Diagnosis and Treatment ofExtraesophageal Reflux

DiseaseRachel Rosen, MD

Aerodigestive Center (ADC) Center for Motility and Functional

Gastrointestinal Disorders

Sinusitis 4.2%

Otitis 2.1%

Dental erosion 40.2°/o

Apparent lifethreatening event 20%Asthma 13.2%

Pneumonia 6.3%

Bronchiectasis 1%

General respiratorysymptoms 57.7%

The uphill battle…….Goldski et al Pediatrics 2010

symptomsNelson et al J Med Economic 2009

Mechanisms of Reflux RelatedRespiratory Disease

• Neurally Mediated• Microaspiration

Making the diagnosis

• Total reflux burden? Acid vs. non-acid?• Symptom correlation?• Distal Reflux Burden?• Proximal Reflux burden?• Esophagitis?• Lung biomarkers?

pH probe

•Pharyngeal pH monitoring

•pH-MII

•Cough catheters

•Cough microphone

•Biomarkers

Pharyngeal pH Monitoring

MII‐pHwith corresponding Restech event

Oropharyngeal pH drop >10% corresponds with MII‐pH changes

100

80

60

40

20

0>10% pHDrop <5.5

pH pH pH<5.0 <4.5 <4.0

No Corresponding MII-pH event Assoc w/ Non-Acid GER

Assoc w/ Acid GER

Correlation of Changes in Oropharyngeal pHwith MII Events

Chiou et al Neurogastro 2011

Multi Channel Intraluminal Impedance (MII)

• pH independent method of measuringreflux

• 7 sensors throughout the esophagus• 1 distal pH sensor• Advantages:

– Height of the refluxate,– Non-acid burden– Composition of reflux (liquid,gas)

Non Acid Reflux in PediatricsVandenplas et al Acta Paediatr. 2007

Percent of nonacid reflux episodes recorded(relative to total number of reflux episodes recorded)

Sifrim (n = 22) Rosen (n = 28) Mousa (n = 25) Wenzl (n = 22)

40 45 49 89

Del Buono (n =20) Corvaglia (n= 5)

69 78

Wenzl (n = 14) 55Condino (n = 24) 51

Condino (n =34) Lopez-Alonso (n= 21) Lopez-Alonso

(n = 7)

46 53 73

Del Buono (n = 16) 56Mattioli ( > 1 yr) (n = 50) 49Mattioli ( < 1 yr) (n = 50) 53

0 20 40 60 80 100

pH SensorImpedance

Sensors

and MIIRosen et al, Clinical Gastro and Hepatol 2006

pH probe MII P Value

Sensitivity in Untreated Patients

80.6±18.2% 76.1±13.5% 0.41

Sensitivity in Treated Patients

47.2±36.0% 80.3±21.1% 0.005

Normal Values?

Shay S, et al. Am J Gastroenterol. 2008Rosen et al JPGN 2008

Lopez-Alonso M, et al. Pediatrics. 2006 Peter et al., J. Pediatrics 2002

Acid Weakly Non- pH only Acid Acid

55 26 1 3

58 13 35

52 98

Total Events

Adults 73

Children 69

Preterm Infants

100

Full Column Reflux MattersJadcherla et al Am J Gastro 2008

SSI: Number of Reflux Events associated with SymptomsTotal Number of Reflux Events

Predictors of SymptomAssociation

Rosen and Nurko, Am J Gastro, 2004

Variable OR P Value

Non-Acid 1.70 (1.03-2.82) 0.04Proximal Reflux 1.31 (1.01-1.69) 0.04Liquid 0.63 (0.42-0.92) 0.02BCT (sec) 1.00 (0.98-1.00) 0.36

p g pOutcome?

Rosen et al JPGN 2010

Improved (N=22)

Not Improved (N=12)

P value

# acid events 13 (5, 25) 18 (5, 72) 0.36# non-acid events 19 (10, 29) 15 (2, 23) 0.21# pH-only events 18 (8, 30) 16 (8, 24) 0.71% full column

reflux38±23 17±14 0.005

% time pH<4 7.9±7.7 13.7±13.8 0.12

p g gevaluation have abnormal testing by

EGD or pH-MIIRosen et al Peds Pulm 2014

7% have EoE

So much is unknown…

• How much full column reflux is too much?• How much full column reflux is too much in

the child that aspirates?• Can we treat full column reflux, other than

fundoplication?

Impedance: The nextgeneration…

30 sec

cough

peristalsis

pH

coughcough

Pres

sure

C

hann

els

Addition of manometry increases cough detectionby 100%

Sifrim, Gut 2005Rosen et al JPGN 2013

10000

lm0

10000

lm100

100

Pr0

0

pJOO

p Ro ...................................................................................................................................................................................................................................................................................................................................................................................................................·········································-·····································································································-································-···································································-································-·····································································································-··················

0

Sul>ine .................................................................................................................................................................................................................................................................................................................................................................................................................. .

I2/09 :53:30

I2/09 :54:00

I2/09:54:30

I2/09 :55:00

microphones

Impedance Sensors

Pressure sensors

(manometry)

Acoustic coughrecording is as

sensitive as esophageal

pressurerecording

Rosen et al NGM 2014

to

Predict Aspiration Risk:Swallow Risk

IndexOmari et al Gastro 2011

Biomarkers

• LLMI• Pepsin• Bile• Bacteria??

