ABSTRACT

Objective: To examine the relationship between gastroesophageal reflux (GER) and COPD exacerbations. Methods: We conducted a systematic search of various electronic databases for articles published up through December of 2012. Studies considered eligible for inclusion were those dealing with COPD, COPD exacerbations, and GER; comparing at least two groups (COPD vs. controls or GER vs. controls); and describing relative risks (RRs) and prevalence ratios-or ORs and their respective 95% CIs (or presenting enough data to allow further calculations) for the association between GER and COPD-as well as exacerbation rates. Using a standardized form, we extracted data related to the study design; criteria for GER diagnosis; age, gender, and number of participants; randomization method; severity scores; methods of evaluating GER symptoms; criteria for defining exacerbations; exacerbation rates (hospitalizations, ER visits, unscheduled clinic visits, prednisone use, and antibiotic use); GER symptoms in COPD group vs. controls; mean number of COPD exacerbations (with symptoms vs. without symptoms); annual frequency of exacerbations; GER treatment; and severity of airflow obstruction. Results: Overall, GER was clearly identified as a risk factor for COPD exacerbations (RR = 7.57; 95% CI: 3.84-14.94), with an increased mean number of exacerbations per year (mean difference: 0.79; 95% CI: 0.22-1.36). The prevalence of GER was significantly higher in patients with COPD than in those without (RR = 13.06; 95% CI: 3.64-46.87; p < 0.001). Conclusions: GER is a risk factor for COPD exacerbations. The role of GER in COPD management should be studied in greater detail.

Keywords: Pulmonary disease, chronic obstructive; Gastroesophageal reflux; Meta-analysis; Risk factors; Evidence-based medicine.

RESUMO

Objetivo: Examinar a relação entre refluxo gastroesofágico (RGE) e exacerbações da DPOC. Métodos: Foi realizada uma revisão sistemática de artigos publicados até dezembro de 2012 utilizando várias bases de dados. Os critérios de elegibilidade incluíram estudos sobre DPOC, exacerbações da DPOC e RGE que comparavam ao menos dois grupos (DPOC vs. controle ou RGE vs. controle) e descrevendo riscos relativos (RRs), razões de prevalência ou ORs e respectivos IC95% (ou com dados que permitissem o seu cálculo) para a associação entre RGE e DPOC, assim como taxas de exacerbações. Os dados foram coletados com um formulário padronizado que incluía o tipo de estudo; critérios para diagnóstico de RGE; idade e gênero dos participantes; número de participantes; método de randomização; escores de gravidade; métodos de avaliação dos sintomas de RGE; critérios de definição de exacerbação; taxa de exacerbações (hospitalizações, visitas à emergência, consultas não programadas, uso de prednisona e uso de antibióticos); sintomas de RGE no grupo DPOC vs. controles; média de exacerbações da DPOC (com sintomas vs. sem sintomas); frequência anual de exacerbações; tratamento para RGE; e gravidade da obstrução. Resultados: O RGE foi claramente identificado como um fator de risco para exacerbações da DPOC (RR = 7,57; IC95%: 3,84-14,94), com um aumento na média de exacerbações por ano (diferença média: 0,79; IC95%: 0,22-1,36). Houve uma prevalência significativamente maior de RGE em pacientes com DPOC do que naqueles sem DPOC (RR = 13,06; IC95%: 3,64-46,87; p < 0,001). Conclusões: O RGE é um fator de risco para exacerbações da DPOC. O papel do RGE no manejo da DPOC deve ser mais profundamente investigado.

Palavras-chave: Doença pulmonar obstrutiva crônica; Refluxo gastroesofágico; Metanálise; Fatores de risco; Medicina baseada em evidências.

Introduction

Exacerbations of COPD are critical events in the natural history and management of the disease because they are related to the worsening of quality of life,(1,2) accelerated decline in lung function,(1,2) hospital admissions,(2-5) increased risk of death,(1,3,5) and high use of health care resources.(1,3,4) Despite the negative impact of exacerbations on the natural course of the disease, little is known about their causes.(2,5)

Recent studies have suggested that the main determinants for COPD exacerbations are a previous history of exacerbations,(2,4) a low level of physical activity,(4) the severity of the disease,(2,4,5) and the presence of comorbidities, such as gastroesophageal reflux (GER), congestive heart failure, coronary artery disease, and chronic renal/liver failure.(4,6-8) However, the role of GER in this setting remains unclear.

