Gastroesophageal reflux disease in COPD: links and risks

Figures & data

Figure 1 Typical and atypical clinical presentations of GERD.

Abbreviations: GERD, gastroesophageal reflux disease; ENT, ears-nose-throat.

Table 1 Diagnostic approaches and prevalence of GERD in COPD

Study	N, sex, age mean (SD)	Disease severity (FEV1% pd)	Questionnaire/objective measure	Prevalence of GERD and symptom descriptions
Symptom-based diagnosis
Mokhlesi et al^Citation12	COPD: n= 100, Sex: NR Age: 70 (8) years Control: n=55, Sex: NR Age: 66 (13) years	NR	Modified Mayo Clinic GER questionnaire: common symptoms (frequency and severity), effect on respiratory symptoms, and medications.	Prevalence in COPD: 26%. Prevalence in controls: 25%. Increase in respiratory symptoms (cough, SOB, wheezing associated with heartburn in 26% of those with GERD).
Phulpoto et al^Citation61	COPD: n= 100, Sex: NR Age: 57 (8) years Control: n= 150 Sex: NR Age: 50 (5) years	NR	Modified Mayo clinic questionnaire: frequency and characterization of reflux or heartburn symptoms over past year.	Prevalence in COPD: 25%. Prevalence in controls: 9%. Heartburn, acid regurgitation more frequent in COPD to controls. More frequent symptoms in those with COPD with FEV1 <50% pd compared to those with FEV1 >50% pd.
Rascon-Aguilar et al^Citation57	COPD: n=91, Sex: 55% male Age: 67 (8) years	NR	Mayo clinic GER questionnaire: frequency and characterization of reflux or heartburn symptoms over past year. Weekly symptoms classed as positive GERD.	Prevalence in COPD: 32%.
Terada et al^Citation52	COPD: n=82, Sex: 94% male Age: 73 (8) years	COPD: 57 (20)% pd	Self-reported FSSG: typical and dysmotility symptoms.	FSSG: Prevalence in COPD: 27%, Prevalence in control: 13%.
	Control: n=40, Sex: 48% male Age: 71 (9) years	Control: 101 (16)% pd	QUEST	QUEST: Prevalence in COPD: 24%, Prevalence in control: 10%.
Rogha et al^Citation55	COPD: n= 110 Sex: 87% male Age: 68 (8) years	NR	Mayo clinic questionnaire: frequency and characterization of reflux or heartburn symptoms over past year. Weekly symptoms classed as positive GERD.	Prevalence in COPD: 54%. 66% with weekly and 34% with daily symptoms.
Bor et al^Citation58	COPD: n= 133 Sex: 26% female Age: NR	NR	Reflux questionnaire: effect of GERD symptoms on respiratory disease; medications, typical reflux symptoms.	Prevalence in COPD: 16.5%. Prevalence in controls: 19.4%. In COPD: occasional (symptoms less than once weekly in last year) heartburn in 11%, occasional regurgitation in 1 1.3%.
Takada et al^Citation60	COPD: n=221 Sex: 95% male Age: 72 (8) years	NR	FSSG: typical and dysmotility symptoms.	Prevalence in COPD: 27%.
Shimizu et al^Citation59	COPD: n=40 Sex: 95% male Age: 70 (10) years Control: n=40 Sex: 55% male Age: 65 (10) years	COPD: 1.4 (0.9) L Control: NR	FSSG: typical and dysmotility symptoms.	Prevalence in COPD: 33%. Prevalence in controls: 28%. Higher proportion of dysmotility symptoms in COPD compared to controls.