Lipid Laden Macrophage Index (LLMI): No relationship with Esophagitis

Chang et al Respiratory Research 2005

Reflux by ImpedanceRosen et al Pediatrics 2008

AspirationReiley et al Laryngoscope 2011

Pepsin in Patients With GERD

1Starosta V, et al. Chest. 2007

Pepsin Sensitivity and Specificity

• 63% sensitivity; 92%specificity if reflux indistal esophagus2

• 75% sensitivity; 91% specificity if reflux in the proximal esophagus2

Peps

inin

BAL

(n

g/m

L)1

2500

1500

500200

100

0

Reflux indexproximal ≥ 2%

Reflux indexproximal < 2%

Peps

inin

BAL

flu

id(n

g/m

L)1

0 25 50 75 100 125 150 175Number of proximal reflux episodes

r = 0.51

P < 0.0001

P = 0.034

Rosen et al Neurogastro 2011

Sensitivity of

Pepsin

Specificity

of PepsinIf Abnormal EGD 67% 59%

If Abnormal pH probe 45% 56%

If Abnormal MII 71% 60%

If Any Abnormal Test (pH/MI/EGD) 57% 65%

Pepsin in the Lung and other ManifestationsRosen et al Neurogastro 2011

Pepsin Negative

n=28

Pepsin Positive

n=22

P Value

Ear Infections 11/28 3/19 0.4

Ear Tubes 4/28 5/22 0.4

Tonsillectomy 6/28 7/22 0.3

Sinus Infection 6/26 6/17 0.3

Pneumonia 6/26 8/19 0.4

Croup 5/27 4/20 0.9

Asthma 25/28 12/19 0.03

Cough 24/28 13/22 0.5

SalivaryPepsin in

GERDpatients

andControls

Hayat et al Gut 2014

pReflux Events

Blondeau et al J Heart Lung Transpl 2009

Bile in bronchoscopy fluid has been

associated with increased lung

rejection

SurvivalMertens et al, American J Transplantation 2011

You made the diagnosis: Nowwhat?

Acid Suppression

Esomeprazole does not improve asthma

outcomeNEJM 2009

RCT of Omeprazole in Treatment of AsthmaStordal et al Arch Dis Child 2005

AsthmaALA Clinical Research Centers, JAMA 2012

Chang et al, BMJ, 2005

Gatta et al, Alim Pharm Ther, 2007

PPI on laryngeal or pharyngeal symptoms

PPI on Cough

Esomeprazole for CoughShaheen et al APT 2010

Lansoprazole for Postnasal DripVaezi et al Gastro 2010

PPI Therapy and RefluxVela et al., Gastroenterology, 2001

Motility Agents

Reglan

Cisapride

Tagaserod

DomperIdone

Macrolides

• Increase antral contractility– Improvement in gastric emptying?– Improvement in reflux?

• Anti-inflammatory effect• Antimicrobial effect

in preterm infantsNg et al JPGN 2003

RCT of Emycin (12.5 mg/kg/dose Q6)

Ng et al Gastro 2007

Prior efficacy data with conflicting results with feeding tolerance

RefluxMertens et al Dig Dis Sci 2009

Azithromycin and its effect

on refluxRohof et al Gut 2012

InjuryWalkey and Weiner Chest 2011

Fundoplication

readmissions?Golden et al, Pediatrics, 2006

RRE: Reflux related eventsARP: Anti‐reflux procedure

22 % of all patients had more reflux related hospitalizations post surgery than pre-surgery

Hospitalization after FundoplicationLee et al J Peds Surg 2008

Fundoplication does not reduce hospitalizations

Barnhart et al JAMAPeds 2013

rate divided by pre-fundoplication rate), with 95% CIs, for refluxrelated hospital admissions (RRH).

Srivastava R et al. BMJ 2009

g yFrancis et al Laryngoscope 2011

Transpyloric Feeding

before and after Initiation of Transpyloric Feeds.

Malcolm et al J Perinatol 2009

pPneumonia free period

Sirvastava et al Pediatrics 2009

hour during feed (JF) and non-feed (NF) periods

Rosen et al, JPGN 2011

JF NF p Value

# Acid Events/hr 0.9±1.0 0.4±0.8 0.02

# Non-Acid Events/hr

1.3±1.3 0.7±1.1 0.04

# pH-Only Events/hr

0.5±0.8 0.3±0.6 0.3

# total MII/hr 2.2±1.4 1.1±1.2 0.003

.$i;lrv $ iN ,-S o l r . i ::.!1< : d o J11Po5mh: - i'd "-It i'-f'o

IO:lJ'I.I F":.,'111"'1..' \.' i1-:,1;- . ":1-. .r Jii"Joitl o.lil'li.:- lt.:.·; ,-1 r1:1 n Dl. l l ! ! . ln i . l

1NARNII\'"{; 1\/kiy c.aiJse ru1Jrin.J.1ing pulmoMIY e-dam . tock i h . ooirerOi.J$- 'I,J!Ier··.: . fi!"XII,Jrln:)ry ulCOillu f f'IC'. DtuL"Y 001 or $ ;:-t$ r•

mGII'hoid cme.m (41XC1J- !'.or u r I"ThOI:hGr in..lla\ )-

.-".'...HH

'...

--- J : l l i.

....,-.... :-. -._: .-:.-. -- t - •'!J-.... -=-"... a.. -::T tL.,:::; - -· ..........-·:--· s-· H- -... =-

f: ,)! -'=· .i'i ; ;

· - '='"?=.. ....

. - ::;: L•..--1

0r·""rH.•

-

...... ·_,:S... 2

.

'! ' .ill!.

:.;:.-

Made by retired rherd.Jlis-s l ivi lg a the""'11/hispe.ing ghs ..home lot" btlmooout AC..Ps

Reord.er by ca IIing 81))-661-5690 oronIine a1'Nw\•IJoocus. m

Summary

• Full column reflux matters• Acid suppression in the aerodigestive

patient requires thought and close followup

• Macrolides may be useful beyond their motility effect

• Fundoplication in the aerodigestive patientneeds thought (and a detailed consent)