Roughly one-half of the adult population in industrialized countries has a personal experience of GER symptoms, and 20-30% suffer from GER disease (GERD).(9) Presumably, GERD is the most common disease of the digestive tract(9,10) and has been shown to worsen asthma control, due to esophagobronchial reflex,(11,12) and to heighten bronchial reactivity.(11,13,14) In addition, GERD is a determinant of microaspiration.(14,15) It has also been reported that GER is accompanied by neutrophilic airway inflammation,(16) and COPD has the same type of inflammation,(17) which in turn could be increased by this association. Moreover, microaspiration of gastric contents or bronchospasm induced by the vagus nerve due to the irritation of the esophagus caused by the gastric acid might contribute to the association between GER and pulmonary disease/symptoms.(4,15,18)

The association between GER and COPD exacerbation remains unclear.(15,19) One explanation is that GER acts as a collaborating factor of COPD exacerbations by increasing airway inflammation. Therefore, the aim of this meta-analysis was to evaluate the impact of GER on COPD exacerbations.

Methods

We conducted a systematic search of the Medline (PubMed, from 1966 to December 2012), EMBASE (from 1974 to December 2012), the Cochrane Controlled Trials Register (1960-2007), and LILACS (from 1982 to December 2012) databases. We created three groups of keywords, using the connectors "OR" and "AND" within each group and between groups, respectively. We used the following keywords in the first group: "COPD", "chronic bronchitis", and "emphysema". For the explanatory variable, the second group comprised the terms "GERD", "GORD", "GOR" "gastroesophageal reflux", "gastro esophageal reflux", "gastroesophageal reflux disease", "gastro esophageal reflux disease", "gastrooesophageal reflux", "gastro oesophageal reflux", "gastrooesophageal reflux disease", "gastro oesophageal reflux disease", "laryngopharyngeal reflux", and "swallowing". The third group of keywords was used in order to restrict the study design: "cohort", "prospective", "retrospective", "clinical trial", "cross sectional", or "case-control". The bibliographic references of all of the selected articles were also searched, even if they had not been identified by the database search.

Eligibility criteria

Eligibility criteria for the selection of articles were as follows: articles published in English, Spanish, or Portuguese; articles involving patients with COPD (defined by the Global Initiative for Chronic Obstructive Lung Disease criteria),(1) emphysema, or chronic bronchitis; articles reporting the rate of COPD exacerbations, defined by the number of hospitalizations, emergency room visits, and unscheduled clinic visits, as well as by the need for prednisone course/antibiotics or the use of the criteria described by Anthonisen et al.(20); articles comparing at least two groups (COPD vs. control, or GER vs. control); articles describing the relative risk, prevalence ratio, or odds ratios for the association between GER and COPD with the corresponding 95% CIs or with sufficient data to allow further calculations; and articles reporting exacerbations rates with corresponding 95% CIs or enough data to allow further calculations. No limitations were set for age or for the definition of GER.

Two reviewers screened the titles and abstracts of the identified citations independently and independently acquired the full text of any article that either one judged potentially eligible. The reviewers independently applied the eligibility criteria to the methods section of potentially eligible trials. Disagreements were solved by discussions with a third reviewer.

Data abstraction

Data abstraction was performed independently by two reviewers, using a protocol adapted from the study by Vandenbroucke et al.(21)

Data collection and analysis

The data were analyzed with freeware MIX, version 1.7.(22) We pooled the included studies to yield the risk ratio (RR) or odds ratio for COPD exacerbations and mean number of exacerbations per year with their respective 95% CIs or standard errors.

Selection of reviews

Data extraction and management

The data were extracted using a standardized form, including type of study design; criteria for GER diagnosis (pH monitoring or questionnaires); age and gender of participants; number of participants; randomization method; severity score (i.e., COPD classification); evaluation methods of GER symptoms; definition criteria for exacerbations; rate of exacerbations (hospitalizations, ER visits, unscheduled clinic visits, prednisone use, and antibiotics use); GER symptoms in COPD group vs. controls; mean number of COPD exacerbations (with symptoms vs. without symptoms); annual frequency of exacerbations; GER treatment; and severity of airflow obstruction.

Assessment of methodological quality of included reviews

Data synthesis

We presented all point estimates as RR or as mean  SE. We used forest plots in order to display the results. The selected trials were combined with freeware MIX.(22) For dichotomous variables, we calculated a fixed-effect RR and the respective 95% CIs for individual studies.