Ambulatory esophageal pH monitoring
Casanova et al^Citation11	COPD: n=42 Sex: 100% male Age: 68 (47–78)* years Control: n= 15 Sex: 88% male Age: 67 (47–78)* years	COPD: 35 (20–49)*% pd Control: 106 (81–130)*% pd	Single-channel (distal), 24-hour pH monitoring. Antireflux medication ceased 7 days prior to study.	Prevalence in COPD: 62%. Prevalence in controls: 19%. Combined reflux pattern (supine and upright) in 73% of those with COPD. Symptomatic (heartburn and acid regurgitation) GERD in 23% of those with COPD.
Andersen and Jensen^Citation63	COPD: n=264 Sex: NR Age: 58 (45)* years Control: n=809 Sex: NR Age: 61 (51)* years	COPD: NR Control: NR	12-hour esophageal pH monitoring. Symptom questionnaire. Status of antireflux medication at the time of study NR.	Prevalence in COPD: 8%. Esophageal symptoms in 14% of COPD compared to 4% control group.
D’Ovidio et al^Citation41	COPD: n=21 Sex: NR Age: 55 (38)* years	20 (23)% pd	Dual-channel, 24-hour pH monitoring. Antireflux medication ceased 2–5 days prior to study.	Prevalence in COPD: 19%, with asymptomatic GERD in 52%. Proximal reflux present in 29%.
Sweet et al^Citation42	COPD: n=21 Sex: NR Age: 55 (46)* years	NR	Dual-channel, 24-hour pH monitoring. Antireflux medication ceased 3–14 days prior to study.	Prevalence in COPD: 43%. Proximal reflux was 25%.
Kempainen et al^Citation56	COPD: n=42 Sex: 43% male Age: 56 (30–65)* years	24 (9)% pd	Dual-channel, 24-hour pH monitoring. Antireflux medication cased 7 days prior to study.	Prevalence in COPD: 52%. Proximal and distal reflux present in 46% and 41 % of patients. 15% had elevated proximal reflux only Asymptomatic reflux in 74%.
Gadel et al^Citation64	COPD: n=40 Sex: 100% male Age: NR Control: n=10 Sex: NR Age: NR	NR	Single-channel, 24-hour pH monitoring. Status of antireflux medication NR.	Prevalence in COPD: 35%. Symptoms of GERD in 55%.
Kamble et al^Citation62	COPD: n=50 Sex: 82% male Age: 56 (5) years	59 (5)% pd	Dual-channel, 24-hour pH monitoring. Questionnaire-based symptom score. Status of antireflux medication NR.	Prevalence in COPD: 78% based on pH monitoring, with asymptomatic GERD in 21%. Those with symptomatic GERD: distal and proximal GERD in 53%, distal only in 29%. Those with asymptomatic GERD: 50% had distal reflux only and 17% had distal and proximal reflux.
Lee et al^Citation49	COPD: n=27 Sex: 78% male Age: 67 (8) years Control: n= 17, Sex: 41% male Age: 37 (15) years	COPD: 47 (17)% pd Control: 96 (9)% pd	Dual-channel, 24-hour pH monitoring. Structured symptom questionnaire. Antireflux medication ceased 7 days prior to study.	Prevalence in COPD: 37%, with asymptomatic reflux in 20%. In COPD, distal reflux only in 80%, proximal and distal reflux in 20%. Prevalence in controls: 18%.

