Effectiveness of Antireflux Surgery for the Cure of Chronic Cough Associated with Gastroesophageal Reflux Disease

DOI 10.1007/s00268-014-2769-7 ORIGINAL SCIENTIFIC REPORT Effectiveness of Antireflux Surgery for the Cure of Chronic Cough Associated with Gastroesophageal Reflux Disease Marialuisa Lugaresi Beatrice Aramini Niccolò Daddi Fabio Baldi Sandro Mattioli Ó Société Internationale de Chirurgie 2014 Abstract Background The effectiveness of surgical therapy for chronic cough secondary to gastroesophageal reflux disease remains controversial. The purpose of this study was to assess the efficacy of surgery and to identify the preoperative clinical profile that could predict the positive effects of treatment on chronic cough. Study Design Of 299 patients who underwent antireflux surgery between 1995 and 2010, 67 patients were affected by chronic cough and typical symptoms. In addition, 83 patients with typical symptoms were selected to form the control group, according to the parameters of age, sex, and the period of surgical activity. Preoperatively, all patients underwent a workup, including symptom assessment, barium swallow, upper gastrointestinal endoscopy, esophageal manometry, and 24-h ph recording or intraluminal impedance/ph monitoring in the absence of esophagitis. Patients with chronic cough also were administered a high-resolution computed tomography scan of the chest, a methacholine challenge test, and spirometry. Surgery was performed on patients positive for gastroesophageal reflux disease and negative for pulmonary diseases. The patients were followed up for a median of 84 months after surgery. Results No significant differences in preoperative reflux symptoms or esophagitis were found between the two groups. After surgery, chronic cough was absent in 57 (85 %) patients. Of the ten patients who still reported chronic cough, reflux symptoms relapsed in five, two of whom developed esophagitis. In the other five patients, typical symptoms were absent, and their chronic cough had improved but had not disappeared. Conclusions Surgery is effective for the treatment of chronic cough secondary to gastroesophageal reflux disease, particularly if associated with severe and long-standing typical symptoms. ClinicalTrials.gov ID NCT01899183; https://register.clinicaltrials. gov/prs/app/action/selectprotocol?sid=s0004bdn&selectaction= View&uid=U0000GED&ts=3&cx=-773yj2. M. Lugaresi F. Baldi S. Mattioli (&) Division of Thoracic Surgery, Center for the Study and Therapy of Diseases of the Esophagus, Alma Mater Studiorum - University of Bologna, Via G. Massarenti 9, 40138 Bologna, Italy e-mail: sandro.mattioli@unibo.it M. Lugaresi F. Baldi S. Mattioli GVM Care and Research, Cotignola, Italy Introduction The effectiveness of surgical fundoplication in treating classical reflux symptoms is well-documented, but the role B. Aramini Ph.D. Course in Pneumo-Cardio-Thoracic Sciences, XXIII Cycle, Alma Mater Studiorum - University of Bologna, Bologna, Italy N. Daddi Thoracic Surgery Unit, University of Perugia, Perugia, Italy

of surgery in alleviating extraesophageal symptoms allegedly secondary to gastroesophageal reflux disease (GERD) remains to be assessed [1]. Respiratory symptoms, including cough and dyspnea, may be present in up to 50 % of patients with GERD [2]. Moreover, in as many as 21 % of patients with chronic persistent cough, GERD is the cause of this symptom [3]. Delayed diagnosis followed by ineffective conservative management can result in severe and irreversible pulmonary complications [4]. The effectiveness of antireflux surgery in treating extraesophageal reflux symptoms varies from 15 to 95 %, and this range is largely attributable to differences in study design and methodology, patient selection, and outcome metrics [1]. To assess whether antireflux surgery has beneficial effects on chronic cough allegedly secondary to GERD and to identify the preoperative clinical profile that could predict positive treatment effects, we evaluated two groups of patients who underwent antireflux surgery for: (1) GERD associated with chronic cough; or (2) typical GERD symptoms alone. Methods Patients referred to the Centre for the Study and Therapy of Diseases of the Esophagus at the University of Bologna are routinely included in prospective protocols to investigate esophageal diseases and the outcomes of surgical therapy [5]. The preoperative workup and the follow-up protocol