We calculated the mean difference (MD) with 95% CI for continuous variables. When standard deviations (SD) were reported, they were used in order to calculate SE using the following formula:
SD = SE × sqrt (N) (1)

If SDs were unavailable for continuous variables, we analyzed them by transforming 95% CIs into SEs according to the following formula:
SE = (upper limit of 95% CI − lower limit of 95% CI) ÷ (1.96 × 2) (2)

In addition, OR was adapted to the relative risk using the following formula(23):

Relative risk = _______OR_______ (3)
(1 − Po) + (Po × OR)
where Po is the observed prevalence.
We quantified inconsistencies among the pooled estimates using the following formula:
I2 = [(Q − df)/Q] × 100% (4)
where Q is chi-square, and df is its degrees of freedom.

This illustrates the percentage of the variability, which, in effect, reveals estimates resulting from heterogeneity rather than from a sampling error.(24) If heterogeneity was found, we used a random-effects model. We performed sensitivity analyses by comparing random-effects and fixed-effect models. Potential for publication bias was assessed using the Egger test and funnel plots.

Results

The electronic database searches identified a total of 543 articles. We excluded 507 articles upon review of the titles and abstracts. The review of titles yielded 36 articles that were further examined. Among the remaining 36 articles, some were further excluded due to the following causes: missing information on COPD, GER, or exacerbations(25-32); review articles(6,12,15,33-37); lack of adequate data for the meta-analysis(18,28,38-42); and inclusion/exclusion criteria that made the study unrepresentative of the population.(43) After that, a review of the abstracts and the full texts yielded 11 articles that appeared to fulfill the inclusion criteria. Of the 11 articles, 7 met the inclusion criteria and were included in the analysis (Figure 1).(4,19,44-48) The characteristics of the studies included in the meta-analysis are presented in Table 1. No unpublished or ongoing studies were included.







Increased risk of COPD exacerbations in GER patients

An elevated risk of COPD exacerbations in GER patients was researched by calculating the RR of COPD exacerbations between patients with and without GER. We found that GER patients showed a risk of having an exacerbation seven times higher than did those without GER (RR = 7.57; 95% CI: 3.84-14.94; z = 5.83; t2 = 0.0; p < 0.0001). We used a fixed-effect model, justified by the low heterogeneity (Q = 1.07; I2 = 0.0; p = 0.89) of the studies (Figure 2). The analysis included 341 patients from all studies.

We further examined the increase in the number of COPD exacerbations in GER patients. In that analysis, we used a random-effects model because of the high heterogeneity (Q = 9.95; p < 0.04; I2 = 59.8%) instead of a fixed-effect model. Patients with GER showed a higher number of exacerbations per year (MD = 0.79; 95% CI: 0.22-1.36; z = 2.69; t2 = 0.23; p < 0.007) than did those without GER (Figure 3). The analysis included 2,418 patients from all studies.



Association between GER and COPD

In order to determine the association between GER and COPD, we used a fixed-effect model (Q = 0.39; p = 0.94). The pooled analysis found a significantly higher prevalence of GER in COPD patients than in those without COPD (RR = 13.06; 95% CI: 3.64-46.87; z = 3.94; t2 = 0.0; p < 0.001; Figure 4). The analysis included 476 patients from all studies.



Discussion

The present systematic review with meta-analysis showed that GER is a risk factor for COPD exacerbations based on the higher risk for exacerbations and the increased number of exacerbations per year in these patients. In addition, our analyses showed a significant association between GER symptoms and COPD diagnosis. This association is corroborated by the increased frequency of exacerbations per year in patients with GER.

This is the first meta-analysis investigating GER as a risk factor for COPD exacerbations. The major issues about the effect of GER in COPD exacerbations are how exacerbations are determined or defined and whether such determinations are carried out prospectively or retrospectively. Recent retrospective studies(47,48) suggested that GER symptoms were associated with exacerbations; however, in those studies, the subjects were asked to report the number of exacerbations that had occurred during the previous year, which was an approach that could result in a recall bias. To solve this type of problem, other studies(19,45) utilized a prospective questionnaire-based data collection system that allowed us to identify exacerbations according to a more reliable definition of COPD exacerbation, such as the modified criteria by Anthonisen et al.(20) The prospective analyses of Terada et al.(19) and Hurst et al.(4) presented the most reliable information about exacerbations and were the most influential studies on the forest plots about the risk of COPD exacerbations associated with GER (Figure 5).



When less rigid criteria for the definition of an exacerbation were used, we found an increase in the frequency of exacerbations among GER patients. We conducted a preliminary analysis including studies with less rigid criteria,(40,41,48) which demonstrated a similar tendency of the risk of exacerbations (RR = 7.68), a similar increase in the frequency of exacerbations (mean increase = 1,02 per year) among GER patients, and a similar increased risk of GER associated with COPD (RR = 2.82) when compared with the results found in our final analysis (data not shown). Although only one study(44) utilized pH monitoring as the gold standard for the diagnosis of GER, the risk of exacerbations and GER in subjects with COPD demonstrated a good homogeneity across the studies.