Note:

* Median (interquartile range).

Abbreviations: GERD, gastroesophageal reflux disease; SD, standard deviation; FEV₁ pd, predicted; forced expiratory volume in 1 second; NR, not reported; GER, gastroesophageal reflux; SOB, shortness of breath; FSSG, frequency scale for the symptoms of GERD; QUEST, Questionnaire for the Diagnosis of Reflux Disease.

Table 2 Studies exploring the effect of GERD on AECOPD

Study	N, age	Disease severity (FEV1% pd)	Definition of GERD	Definition of AECOPD	Key findings
Rascon-Aguilar et al^Citation57	COPD: n=91 Age: 67 years	NR	Mayo Clinic GERD	Worsening dyspnea, increasing sputum volume or purulent sputum in conjunction with corticosteroids or antibiotics, hospitalization or emergency department visits in previous 12 months.	Greater number of AECOPD in those with GERD symptoms (3.2 vs 1.6, P=0.02). Average of 1.56 more AECOPD (95% CI 0.44–2.69) in those with weekly GERD symptoms. Those with GERD had increased rate of hospitalizations.
Terada et al^Citation52	COPD: n=82 Age: 73 years Control: n=40 Age: 71 years	COPD: 60% pd Control: 101% pd	Self-reported FSSG questionnaire	Modified Anthonisen’s criteria (two or more of three major symptoms (increase in dyspnea, sputum purulence, or quantity) or any major symptoms with one minor symptom (wheeze, sore throat, cough, fever, and nasal discharge) for at least 2 consecutive days.	Higher incidence of exacerbations in those with GERD symptoms (RR 1.93 [95% CI 1.32–2.84]). FSSG score correlated with number of exacerbations (r=0.24).
Eryuksel et al^Citation79	COPD: n=29 Age: NR	NR	Laryngeal reflux: LPR criteria (reflux symptoms index, reflux finding score and laryngoscope)	Worsening of dyspnea, sputum volume, or color change in last year.	Increased risk of AECOPD in those with LPR (3.67 [95% CI 0.17–79.61]). No difference in number of AECOPD.
Hurst et al^Citation112	n=2, 138 Age: 63 years	NR	Self-reported symptoms and history of heartburn	Physician prescription of systemic corticosteroids or antibiotics, alone or in combination.	Risk of AECOPD in those with GERD (OR 1.69 [95% CI 1.38–2.06]).
Rogha et al^Citation55	COPD: n=110 Age: 68 years	NR	Mayo GERQ	Increase in cough frequency, severity, increase in dyspnea or change in volume, and/or sputum purulence.	Increased number of exacerbations in those with GERD (2.1 vs 1.4, P<0.001) and increased rate of hospitalizations (1.7 vs 1.1, P<0.005). Correlations between frequency of GERD symptoms and exacerbation frequency (r=0.32), frequency of hospitalization (r=0.26).
Terada et al^Citation83	COPD: n=67 Age: 74 (72–75)* years Control: n=19 Age: 70 (67–74)* years	COPD: 56 (52–61)*% pd Control: 105 (96–114)*% pd	FSSG questionnaire	Modified Anthonisen’s criteria.	Increased risk of AECOPD in those with GERD (RR 6.24 [95% CI 0.90–3.34]). Abnormal swallowing reflex associated with >3 AECOPD/year.
Takada et al^Citation60	COPD: n=221 Age: 72 years	68 (27)% pd	FSSG questionnaire	Modified Anthonisen’s criteria and prescription of additional systemic corticosteroids or antibiotics.	GERD increased frequency of AECOPD (RR 3.42 [95% CI 2.06–5.69]). GERD increased frequency of hospitalization due to AECOPD with RR 3.66 (95% 1.62–8.24). Significant correlation between FSSG acid reflux score and number of AECOPD (r=0.46) and number of hospitalizations due to AECOPD (r=0.45).
Liang and Feng^Citation54	COPD: n=428 Age: 57–74# years	47–71#% pd	RDQ	CAT score: increase in 5 points considered to have an exacerbation.	Those with exacerbations had higher RDG scores (high risk with score > 12). High GERD risk increased risk of AECOPD (OR 3.02 [95% CI 1.76–4.31]).
Ozyilmaz et al^Citation110	COPD: n=107 Age: 66 years	51 (18)% pd	Modified simple questionnaire of symptoms (heartburn, regurgitation, dyspepsia, dysphagia, nausea, vomiting, abdominal pain, dry cough, chest pain). Those with at least two symptoms weekly with antireflux therapy classed as GERD	AECOPD requiring oral steroids and/or antibiotics resulting in emergency room admission or hospitalization defined as severe.	Higher prevalence of GERD symptoms in frequent exacerbators (58% vs 22%, P<0.00l). GERD symptoms were increased risk of AECOPD (OR 3.59 [95% CI 1.18–10.90]).
Ingebrigtsen et al^Citation113	COPD: n=1,259 Age: NR	NR	Question relating to the experience of heartburn (daytime or nocturnal)	Prescription of oral corticosteroids with/without antibiotics dispensed <4 weeks apart.	Coexisting nocturnal and daytime GERD increased risk of AECOPD in those not using acid inhibitory treatment (HR 2.1 [95% CI 1.1–4.1]). Attributable risk of AECOPD was 31% in those with daytime and nocturnal GERD due to lack of regular acid inhibitory treatment.

Notes:

* Mean (range).

# Range.

Abbreviations: GERD, gastroesophageal reflux disease; AECOPD, acute exacerbation of COPD; FEV₁, forced expiratory volume in 1 second; NR, not reported; CI, confidence interval; FSSG, frequency scale for the symptoms of GERD; RR, risk ratio; LPR, laryngopharyngeal reflux; OR, odds ratio; GERQ, gastroesophageal reflux questionnaire; RDQ, reflux diagnostic questionnaire; CAT, COPD Assessment Test; RDG, Reflux Disease Questionnaire; HR, hazard ratio.