are standardised for each disease; adjunct/additional investigations are planned for research in defined areas. Preoperatively, the patients in this study routinely underwent symptom assessment, barium swallow, upper gastrointestinal (GI) endoscopy, and esophageal manometry [5]. The type and severity of symptoms and the grade of reflux esophagitis were scored using a questionnaire with semiquantitative scales (Table 1) [5]. The upper GI endoscopy, barium swallow, and esophageal manometry were performed according to standard techniques [5], and reflux esophagitis was reported according to the Los Angeles classification [6]. In the absence of esophagitis of Los Angeles grade A or higher [6], the patients underwent 24-h ph recording or intraluminal impedance/ph monitoring. Patients complaining of chronic cough were submitted to a specific workup, consisting of a high-resolution computed tomography (HRCT) scan of the chest, a methacholine challenge test, and spirometry, to exclude pulmonary diseases. In all patients, an ENT assessment was performed to rule out postnasal drip syndrome. Surgery was performed in patients who tested negative for pulmonary diseases on the HRCT scan of the chest, the methacholine challenge test and spirometry, considering Table 1 Semiquantitative scales for evaluating the severity of reflux symptoms (RS), dysphagia (S), dyspepsia (D), reflux esophagitis (RE), and chronic cough (CC) RS0 = Absence of reflux symptoms RS1 = Spontaneous or postural retrosternal heartburn or pain and/ or regurgitation occurring two to four times per month RS2 = Spontaneous or postural retrosternal heartburn or pain and/ or regurgitation occurring two to four times per week, with or without occasional aspiration RS3 = Spontaneous or postural retrosternal heartburn or pain and/ or regurgitation occurring on a daily basis, with or without frequent aspiration S0 = Absence of dysphagia S1 = Sticking of solid foods or liquids 2 4 times per month S2 = Sticking of solid foods or liquids 2 4 times per week S3 = Sticking of solid foods or liquids on a daily basis D0 = Absence of dyspepsia D1 = Dyspepsia occurring 2 4 times per month D2 = Dyspepsia occurring 2 4 times per week D3 = Dyspepsia occurring on a daily basis RE0 = Normal RE1 = Hyperaemia, oedema and/or histology positive for reflux esophagitis RE2 = Single or multiple non-confluent or confluent erosions RE3 = Deep ulcers, stenosis, or Barrett s esophagus Excellent = RS0, S0, D0, RE0 Good = RS1, S1, D1, RE0 Fair = RS2, S2, D2, RE1 Poor = RS3, S3, D3, RE2 3 CC0 = Absence of chronic cough CC1 = Chronic cough occurring 2 4 times per month CC2 = Chronic cough occurring 2 4 times per week CC3 = Chronic cough occurring on a daily basis the fact that the patients had primarily been referred for therapy for chronic cough. When proposing antireflux surgical therapy, surgery was indicated according to the current guidelines for GERD therapy [7] and the guidelines of the American College of Chest Physicians [8] for the cure of chronic cough due to GERD. A standard laparoscopic floppy Nissen procedure, associated with a left thoracoscopic Collis-laparoscopic Nissen procedure in cases of a short esophagus, was performed [5, 6]. A short esophagus was considered as a condition characterized by the inability to reduce the esophagogastric junction below the diaphragm intraoperatively after extensive esophageal mediastinal mobilisation [9]. Postoperatively, the patients participated in a free-ofcharge outpatient follow-up programme at 6, 12 months,

Table 2 Preoperative evaluation of GERD patients in group 1 and group 2 Group 1 GERD symptoms? chronic cough 67 Patients Group 2 GERD symptoms 83 Patients Mean age (years) (Median, IQR) 52 (51, 42.2 64.5) 52 (52, 40 67) p = 0.970 group 1 vs. group 2 Sex Men no. (%), women no. (%) Men 29 (43 %) Women 38 (57 %) Men 36 (43 %) Women 47 (57 %) p = 1.000 group 1 vs. group 2 Reflux symptoms (typical) 0 2 (3 %) 1 (1 %) 1 12 (18 %) 5 (6 %) 2 24 (36 %) 34 (41 %) 3 29 (43 %) 43 (52 %) p = 0.095 group 1 vs. group 2 Reflux esophagitis 0 23 (35 %) 16 (19 %) 1 13 (19 %) 16 (19 %) 2 13 (19 %) 39 (47 %) 3 18 (27 %) 12 (15 %) p = 0.368 group 1 vs. group 2 Dysphagia 0 20 (30 %) 8 (9 %) 1 35 (52 %) 43 (52 %) 2 11 (17 %) 28 (34 %) 3 1 (1 %) 4 (5 %) p = 0.000 group 1 vs. group 2 Dyspepsia 0 58 (87 %) 42 (51 %) 1 2 (3 %) 31 (37 %) 2 5 (7 %) 9 (11 %) 3 2 (3 %) 1 (1 %) p = 0.000 group 1 vs. group 2 Preoperative 24 h