Exacerbations of COPD are an important outcome in the natural history of the disease,(29,49-52) not only because they pose a considerable economic burden,(53) but, more importantly, because repeated COPD exacerbations can deteriorate health-related quality of life, accelerate the progression of the disease,(50-52) and lead to premature death.(3,50,52)

Over time, COPD exacerbations become more frequent and more severe, and this is associated with increasing functional impairment.(52) Risk factors for repeated exacerbations include low pre-treatment FEV1,(4,49,51) increased use of bronchodilators or corticosteroids,(4,48) previous exacerbations (more than two in the last two years),(4,49) prior use of antibiotics,(4,51) and presence of comorbid conditions.(4,29)

Studies have reported in-hospital mortality rates of 11-24%(17) and of 35.6%(50) after two years. Patients with frequent exacerbations had the highest mortality rates (p < 0.001), with a risk of death 4.3 times greater than that for patients requiring no hospital management.(51) Thus, the exacerbation itself might be a significant factor associated with increased mortality in COPD patients; however, the severity of the underlying disease might influence the patient outcome. Some studies(4,19,45,47,48) demonstrated an increase in the number of exacerbations per year related to GER, but its independent association with GER, using adequately controlled multivariate analysis, is yet to be tested.(25)

Another issue is the lack of a gold standard or of objective measurements in order to diagnose GER in the different studies, which makes it difficult to select studies and homogenize the data regarding the diagnosis of GER. The lack of a gold standard can overestimate or underestimate GER in some populations or samples. Respiratory patients frequently experience chest discomfort that can be confused with reflux symptoms, primarily pyrosis, leading to an overestimation of reflux symptoms. According to Sweet et al.,(6) the typical reflux symptoms (heartburn, regurgitation, and dysphagia), have a limited correlation with objectively measured reflux, reaching a sensitivity of 89.5% and a specificity of only 47.1%. These data make studies based on symptom questionnaires inaccurate when compared with those based on more specific tests, such as 24-h pH monitoring and esophageal scintigraphy.(30) In our meta-analysis, 6 of the 7 studies included were based on questionnaires, and, therefore, all of the conclusions should be inferred from GER symptoms as a risk factor, since there was no diagnostic confirmation of GER. However, the impact of studies based on questionnaires might underestimate this association. The only study(44) included in the present meta-analysis that had objective criteria demonstrated the strongest association between GER symptoms and COPD exacerbations. Prospective studies must be designed in order to identify GER objectively and to demonstrate the impact of GER treatment on COPD exacerbations.

A subanalysis of COPD patients receiving antireflux therapy(47) has shown that the number of COPD exacerbations per year in those patients who had controlled or non-symptomatic GER tended to decrease. In a randomized controlled trial, Sasaki et al.(25) showed that the treatment with lansoprazole (15 mg/day) in COPD patients without GER was capable to avoid COPD exacerbations in 77% of the patients (OR = 0.23). Those results must be seen with caution. Some authors(9,10) are skeptical about such data, since the association between asthma and GER is apparently stronger(14,16) than is the association between COPD and GER. In addition, intensive acid suppression in asthma patients, a population more likely to experience acid reflux, with esomeprazole (40 mg bid) did not reduce the number of exacerbations.(11,13) Clinically, silent acid reflux is not a reliable predictor of the success of antireflux treatment in asthma patients.(10)

The reason for such an association is unclear. The most common explanation is that the aspiration of reflux, either acid or not, increases airway inflammation and leads to an increased risk of exacerbations. However, the occurrence of chronic bronchitis clinically increases the risk of COPD exacerbations. A comparative analysis of COPD patients with and without chronic bronchitis, corrected for smoking status, body mass index, medication use, and pulmonary function, would be a much stronger argument for the presence or absence of a role played by GER in COPD exacerbations than would the present analysis. However, the differentiation between chronic bronchitis and emphysema was not performed in the studies included here.(2) We can speculate that there is a higher risk of COPD exacerbations or of GER in COPD patients with a history of chronic bronchitis.

