisstudywouldbeexpensiveandchallengingtoconduct,soIamnotcertainthatwewillgetagoodanswertothisquestion.

G&H Should patients with asthma and symptomatic GERD receive the same treatment as GERD patients without asthma?

JGM Yes, anasthmapatientwith symptomaticGERDshould be treated the same as a nonasthmatic patientwith symptomatic GERD. GERD treatment should befocused on reducing GERD symptoms and preventingsequelae,as itdoesnothavemuchofan impactonthepatient’sasthma,aspreviouslydiscussed.

Likewise,whendeterminingwhetherthesepatientsshould receive surgical therapy,doctors should followthe standard guidelines for treatment of refractoryGERD.Therefore,ifanasthmapatientwhohassevereGERD continues to have GERD symptoms despitestandard medical treatment, a Nissen fundoplicationshouldbeconsidered,justasifthepatientwereanon-asthmaticwithsevereGERD.

Gastroenterology & Hepatology Volume 8, Issue 6 June 2012 403

GE

RD

G&H Has the general community adopted these new treatment guidelines (ie, that asthma patients with silent GERD should no longer receive GERD treatment)? Is there harm in continuing to administer GERD treatment to patients with silent GERD?

JGM Therearenodataavailableontheimpactoftheserecent data on clinical practice. It will be interesting toseehowtheNIHasthmaguidelinesreviewthisissue,asIexpectthattheNIHmaychangeitspreviousrecommen-dation fora trialof empiricGERDtreatment inpoorlycontrolledasthmatics.

Therearegrowingconcernsofsideeffectsofprotonpumpinhibitortherapy,includingapotentialincreaseinupperrespiratoryinfectionsorpneumoniasaswellasfrac-turesinchildren.Inaddition,thesemedicationsareveryexpensive. However, my major concern is that a protonpumpinhibitortrialinasthmapatientswithasymptomaticGERDwillhavenoimpactontheirasthmaandjustdelaysothertherapiesfocusedontheirasthma.

G&H What are the next steps in research?

JGM As mentioned above, the relationship betweenalkali refluxandasthma shouldbe further investigated.It would also be good to conduct a definitive trial ofGERDandasthmacomparingsurgicaltreatments(suchasNissen fundoplicationor laparoscopic therapies)andmedical treatments; however, as mentioned previously,this trialwouldbeexpensive, require shamprocedures/surgery, and need a very large patient population for

adequatepower. Atthistime,themajorneediseducationregarding the new evidence that asymptomatic GERDdoesnot impact asthma,whichwill hopefully steer cli-nicians toward other, more effective therapies for theirpatientswithpoorlycontrolledasthma.

Suggested Reading

WritingCommitteefortheAmericanLungAssociationAsthmaClinicalResearchCenters;Holbrook JT,WiseRA,GoldBD,et al.Lansoprazole for childrenwithpoorlycontrolledasthma:arandomizedcontrolledtrial.JAMA.2012;307:373-381.

Riscili BP, Parsons JP, Mastronarde JG. Treating silent reflux disease does notimprovepoorlycontrolledasthma.Cleve Clin J Med.2010;77:155-160.

DiMangoE,HolbrookJT,SimpsonE,etal;AmericanLungAssociationAsthmaClinical Research Centers. Effects of asymptomatic proximal and distal gastro-esophagealrefluxonasthmaseverity.Am J Respir Crit Care Med.2009;180:809-816.

Parsons JP, Mastronarde JG. Gastroesophageal reflux disease and asthma. Curr Opin Pulm Med.2010;16:60-63.

AmericanLungAssociationAsthmaClinicalResearchCenters;MastronardeJG,AnthonisenNR,CastroM,etal.Efficacyofesomeprazolefortreatmentofpoorlycontrolledasthma.N Engl J Med.2009;360:1487-1499.

Littner MR, Leung FW, Ballard ED 2nd, Huang B, Samra NK; LansoprazoleAsthma Study Group. Effects of 24 weeks of lansoprazole therapy on asthmasymptoms,exacerbations,qualityof life,andpulmonaryfunctioninadultasth-maticpatientswithacidrefluxsymptoms.Chest.2005;128:1128-1135.

KiljanderTO,HardingSM,FieldSK,etal.Effectsofesomeprazole40mgtwicedailyonasthma:arandomizedplacebo-controlledtrial.Am J Respir Crit Care Med.2006;173:1091-1097.

KiljanderTO,JunghardO,BeckmanO,LindT.Effectofesomeprazole40mgonceortwicedailyonasthma:arandomized,placebo-controlledstudy.Am J Respir Crit Care Med.2010;181:1042-1048.

ChanWW,ChiouE,ObsteinKL,TignorAS,WhitlockTL.Theefficacyofprotonpumpinhibitorsforthetreatmentofasthmainadults:ameta-analysis.Arch Intern Med.2011;171:620-629.

BenningerC,Parsons JP,Mastronarde JG.Vocal corddysfunctionandasthma.Curr Opin Pulm Med.2011;17:45-49.