ph recording: total time at 9 % (7 9) 10 % (6 10) ph \4 (%), median (IQR) p = 0.073 group 1 vs. group 2 DeMeester score, median (IQR) 32 (23 33) 33 (17.9 36) p = 0.060 group 1 vs. group 2 Body mass index (kg/m 2 ), median (IQR) 28 (26 32) 28 (27 32) p = 0.236 group 1 vs. group 2 Surgery no. (%) Nissen 54 (80 %) Nissen 65 (78 %) Collis-Nissen 13 (20 %) Collis-Nissen 18 (22 %) Reflux symptoms (RS), reflux esophagitis (RE), dysphagia (S), and dyspepsia (D) were graded according to semiquantitative scales (see text and Table 1) Data are numbers with percentages in parentheses unless otherwise indicated and every year thereafter for 5 years. At 1, 3, and 5 years, they were submitted to a clinical interview, upper GI endoscopy, and barium swallow. Afterwards, they were offered free outpatient clinical consultation, endoscopy, and radiological examination of the esophagus and stomach every 3 years. The length of the follow-up was calculated from the day of the surgery to the day that the patient underwent the last follow-up.

Fig. 1 Preoperative (a) and postoperative (b) evaluations of chronic cough (CC) among patients in group 1, graded according to semiquantitative scales. The absolute numbers are indicated in parentheses. 0 Absence of chronic cough; 1 chronic cough occurring 2 4 times per month; 2 chronic cough occurring 2 4 times per week; 3 chronic cough occurring on a daily basis. Preoperative versus postoperative evaluation, p = 0.000 Institutional Review Board approval The follow-up procedures were developed according to good practice criteria. The patients were informed about the rationale, advantages, and disadvantages of follow-up after surgery for benign diseases of the esophagus, and they voluntarily accepted the proposed programme. The local institutional review board approved the use of its database for a retrospective review of the case files. Statistical analysis Data are expressed as median values and interquartile ranges (IQRs) unless otherwise stated. The Mann Whitney U test was used for comparisons of ordinal qualitative variables, and the v 2 test or Fisher s test was used, as appropriate, to evaluate nominal qualitative variables. Student s t test for unpaired data was performed for comparisons of continuous quantitative variables. The Wilcoxon signed-rank test was adopted to compare the preoperative and postoperative data between the groups. Multivariate analysis was performed using the logistic regression method to identify the preoperative predictors of response to antireflux surgery for the cure of chronic cough. Only variables found to be statistically significant in the univariate analysis were entered into the multivariate model. Continuous variables were dichotomised at the median value (preoperative duration of symptoms, body mass index). The severity of reflux symptoms (absent/mild vs. moderate/severe), the percentage of time at ph \4 (normal vs. abnormal), and the DeMeester score (normal vs. abnormal) were considered as categorical variables. A p value\0.05 was considered statistically significant. Statistical analyses were performed with the SPSS 13.0 software package (SPSS Inc., Chicago, IL, USA). Results This study of patients complaining of typical and atypical GERD symptoms was initiated in 1995 and completed in 2010. Of 299 patients operated on during that period, 67 patients [38 women (56 %), 29 men (44 %); median age = 52; IQR = 42 64] were affected by chronic cough ([8 weeks in duration) associated with typical GERD symptoms. The patients had not been exposed to environmental irritants. Additionally, they were not current smokers and were not taking an angiotensin-converting enzyme inhibitor. A poor response of chronic cough to intense medical therapy was the primary reason why these patients were referred to the surgeon. In total, 83 patients [47 women (56 %), 36 men (44 %); median age = 52; IQR = 40 67] with GERD-related typical symptoms alone were selected from the general database using a sequence of random numbers to form the control group according to age, sex, and the period during which the study group was enrolled (frequency matching). A comparison between the study and the control groups investigated the preoperative clinical patterns of patients presenting with or without cough. The frequency and the grade of the severity of reflux symptoms, including esophagitis, dysphagia, and dyspepsia (as assessed at the preoperative workup) are reported in Table 2. Dysphagia (p = 0.000) and dyspepsia (p = 0.000) were more severe in the control group than in the study group. In the study group, the frequency of