Alternatively, it has been suggested by a number of investigators(26,28,34,47,54,55) that the association between GER and a wide range of respiratory diseases is best explained by the diseases causing or contributing to GER. There are various plausible hypotheses supporting this explanation. First, the high prevalence of hiatus hernia is due to chronic cough associated with different lung diseases.(26,39) Although there is not a perfect correlation between hiatus hernia and reflux, reflux is more likely to occur in the presence of larger hiatus hernia.(10) The diaphragm contributes to reduce the esophageal function, and any alteration between the two will affect its function. Second, bronchodilators also relax gastrointestinal smooth muscles and can facilitate reflux, and some drugs, such as theophylline, increase the production of gastric acid and, consequently, can cause acid reflux.(18,27,38,48)

In conclusion, we found that COPD patients with GER symptoms were more likely to experience exacerbations than were those lacking these symptoms. Objectively evaluating the presence of GER in such patients might determine future strategies to reduce or control GER and, subsequently, decrease the number of COPD exacerbations.


References


1. Global Initiative for Chronic Obstructive Lung Disease [homepage on the Internet]. Bethesda: Global Initiative for Chronic Obstructive Lung Disease [cited]. Available from: http://www.goldcopd.com

2. Rabe KF, Hurd S, Anzueto A, Barnes PJ, Buist SA, Calverley P, et al. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am J Respir Crit Care Med. 2007;176(6):532-55. http://dx.doi.org/10.1164/rccm.200703-456SO PMid:17507545

3. Connors AF Jr, Dawson NV, Thomas C, Harrell FE Jr, Desbiens N, Fulkerson WJ, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;154(4 Pt 1):959-67. Erratum in: Am J Respir Crit Care Med 1997;155(1):386. http://dx.doi.org/10.1164/ajrccm.154.4.8887592 PMid:8887592

4. Hurst JR, Vestbo J, Anzueto A, Locantore N, Müllerova H, Tal-Singer R, et al. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-38. http://dx.doi.org/10.1056/NEJMoa0909883 PMid:20843247

5. Anzueto A, Sethi S, Martinez FJ. Exacerbations of chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2007;4(7):554-64. http://dx.doi.org/10.1513/pats.200701-003FM PMid:17878469

6. Sweet MP, Patti MG, Hoopes C, Hays SR, Golden JA. Gastro-oesophageal reflux and aspiration in patients with advanced lung disease. Thorax. 2009;64(2):167-73. http://dx.doi.org/10.1136/thx.2007.082719 PMid:19176842

7. Lindberg A, Larsson LG, Rönmark E, Lundbäck B. Co-morbidity in mild-to-moderate COPD: comparison to normal and restrictive lung function. COPD. 2011;8(6):421-8. http://dx.doi.org/10.3109/15412555.2011.629858 PMid:22149402

8. Takada K, Matsumoto S, Kojima E, Iwata S, Okachi S, Ninomiya K, et al. Prospective evaluation of the relationship between acute exacerbations of COPD and gastroesophageal reflux disease diagnosed by questionnaire. Respir Med. 2011;105(10):1531-6. http://dx.doi.org/10.1016/j.rmed.2011.03.009 PMid:21454063

9. Moayyedi P, Axon AT. Review article: gastro-oesophageal reflux disease--the extent of the problem. Aliment Pharmacol Ther. 2005;22 Suppl 1:11-9. http://dx.doi.org/10.1111/j.1365-2036.2005.02605.x PMid:16042655

10. Labenz J. Facts and fantasies in extra-oesophageal symptoms in GORD. Best Pract Res Clin Gastroenterol. 2010;24(6):893-904. http://dx.doi.org/10.1016/j.bpg.2010.08.012 PMid:21126702

11. Kiljander TO, Junghard O, Beckman O, Lind T. Effect of esomeprazole
40 mg once or twice daily on asthma: a randomized, placebo-controlled study. Am J Respir Crit Care Med. 2010;181(10):1042-8. http://dx.doi.org/10.1164/rccm.200910-1537OC PMid:20110554

12. Malfertheiner P, Hallerbäck B. Clinical manifestations and complications of gastroesophageal reflux disease (GERD). Int J Clin Pract. 2005;59(3):346-55. http://dx.doi.org/10.1111/j.1742-1241.2005.00370.x PMid:15857335

13. Kiljander TO, Harding SM, Field SK, Stein MR, Nelson HS, Ekelund J, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med. 2006;173(10):1091-7. http://dx.doi.org/10.1164/rccm.200507-1167OC PMid:16357331

14. Alexander JA, Hunt LW, Patel AM. Prevalence, pathophysiology, and treatment of patients with asthma and gastroesophageal reflux disease. Mayo Clin Proc. 2000;75(10):1055-63. http://dx.doi.org/10.4065/75.10.1055 PMid:11040853

15. Mokhlesi B. Clinical implications of gastroesophageal reflux disease and swallowing dysfunction in COPD. Am J Respir Med. 2003;2(2):117-21. http://dx.doi.org/10.1007/BF03256643 PMid:14720011

