Exacerbations of COPD and symptoms of gastroesophageal reflux: a systematic review and meta-analysis

Sakae, Thiago Mamôru; Pizzichini, Márcia Margaret Menezes; Teixeira, Paulo José Zimermann; Silva, Rosemeri Maurici da; Trevisol, Daisson José; Pizzichini, Emilio

doi:10.1590/S1806-37132013000300002

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Brasil

Jornal Brasileiro de Pneumologia

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Sumário

Meta-analysis • J. bras. pneumol. 39 (3) • June 2013 • https://doi.org/10.1590/S1806-37132013000300002 copy

Exacerbations of COPD and symptoms of gastroesophageal reflux: a systematic review and meta-analysis^* * Study carried out under the auspices of the Graduate Program in Medical Sciences, Federal University of Santa Catarina, Florianópolis, Brazil. ^ A versão completa em português deste artigo está disponível em www.jornaldepneumologia.com.br

Authorship SCIMAGO INSTITUTIONS RANKINGS

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.

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

Study	Characteristics of the study	Results	Comments
Hurst et al.⁽⁴⁾	Population-based cohort study; 2,138 COPD patients; stages 2 to 4 according to GOLD criteria; females/males: 35%/65%; mean age = 63 years; self-reported symptoms and history of GER or heartburn.	Mean number of COPD exacerbations: GER group = 1.41 per person per year; no GER group = 1.11 per person per year; risk of exacerbations in first year: OR =1.69 (95% CI: 1.38-2.06).	Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study.
Terada et al.⁽⁴⁵⁾	Population sample; 67 COPD patients and 19 controls; both genders.	Number of exacerbations: COPD group = 2.82 (95% CI: 1.92-3.72) per year; controls = 1.56 (95% CI: 0,92-2.19 ) per year; GER risk for COPD exacerbations: RR = 6.24 (95% CI: 0.90-43.34); in the multivariate analysis, abnormal swallowing reflex was associated with ≥ 3 exacerbations per year; p=0,01).	Abnormal swallowing reflex: COPD (22/67), controls (1/19; p = 0.02).
Eryuksel et al.⁽⁴⁸⁾	29 COPD patients (ATS criteria); LPR criteria: reflux symptoms index by Belafsky et al., reflux finding score (Belafsky et al.) and indirect laryngoscope.	13/29 patients with LPR (44%); number of exacerbations in the last year: GER (or LPR) = 1.38 ± 1.5; no GER (or no LPR) = 1.06 ± 1.06.	COPD symptom score: patients were asked about the severity of dyspnea, cough, wheezing, and the frequency of use of short-acting ß2 agonist during the last month. Definition of COPD exacerbation: any worsening of dyspnea, increase in the amount of sputum, or change in the color of sputum during the previous year. The frequency of exacerbations in each subject was retrospectively collected. At baseline, the groups were similar in terms of the incidences of antibiotic use (p = 0.652), steroid use (p = 0.267), ER visits (p = 0.677), outpatient visits (p = 0.620), hospitalizations (p = 0.448), and number of exacerbations (p = 0.52) during the last year.
Terada et al.⁽¹⁹⁾	Prospective and retrospective study; 82 COPD patients and 40 matched controls; moderate to severe COPD (GOLD criteria); symptoms evaluated by questionnaire (FSSG), surveyed for 6 months; exacerbations defined according to criteria by Anthonisen et al.⁽²⁰⁾	Simple analysis: GER symptoms vs COPD exacerbation: RR = 1.93 (p < 0.01); mean number of COPD exacerbations (retrospective - previous year): with GER symptoms: 1.73 ± 1.58; without GER symptoms: 0.70 ± 1.20. Additional 6 months surveyed: GER symptoms were also significantly associated with annual frequency; the frequency was 2.6 ± 2.0 in subjects with GER symptoms and 1.5 ± 1.7 in subjects without such symptoms (p = 0.048). GERD symptoms were significantly related to frequent (≥ 3 episodes per year) exacerbations (RR = 2.18; 95% CI: 1.10-5.70; p = 0.046). GER symptoms vs. COPD: RR = 2.15 (95% CI: 0.88-5.25).	GER symptoms: 22/82 (COPD), 5/40 (controls). Frequency of exacerbations associated with FSSG score (p = 0.03; r = 0.24). EBC pH was significantly lower in subjects with GER symptoms than in subjects without GER symptoms (6.47 ± 1.22 vs. 7.17 ± 1.05; p = 0.02) in COPD patients and in controls (6.34 ± 1.22 vs. 7.22 ± 0.53; p = 0.03). Multiple regression: association between GERD symptoms and occurrence of exacerbations (RR = 6.55).
Rascon-Aguillar et al.⁽⁴⁷⁾	GER definition: heartburn and/or acid regurgitation weekly. Patients with COPD: FEV1/FVC ratio < 70%; 91 patients: 5 lost to follow-up, 1 twice; total: 86 patients (32 GER+, 54 GER−) GER+ = 37% of the sample.	Exacerbations/year (GER+ vs. GER− groups) = 3.2 ± 3.1; SE = 0.548 vs. 1.6 ± 1.6; SE = 0,21 (p = 0.02; RR = 2.0; SE = 2.60). Patients who had weekly GER symptoms had significantly more hospitalizations due to COPD than did those without weekly GER symptoms (p = 0.007). All types of exacerbations were also significantly increased in the weekly GER group with the exception of prednisone use, which showed only an increased numerical trend.	A subanalysis of the patients receiving antireflux therapy demonstrated that the number of COPD exacerbations in the patients who were receiving PPIs and had controlled or non-symptomatic GER had a mean of 1.6 ± 0.9 exacerbations/year compared with symptomatic GER group receiving PPIs (3.7 ± 3.3 exacerbations/year; p = 0.09), indicating a trend toward a higher number of yearly exacerbations.
Phulpoto et al.⁽⁴⁶⁾	Prospective case-control study; 100 COPD patients, 150 controls.	Patients with GER: COPD group, 25%; controls, 9.33%; p = 0.001. GER and COPD: RR = 2.68 (95% CI: 1.47-4.90).	GER symptoms vs. reduced FEV1 (25% vs. 0%; p = 0.001).
Casanova et al.⁽⁴⁴⁾	42 COPD male patients, 16 volunteers; 24-h pH monitoring for GERD diagnosis.	GER: 26/42 COPD patients (62%) and 3/16 controls (19%); RR = 3.30 (95% CI: 1.16-9.41).	58% presented with any GER symptoms; decreased saturation coincided with esophageal acidity in 40% in the GER group.

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[1] 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