Table 3 Pre- and postoperative evaluation of GERD patients in group 1 Group 1 GERD symptoms? chronic cough 67 patients Preoperative Postoperative Reflux symptoms (typical) 0 2 (3 %) 53 (79 %) 1 12 (18 %) 13 (20 %) 2 24 (36 %) 1 (1 %) 3 29 (43 %) p (preoperative vs. postoperative) p = 0.000 Dysphagia 0 20 (30 %) 48 (72 %) 1 35 (52 %) 16 (24 %) 2 11 (17 %) 3 (4 %) 3 1 (1 %) p (preoperative vs. postoperative) p = 0.000 Dyspepsia 0 58 (87 %) 61 (91 %) 1 2 (3 %) 6 (9 %) 2 5 (7 %) 3 2 (3 %) p (preoperative vs. postoperative) p = 0.035 Reflux esophagitis no. (%) 0 23 (35 %) 62 (93 %) 1 13 (19 %) 3 (4 %) 2 13 (19 %) 2 (3 %) 3 18 (27 %) p (preoperative vs. postoperative) p = 0.000 Global outcome no. (%) Excellent = RS0, S0, D0, RE0 41 (61 %) Good = RS1, S1, D1, RE0 17 (25 %) Fair = RS2, S2, D2, RE1 5 (8 %) Poor = RS3, S3, D3, RE2-3 4 (7 %) Data are numbers with percentages in parentheses unless otherwise indicated preoperative chronic cough was severe (grade 3 = daily) in 24 % of patients (16/67), moderate (grade 2 = 2 4 times/ week) in 51 % (34/67), and mild (grade 1 = 2 4 times/ month) in 25 % (17/67; Fig. 1a). Floppy Nissen fundoplication was performed in 54 (81 %) patients, and the Collis- Nissen procedure was performed in 13 (19 %). All 67 patients in the study group received follow-up care (median = 84 months, IQR = 48 132). In all cases, barium swallow showed the integrity of the fundoplication and no hiatal hernia recurrence. The postoperative results of the study group are reported in Table 3. Statistically significant differences were noted between the preoperative and the postoperative results regarding reflux symptoms (p = 0.000), reflux esophagitis (p = 0.000), dysphagia (p = 0.000), and dyspepsia (p = 0.035), demonstrating the improvement in typical GERD systems achieved by the antireflux surgery. Antireflux surgery also significantly improved chronic cough (pre- vs. post-operative evaluation, p = 0.000; Fig. 1b), as chronic cough was absent after surgery in 85 % (57/67) of patients in the study group (Floppy Nissen = 45 and Collis-Nissen = 12; median follow-up = 108 months, IQR 60 180). Of ten patients reporting chronic cough after surgery (Floppy Nissen = 9 and Collis-Nissen = 1), typical GERD symptoms relapsed in five (median followup = 60 months, IQR = 36 96), two of whom developed esophagitis. In the other five patients (median followup = 36 months, IQR = 36 54), typical reflux symptoms were absent, and chronic cough scores improved from grade 3 to grade 1 in three patients and from grade 2 to grade 1 in two patients. A statistical comparison between the 57 patients whose chronic cough disappeared and the group of ten patients whose chronic cough persisted showed the presence of more severe preoperative GERD symptoms in the former group. Significant differences in the preoperative severity of reflux symptoms (p = 0.028), the percentage of total time at ph \ 4 in the distal esophagus (p = 0.007), the DeMeester score (p = 0.005), the body mass index (BMI) (p = 0.000), and the preoperative duration of symptoms (p = 0.014) were calculated (Table 4). The multivariate statistical analysis identified only the percentage of total time at ph \4 in the distal esophagus (p = 0.020) and the preoperative BMI (p = 0.025) as predictors of the response to antireflux surgery for the cure of chronic cough. Discussion According to a review conducted by Iqbal, which was based on 13 studies from 1995 to 2006 that evaluated the role of surgery in the clinical presentation of reflux-associated cough, 60 100 % of patients improved after surgery, and 13 96 % of patients were cured [1, 2, 10 19]. Data overlap was evident, and the literature suggests that patient selection for surgery represents a key factor in such overlap between studies [1, 2, 10 19]. In fact, most published studies have highlighted the importance of performing a specific diagnostic workup to investigate and demonstrate the relationship between cough and reflux and to rule out other causes of cough [1, 2, 10 19]. Because chronic cough is a nonspecific symptom of many pathologies, the outcome of surgical therapy is less predictable than for typical GERD, and additional preoperative investigations are required to rule out other aetiologies [1].