16. Carpagnano GE, Resta O, Ventura MT, Amoruso AC, Di Gioia G, Giliberti T, et al. Airway inflammation in subjects with gastro-oesophageal reflux and gastro-oesophageal reflux-related asthma. J Intern Med. 2006;259(3):323-31. http://dx.doi.org/10.1111/j.1365-2796.2005.01611.x PMid:16476110

17. Crooks SW, Bayley DL, Hill SL, Stockley RA. Bronchial inflammation in acute bacterial exacerbations of chronic bronchitis: the role of leukotriene B4. Eur Respir J. 2000;15(2):274-80. http://dx.doi.org/10.1034/j.1399-3003.2000.15b09.x PMid:10706491

18. Mokhlesi B, Morris AL, Huang CF, Curcio AJ, Barrett TA, Kamp DW. Increased prevalence of gastroesophageal reflux symptoms in patients with COPD. Chest. 2001;119(4):1043-8. http://dx.doi.org/10.1378/chest.119.4.1043 PMid:11296167

19. Terada K, Muro S, Sato S, Ohara T, Haruna A, Marumo S, et al. Impact of gastro-oesophageal reflux disease symptoms on COPD exacerbation. Thorax. 2008;63(11):951-5. http://dx.doi.org/10.1136/thx.2007.092858 PMid:18535116

20. Anthonisen NR, Manfreda J, Warren CP, Hershfield ES, Harding GK, Nelson NA. Antibiotic therapy in exacerbations of chronic obstructive pulmonary disease. Ann Intern Med. 1987;106(2):196-204. http://dx.doi.org/10.7326/0003-4819-106-2-196 PMid:3492164

21. Vandenbroucke JP, von Elm E, Altman DG, Gøtzsche PC, Mulrow CD, Pocock SJ, et al. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE): explanation and elaboration. PLoS Med. 2007;4(10):e297. http://dx.doi.org/10.1371/journal.pmed.0040297 PMid:17941715 PMCid:2020496

22. Bax L, Yu LM, Ikeda N, Tsuruta H, Moons KG. Development and validation of MIX: comprehensive free software for meta-analysis of causal research data. BMC Med Res Methodol. 2006;6:50. http://dx.doi.org/10.1186/1471-2288-6-50 PMid:17038197 PMCid:1626481

23. Zhang J, Yu KF. What's the relative risk? A method of correcting the odds ratio in cohort studies of common outcomes. JAMA. 1998;280(19):1690-1. http://dx.doi.org/10.1001/jama.280.19.1690

24. Lefebvre C, Manheimer E, Glanville J. The Cochrane Highly Sensitive Search Strategies for identifying randomized trials in MEDLINE. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions 4.2.5. Chichester: John Wiley & Sons; 2005.

25. Sasaki T, Nakayama K, Yasuda H, Yoshida M, Asamura T, Ohrui T, et al. A randomized, single-blind study of lansoprazole for the prevention of exacerbations of chronic obstructive pulmonary disease in older patients. J Am Geriatr Soc. 2009;57(8):1453-7. http://dx.doi.org/10.1111/j.1532-5415.2009.02349.x PMid:19515110

26. Blondeau K, Mertens V, Vanaudenaerde BA, Verleden GM, Van Raemdonck
DE, Sifrim D, et al. Nocturnal weakly acidic reflux promotes aspiration of bile acids in lung transplant recipients. J Heart Lung Transplant. 2009;28(2):141-8. http://dx.doi.org/10.1016/j.healun.2008.11.906 PMid:19201339

27. Orr WC, Shamma-Othman Z, Allen M, Robinson MG. Esophageal function and gastroesophageal reflux during sleep and waking in patients with chronic obstructive pulmonary disease. Chest. 1992;101(6):1521-5. http://dx.doi.org/10.1378/chest.101.6.1521 PMid:1600768

28. Niklasson A, Strid H, Simrén M, Engström CP, Björnsson E. Prevalence of gastrointestinal symptoms in patients with chronic obstructive pulmonary disease. Eur J Gastroenterol Hepatol. 2008;20(4):335-41. http://dx.doi.org/10.1097/MEG.0b013e3282f2d0ec PMid:18334878

29. Makris D, Moschandreas J, Damianaki A, Ntaoukakis E, Siafakas NM, Milic Emili J, et al. Exacerbations and lung function decline in COPD: new insights in current and ex-smokers. Respir Med. 2007;101(6):1305-12. http://dx.doi.org/10.1016/j.rmed.2006.10.012 PMid:17112715

30. Dent J, Vakil N, Jones R, Bytzer P, Schöning U, Halling K, et al. Accuracy of the diagnosis of GORD by questionnaire, physicians and a trial of proton pump inhibitor treatment: the Diamond Study. Gut. 2010;59(6):714-21. http://dx.doi.org/10.1136/gut.2009.200063 PMid:20551454

31. Fahim A, Dettmar PW, Morice AH, Hart SP. Gastroesophageal reflux and idiopathic pulmonary fibrosis: a prospective study. Medicina (Kaunas). 2011;47(4):200-5.