Table 3 Effects of medical and surgical treatment on GERD in COPD

Study	N	Treatment approach	Effects of treatment
Medical therapy
Mokhlesi et al^Citation12	100	Antireflux therapy (duration not specified) Antacids (43% of participants) PPI (28% of participants) H2-RA (6% of participants)	Significant respiratory and GER symptoms in 9% of patients, despite H2-RA and PPI therapy. Resolution of GER symptoms and chronic cough in 2% of patients, without change in PFTs.
Kempainen et al^Citation56	42	Antireflux therapy (duration not specified) PPI (29% of participants) H2-RA (2% of participants)	NR.
Rascon-Aguilar^Citation57	91	Antireflux therapy (duration not specified) Antacids (51% of participants) H2-RA (22% of participants) PPI (38% of participants) 34% receiving a combination of at least two types of medication	NR.
Sasaki et al^Citation118	100	Antireflux therapy (12 months), Comparison of treatment (PPI therapy) vs usual care (bronchodilator therapy, smoking cessation) PPI therapy	Fewer exacerbations with PPI over 12 months compared to control (0.34 vs 1.18, P=0.03); fewer patients in the PPI group experienced COPD exacerbations more than once (24% vs 52%; P<0.004). Trend toward fewer common colds (1.22 vs 2.04) and less frequent common colds (>3 per year) with PPI therapy compared to control. PPI therapy independently reduced risk of exacerbation of COPD (OR 0.23 [95% CI 0.08–0.62]).
Eryuksel et al^Citation79	30	Antireflux therapy (2 months) PPI therapy	Reduced COPD symptoms (P<0.01), reduction in laryngopharyngeal reflux symptoms (P<0.01), and improved laryngeal examinations (P<0.001).
Ingebrigtsen et al^Citation113	1,259	Regular use of acid inhibitory therapy (59%) in those with nighttime and/or daytime GERD	NR.
Surgical treatment
Hartwig et al^Citation120	20	Following bilateral lung transplantation, Nissen fundoplication (<365 days post-transplant) undertaken in selected patients	FEV1 greater at 1-year with fundoplication compared to no fundoplication (8.8% difference).
Hoppo et al^Citation122	11	Pretransplant Nissen fundoplication	Improved FEV1 and FVC% predicted in overall group (separate outcomes for COPD not reported).

Abbreviations: GER, gastroesophageal reflux; H₂-RA, H₂ receptor antagonist; PPI, proton pump inhibitor; PFTs, pulmonary function tests; NR, not reported; OR, odds ratio; CI, confidence interval; GERD, gastroesophageal reflux disease; FEV₁, forced expiratory volume in 1 second; FVC, forced vital capacity.

MokhlesiBMorrisAHuangC-FCurcioABarrettTKampDIncreased prevalence of gastroesophageal reflux symptoms in patients with COPDChest200111941043104811296167

 PubMed Web of Science ®Google Scholar

PhulpotoMOzyyumSRizviNKhuhawareSProportion of gastroesophageal symptoms in patients with chronic obstructive pulmonary diseaseJ Pak Med Assoc20055527627916108509

 PubMedGoogle Scholar

Rascon-AguilarIEPamerMWludykaPRole of gastroe-sophageal reflux symptoms in exacerbations of COPDChest20061301096110117035443

 PubMed Web of Science ®Google Scholar

TeradaKMuroSSatoSImpact of gastro-oesophageal reflux disease symptoms on chronic obstructive pulmonary disease exacerbationThorax20086395195518535116

 PubMed Web of Science ®Google Scholar

RoghaMBehraveshBPourmoghaddasZAssociation of gastroesophageal reflux disease symptoms with exacerbations of chronic obstructive pulmonary diseaseJ Gastrointest Liver Dis2010193253256

 Web of Science ®Google Scholar

BorSKitapciogluGSolakZErtilavMErdincMPrevalence of gastroesophageal reflux disease in patients with asthma and chronic obstructive pulmonary diseaseJ Gastroenterol Hepatol20102530931319817951