Table 4 Comparison between patients whose chronic cough disappeared (resolved cough group) and patients whose chronic cough persisted after surgery (persistent cough group) Resolved cough group 57 patients Persistent cough group 10 patients p (success vs. failure) Age (years), median (IQR) 51 (42 62) 55.5 (43.5 67.2) 0.681 Preoperative reflux symptoms (typical) 0 2 (20 %) 0.028 1 11 (19 %) 1 (10 %) 2 18 (32 %) 6 (60 %) 3 28 (49 %) 1 (10 %) Preoperative dysphagia 0 15 (26 %) 5 (50 %) 0.149 1 31 (54 %) 4 40(%) 2 10 (18 %) 1 (10 %) 3 1 (2 %) Preoperative dyspepsia 0 50 (88 %) 8 (80 %) 0.513 1 2 (3 %) 2 3 (6 %) 2 (20 %) 3 2 (3 %) Preoperative esophagitis 0 17 (30 %) 6 (60 %) 0.079 1 13 (23 %) 2 9 (16 %) 4 (40 %) 3 18 (31 %) Preoperative chronic cough 0 0.584 1 14 (25 %) 3 (30 %) 2 31 (54 %) 3 (30 %) 3 12 (21 %) 4 (40 %) Preoperative presence of Barrett s esophagus 18 (32 %) 0.052 Lower esophageal sphincter tone (mmhg), median (IQR) 9 (8 12) 9.5 (8 12.7) 0.632 Distal esophagus 9 % (7.2 9) 6 % (4.8 8.2) 0.007 Preoperative 24-h ph recording: total time at ph\4 (%), median (IQR) Supine time at ph \4 (%), median (IQR) 7 % (6 8) 6 % (5.4 7.5) 0.625 Upright time at ph \4 (%), median (IQR) 8 % (6.2 9) 7 % (6.2 8) 0.230 Proximal esophagus 2.5 % (1.8 2.8) 1.6 % (1.1 2.1) 0.078 Preoperative 24-h ph recording: total time at ph\4 (%), median (IQR) Symptom index (%), median (IQR) 62 (60 64.7) 60 (59.5 62) 0.165 Symptom Sensitivity index (%), median (IQR) 30 (28 34) 28 (25.7 29.5) 0.177 DeMeester score, median (IQR) 32 (27.5 33) 20.5 (16.7 27.2) 0.005 Body mass index (kg/m 2 ), median (IQR) 28 (26 32) 26.5 (26 27.2) 0.000 Preoperative duration of symptoms (months), median (IQR) 96 (72 180) 54 (36 120) 0.014 Data are numbers with percentages in parentheses unless otherwise indicated It has been suggested that patients may completely or partially respond to surgical therapy [1, 2, 10 19], although it is difficult to identify the patients who will benefit most from surgery. The guidelines of the American College of Chest Physicians [8] for the cure of chronic cough allegedly secondary to GERD recommend the adoption of a clinical profile that has been shown to be highly predictive (approximately 91 %) of the response of cough symptoms

to antireflux treatment. This predictive clinical profile includes the execution of an accurate diagnostic work-up to rule out other causes of chronic cough, and mainly pulmonary diseases (asthma, rhinosinus diseases, silent sinusitis, eosinophilic bronchitis) [8]. To identify the group of patients who would most likely respond to surgical treatment, 24-h ph recording or intraluminal impedance/ph monitoring, which have the advantage of identifying and characterising both acidic and non-acid reflux episodes [20], and the corresponding correlation between symptoms and reflux episodes are considered the gold standard [1, 11]. It has been suggested that the response to surgical therapy in patients with chronic cough may be dependent on the concomitant baseline presence of typical GERD symptoms (heartburn and regurgitation) [21 23]. In a study reported by Francis, preoperative heartburn with or without regurgitation and esophageal acid exposure greater than 12 % at baseline were significant predictors of the response to antireflux surgery; in fact, there was a 90 % probability of symptom improvement if both symptoms were present [23]. In the present study, we investigated 67 patients who were referred for surgery due to chronic cough allegedly secondary to GERD with a poor response to intense medical therapy. These patients underwent antireflux surgery after a workup confirmed the existence of GERD and excluded a primary pulmonary cause for the chronic cough. We also compared the clinical profile of the group of patients with typical reflux symptoms and chronic