32. Liang BM, Feng YL. Association of gastroesophageal reflux disease symptoms with stable chronic obstructive pulmonary disease. Lung. 2012;190(3):277-82. http://dx.doi.org/10.1007/s00408-011-9365-5 PMid:22258420

33. Chatila WM, Thomashow BM, Minai OA, Criner GJ, Make BJ. Comorbidities in chronic obstructive pulmonary disease. Proc Am Thorac Soc. 2008;5(4):549-55. http://dx.doi.org/10.1513/pats.200709-148ET PMid:18453370 PMCid:2645334

34. Pashinsky YY, Jaffin BW, Litle VR. Gastroesophageal reflux disease and idiopathic pulmonary fibrosis. Mt Sinai J Med. 2009;76(1):24-9. http://dx.doi.org/10.1002/msj.20088 PMid:19170215

35. Dent J, El-Serag HB, Wallander MA, Johansson S. Epidemiology of gastro-oesophageal reflux disease: a systematic review. Gut. 2005;54(5):710-7. http://dx.doi.org/10.1136/gut.2004.051821 PMid:15831922 PMCid:1774487

36. Fahim A, Crooks M, Hart SP. Gastroesophageal reflux and idiopathic pulmonary fibrosis: a review. Pulm Med. 2011;2011:634613.

37. Hershcovici T, Jha LK, Johnson T, Gerson L, Stave C, Malo J, et al. Systematic review: the relationship between interstitial lung diseases and gastro-oesophageal reflux disease. Aliment Pharmacol Ther. 2011;34(11-

12):1295-305. http://dx.doi.org/10.1111/j.1365-2036.2011.04870.x PMid:21999527

38. Kempainen RR, Savik K, Whelan TP, Dunitz JM, Herrington CS, Billings JL. High prevalence of proximal and distal gastroesophageal reflux disease in advanced COPD. Chest. 2007;131(6):1666-71. http://dx.doi.org/10.1378/chest.06-2264 PMid:17400682

39. Andersen LI, Jensen G. Prevalence of benign oesophageal disease in the Danish population with special reference to pulmonary disease. J Intern Med. 1989;225(6):393-402. http://dx.doi.org/10.1111/j.1365-2796.1989.tb00102.x

40. Schneider C, Jick SS, Bothner U, Meier CR. Reflux disease, gastrointestinal ulcer or weight loss in patients with COPD. COPD. 2010;7(3):172-8. http://dx.doi.org/10.3109/15412555.2010.481698 PMid:20486815

41. García Rodríguez LA, Ruigómez A, Martín-Merino E, Johansson S, Wallander MA. Relationship between gastroesophageal reflux disease and COPD in UK primary care. Chest. 2008;134(6):1223-30. http://dx.doi.org/10.1378/chest.08-0902 PMid:18689591

42. Timms C, Thomas PS, Yates DH. Detection of gastro-oesophageal reflux disease (GORD) in patients with obstructive lung disease using exhaled breath profiling. J Breath Res. 2012;6(1):016003. http://dx.doi.org/10.1088/1752-7155/6/1/016003 PMid:22233591

43. Soares RV, Forsythe A, Hogarth K, Sweiss NJ, Noth I, Patti MG. Interstitial lung disease and gastroesophageal reflux disease: key role of esophageal function tests in the diagnosis and treatment. Arq Gastroenterol. 2011;48(2):91-7. http://dx.doi.org/10.1590/S0004-28032011000200002 PMid:21709948

44. Casanova C, Baudet JS, del Valle Velasco M, Martin JM, Aguirre-Jaime A, de Torres JP, et al. Increased gastro-oesophageal reflux disease in patients with severe COPD. Eur Respir J. 2004;23(6):841-5. Erratum in: Eur Respir J. 2004;24(6):1074. Pablo de Torres, J [corrected to de Torres, JP]. http://dx.doi.org/10.1183/09031936.04.00107004 PMid:15218995