 PubMed Web of Science ®Google Scholar

TakadaKMatsumotoSKojimaEProspective evaluation of the relationship between acute exacerbations of COPD and gastroesophageal reflux disease diagnosed by questionnaireRespir Med20111051531153621454063

 PubMed Web of Science ®Google Scholar

ShimizuYDobashiKKusanoMMoriMDifferent gastroesophageal reflux symptoms of middle-aged to elderly asthma and chronic objective pulmonary disease patientsJ Clin Biochem Nutr201150216917522448100

 PubMed Web of Science ®Google Scholar

CasanovaCBaudetJSdel Valle VelascoMIncreased gastro-oesophageal reflux disease in patients with severe COPDEur Respir J20042384184515218995

 PubMed Web of Science ®Google Scholar

AndersenLJensenGPrevalence of benign oesophageal disease in the Danish population with special reference to pulmonary diseaseJ Intern Med19892253934012787376

 PubMed Web of Science ®Google Scholar

D’OvidioFSingerLGHadjiliadisDPrevalence of gastroesophageal reflux in end-stage lung disease candidates for lung transplantAnn Thorac Surg2005801254126116181849

 PubMed Web of Science ®Google Scholar

SweetMPHerbellaFALeardLThe prevalence of distal and proximal gastroesophageal reflux in patients awaiting lung transplantationAnn Surg2006244449149716998357

 PubMed Web of Science ®Google Scholar

KempainenRSavikKWhelanTDunitzJHerringtonCBillingsJHigh prevalence of proximal and distal gastroesophageal reflux disease in advanced COPDChest20071311666167117400682

 PubMed Web of Science ®Google Scholar

GadelAAMostafaMYounisAHaleemMEsophageal motility pattern and gastroesophageal reflux in chronic obstructive pulmonary diseaseHepatogastroenterology2012591202498250223178615

 PubMedGoogle Scholar

KambleNKhanNKumarNNayakHDagaMStudy of gastrooesophageal reflux disease in patients with mild-to-moderate chronic obstructive pulmonary disease in IndiaRespirology20131846346723062059

 PubMed Web of Science ®Google Scholar

LeeALButtonBDenehyLProximal and distal gastro-oesophageal reflux in chronic obstructive pulmonary disease and bronchiectasisRespirology201419221121724033416

 PubMed Web of Science ®Google Scholar

EryukselEDoganMOlgunSKocakICelikelTIncidence and treatment results of laryngopharyngeal reflux in chronic obstructive pulmonary diseaseEur Arch Otorhinolaryngol200926681267127119221778

 PubMed Web of Science ®Google Scholar

HurstJVestboJAnzuetoASusceptibility to exacerbation in chronic obstructive pulmonary diseaseN Engl J Med2010363121128113820843247

 PubMed Web of Science ®Google Scholar

TeradaKMuroSOharaTAbnormal swallowing reflex and COPD exacerbationsChest2010137232633219783670

 PubMed Web of Science ®Google Scholar

LiangB-MFengY-LAssociation of gastroesophageal reflux disease symptoms with stable chronic obstructive pulmonary diseaseLung201219027728222258420

 PubMed Web of Science ®Google Scholar

OzyilmazEKokturkNTeksutGTatliciogluTUnsuspected risk factors of frequent exacerbations requiring hospital admission in chronic obstructive pulmonary diseaseInter J Clin Pract201367691697

 PubMed Web of Science ®Google Scholar

IngebrigtsenTMarottJVestboJNordestgaardBHallasJLangePGastroesophageal reflux disease and exacerbations in chronic obstructive pulmonary diseaseRespirology20152010110725297724

 PubMed Web of Science ®Google Scholar

SasakiTNakayamaKYasudaHA randomised, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patientsJ Am Geriatr Soc20095781453145719515110

 PubMed Web of Science ®Google Scholar

HartwigMGAndersonDJOnaitisMWFundoplication after lung transplantation prevents the allograft dysfunction associated with refluxAnn Thorac Surg201192246246821801907

 PubMed Web of Science ®Google Scholar

HoppoTJaridoVPennathurAAntireflux surgery preserves lung function in patients with gastroesophageal reflux disease and end-stage lung disease before and after lung transplantationArch Surg201114691041104721931001

 PubMedGoogle Scholar