cough to that of a group of 83 patients with typical GERD symptoms alone, which was similar to the study group in terms of age, sex, and the period of surgery. In 57 of 67 patients (86 %), after a median postsurgical follow-up of 108 months (IQR 60 180), the chronic cough had disappeared. In 5 of 67 patients (7 %) (median follow-up = 36 months), reflux symptoms were absent, and the chronic cough had improved but not disappeared. Additionally, in 5 of 67 patients (7 %) (median follow-up = 60 months), gastroesophageal reflux had recurred, and chronic cough was present, as it was before surgery. No statistically significant differences in preoperative reflux symptoms or esophagitis, percentage of total time at ph \4, and DeMeester score were found between the group of patients with typical reflux symptoms and chronic cough and the group of patients with typical GERD symptoms only. Therefore, the GERD clinical profile of patients affected by GERD and chronic cough is not different from that of typical reflux patients. However, severe GERD likely has a predictive effect on surgical therapy for chronic cough, as we observed optimal results in the group of patients who had more severe reflux symptoms, a higher percentage of total time at ph \4, a higher DeMeester score, a higher BMI, and a greater duration of symptoms preoperatively. Literature data have consistently supported the relationship between BMI and severity of GERD [24 27]. In fact, the increase in BMI has been shown to be associated with the rise in the prevalence of GERD symptoms, esophageal mucosal injury, and GERD complications [24 27]. Therefore, our findings suggest that a higher BMI seems to be associated with a higher severity of GERD. The five patients whose chronic cough was attenuated but did not disappear after surgery refused to undergo postoperative 24-h ph or intraluminal impedance/ph monitoring tests. This clinical situation persisted for at least 36 months of follow-up and definitely after the 6 12 months following surgical therapy, which is generally described in the literature as a period that is considered to be too short for a definitive evaluation [1, 17, 28]. Thus, we cannot exclude the possibility that the cause of these patients chronic persistent cough was subclinical gastroesophageal reflux. In fact, previous studies have theorized that patients with airway symptoms may have hypersensitive responses to airway and esophageal inflammation [29], such that only a small amount of persistent reflux (which might otherwise be considered normal) may cause persistent symptoms. In addition, Irwin et al. [30] suggested that chronic reflux may initiate a cascade of airway pathology that becomes irreversible, such that the process and symptoms may persist even when reflux is eliminated. In conclusion, patients with well-documented GERD, notably those with severe and long-standing disease, for whom pulmonary diseases are excluded by an appropriate specific workup, can reasonably expect the resolution of chronic cough when effective surgical control of gastroesophageal reflux is achieved by antireflux surgery. Conflict of interest References None. 1. Iqbal M, Batch AJ, Spychal RT, Cooper BT (2008) Outcome of surgical fundoplication for extraesophageal (atypical) manifestations of gastroesophageal reflux disease in adults: a systematic review. J Laparoendosc Adv Surg Tech A 18(6):789 796 2. Novitsky Y, Zawacki JK, Irwin RS et al (2002) Chronic cough due to gastroesophageal reflux disease: efficacy of antireflux surgery. Surg Endosc 16:567 571 3. Irwin RS, Curley FJ, French CL (1990) Chronic cough. The spectrum and frequency of causes, key components of the diagnostic evaluation, and outcome of specific therapy. Am Rev Respir Dis 141(3):640 647 4. 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