45. Terada K, Muro S, Ohara T, Kudo M, Ogawa E, Hoshino Y, et al. Abnormal swallowing reflex and COPD exacerbations. Chest. 2010;137(2):326-32. http://dx.doi.org/10.1378/chest.09-0482 PMid:19783670

46. Phulpoto MA, Qayyum S, Rizvi N, Khuhawar SM. Proportion of gastroesophageal reflux symptoms in patients with chronic obstructive pulmonary disease. J Pak Med Assoc. 2005;55(7):276-9. PMid:16108509

47. Rascon-Aguilar IE, Pamer M, Wludyka P, Cury J, Coultas D, Lambiase LR, et al. Role of gastroesophageal reflux symptoms in exacerbations of COPD. Chest. 2006;130(4):1096-101. http://dx.doi.org/10.1378/chest.130.4.1096 PMid:17035443

48. Eryuksel E, Dogan M, Olgun S, Kocak I, Celikel T. Incidence and treatment results of laryngopharyngeal reflux in chronic obstructive pulmonary disease. Eur Arch Otorhinolaryngol. 2009;266(8):1267-71. http://dx.doi.org/10.1007/s00405-009-0922-y PMid:19221778

49. Miravitlles M, Guerrero T, Mayordomo C, Sánchez-Agudo L, Nicolau F, Segú JL. Factors associated with increased risk of exacerbation and hospital admission in a cohort of ambulatory COPD patients: a multiple logistic regression analysis. The EOLO Study Group. Respiration. 2000;67(5):495-501. http://dx.doi.org/10.1159/000067462 PMid:11070451

50. Groenewegen KH, Schols AM, Wouters EF. Mortality and mortality-related factors after hospitalization for acute exacerbation of COPD. Chest. 2003;124(2):459-67. http://dx.doi.org/10.1378/chest.124.2.459 PMid:12907529

51. Soler-Catalu-a JJ, Martínez-García MA, Román Sánchez P, Salcedo E, Navarro M, Ochando R. Severe acute exacerbations and mortality in patients with chronic obstructive pulmonary disease. Thorax. 2005;60(11):925-31. http://dx.doi.org/10.1136/thx.2005.040527 PMid:16055622 PMCid:1747235

52. Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002 Oct;57(10):847-52. Erratum in: Thorax. 2008;63(8):753. http://dx.doi.org/10.1136/thorax.57.10.847 PMid:12324669 PMCid:1746193

53. Murray CJ, Lopez AD. Alternative projections of mortality and disability by cause 1990-2020: Global Burden of Disease Study. Lancet. 1997;349(9064):1498-504. http://dx.doi.org/10.1016/S0140-6736(96)07492-2

54. Cholongitas E, Pipili C, Dasenaki M, Goudras S. Are upper gastrointestinal symptoms associated with exacerbations of COPD? Int J Clin Pract. 2008;62(6):967. http://dx.doi.org/10.1111/j.1742-1241.2008.01772.x PMid:18479287

55. Rogha M, Behravesh B, Pourmoghaddas Z. Association of gastroesophageal reflux disease symptoms with exacerbations of chronic obstructive pulmonary disease. J Gastrointestin Liver Dis. 2010;19(3):253-6. PMid:20922187



Study carried out under the auspices of the Graduate Program in Medical Sciences, Federal University of Santa Catarina, Florianópolis, Brazil.
Correspondence to: Emilio Pizzichini. Universidade Federal de Santa Catarina, Hospital Universitário, Campus Universitário, Trindade, CEP 88040-970, Florianópolis, SC, Brasil.
Tel./Fax: 55 48 3234-7711. Email: pizzichi@matrix.com.br
Financial support: None.
Submitted: 10 January 2013. Accepted, after review: 1 February 2013.


About the authors

Thiago Mamôru Sakae
Professor of Epidemiology. Graduate Program in Medical Sciences, Federal University of Santa Catarina, Florianópolis, Brazil.

Márcia Margaret Menezes Pizzichini
Adjunct Professor. Graduate Program in Medical Sciences, Federal University of Santa Catarina, Florianópolis, Brazil.

Paulo José Zimermann Teixeira
Adjunct Professor. Federal University of Health Sciences of Porto Alegre; and Physician. Pereira Filho Ward, Santa Casa Hospital Complex in Porto Alegre, Porto Alegre, Brazil.

Rosemeri Maurici da Silva
Professor. University of Southern Santa Catarina, Florianópolis, Brazil.

Daisson José Trevisol
Professor. University of Southern Santa Catarina, Florianópolis, Brazil.

Emilio Pizzichini
Adjunct Professor. Graduate Program in Medical Sciences, Federal University of Santa Catarina, Florianópolis, Brazil.