Gastroesophageal reflux-associated respiratory disease and its surgical treatment Abstract: Gastroesophageal reflux (GER)-associated respiratory disease is a multidisciplinary disease entity involving digestive, respiratory, ear, nose and throat, oral and even vascular surgery. Studies have confirmed a significantly higher rate of GERD comorbidity in asthma, chronic cough, chronic inflammatory ear, nose and throat diseases, and certain progressive and even advanced respiratory diseases including atopic pulmonary fibrosis, bronchiectasis, cystic fibrosis, chronic obstructive pulmonary disease, and scleroderma than in the apparently general population, where microaspiration is also prevalent. Transpharyngeal ejection of high-grade reflux is an important cause of microaspiration and its respiratory invasion, so GER-related respiratory disease can be considered as a disease entity that can be effectively controlled with anti-reflux therapy. Current studies have shown no significant efficacy of proton pump inhibitors (PPI) relative to placebo, and it is still recommended as an empirical or experimental agent for well-chosen patients. Surgical treatment as a more comprehensive and effective anti-reflux tool has shown good surgical results in the vast majority of studies for GER-related respiratory disease and can result in complete disappearance of symptoms in some patients, reaching a clinical cure-like effect. The surgical treatment has a promising application and is another proof of the close association between GER and some respiratory diseases, but the causal relationship has not been elucidated. The poor response or ineffectiveness of surgical treatment in some patients still suggests that a lot of research and studies are still needed on how to accurately select patients for surgery and how to further improve the efficacy. Keywords: gastroesophageal reflux disease; asthma; cough; bronchiectasis; pulmonary fibrosis; laparoscopic fundoplication; radiofrequency Gastroesophageal reflux related respiratory disease and anti-reflux surgical intervention Abstract. Gastroesophageal reflux (GER) related respiratory disease is an entity with multidiscipline affection, including gastroenterology, respiratory, It has been identified that comparing with the general population GERD has significantly higher prevalence in various chronic respiratory disease, such as asthma, chronic cough, chronic ENT diseases, and even some late stage respiratory disease GERD has significantly higher prevalence in various chronic respiratory diseases, such as asthma, chronic cough, chronic ENT diseases, and even some late stage respiratory disease, including idiopathic pulmonary fibrosis, brochiectasis, cystic fibrosis, COPD and scleroderma, moreover, microaspiration is common in these patients. Trans-pharyngeal spraying of high lever reluxate is an important source for microaspiration and consequently the airway insult. Hypothetically, GER related respiratory disease could be considered as an anti-reflux controllable entity. To date, proton pump inhibitor (PPI) has not shown significant therapeutic effect in asthma control in asthma patient with GERD. Serving as a more radical therapy, surgical intervention has been convinced to be effective in GER related respiratory disease in The majority of reported studies, with even complete clearance of symptoms which can be considered cure in some of the patients. Surgical treatment is expected to have a wider application the future in this issue, which otherwise also serves as a strong evidence that GER and part of respiratory disease are closely related though the causal relationship has As patients who have no or little response to surgical therapy still exist, the issue of precise selection of patients before operation is not considered in some of the patients. As patients who have no or little response to surgical therapy still exist, the issue of precise selection of patient before operation still requires massive research. GERD is a common gastrointestinal motility disorder with a prevalence of 10-20% of the population in Western countries [1] and 6-10% in Asia [2]. The typical symptoms of gastroesophageal reflux (GER) are usually reflux, heartburn and retrosternal pain and discomfort. In clinical and experimental studies of GERD since 2006, our research team found that GERD is also a heterogeneous disease with a wide range of symptoms that can involve the gastroesophagus, ear, nose and throat, upper respiratory tract, lower respiratory tract and oral cavity [3]. The resulting respiratory-related diseases can be treated satisfactorily or even cured clinically through pharmacological and surgical treatments. The author reviewed the relevant domestic and international literature and reviewed the clinical features and surgical treatment of GER and related respiratory diseases as follows. 1., Mechanisms of GER respiratory damage 1.1 Mechanisms of GER: The mechanisms of GER are now relatively clear and mainly include increased transient lower esophageal sphincter relaxation (TLESRs), widened cardia relaxation, reduced LES pressure and/or esophageal fissure insufficiency and canal fissure hernia [4]. In addition, superior mesenteric artery syndrome can also cause duodenal stasis resulting in reflux and even respiratory symptoms [5]. In addition coughing and wheezing symptoms that cause increased abdominal pressure are also important causes or aggravation of GER [6]. Due to the large increase in gastrointestinal surgery, reflux can also be caused by medically induced structural and functional changes in the intestinal tract; Billroth gastrectomy can lead to duodenal bile and pancreatic reflux [7, 8]; proximal gastric and lower esophageal resection by esophagogastric anastomosis or gastric substitution for esophagus and pyloroplasty can cause GER1 due to the absence of anti-reflux barrier in the lower esophagus and impaired pyloric emptying [9, 10]. The aforementioned reflux can also cause respiratory symptoms due to aspiration and airway invasion. 1.2 Correlation between GERD and respiratory diseases: a global consensus based on evidence-based medicine suggests a clear correlation between reflux cough, reflux laryngitis and reflux asthma syndrome and GERD [1].The high co-morbidity of GERD and asthma is considered to be important evidence of their close association, with GER symptoms, abnormal pH tests, esophagitis and esophageal hiatal hernia in asthma patients at a rate of 59.2%, 50.9%, 37.3% and 51.2%, respectively, and the prevalence of asthma among GERD patients was 4.6% compared to 3.9% in the control population [11]. When GERD forms high esophageal reflux, even breaking through the pharyngeal nozzle composed of the high-pressure band of the upper esophageal sphincter, different forms of transpharyngeal spurting, i.e., the 3S phenomenon (spilling, spraying, spurting), result in microaspiration of the reflux, which leads to immediate respiratory irritation and subsequent hypersensitivity [12]. Symptoms of respiratory diseases such as asthma are induced or exacerbated through neuroreflex pathways [13] or immunoinflammatory pathways [14]. Chronic cough is defined as a cough with a prolonged duration of more than 8 weeks, while postnasal drip, gastroesophageal reflux and asthma are among the top three most common causes of chronic cough, and it is estimated that about 21-41% of chronic cough is associated with GER [15].GER causes mechanical and pH-sensitive irritation of the pharyngeal airways and chronic inflammation resulting in increased sensitivity of the peripheral nerves mediating cough [16]. GER is also a possible cause of some chronic symptoms or lesions of the ear, nose and throat (ENT), and GER is an important risk factor in such patients on examination, but its causality has not been established due to the lack of controlled studies [16]. In the majority of cases treated at our center that presented mainly with respiratory symptoms and were evaluated for GRE, the majority of patients had no significant abnormalities on pulmonary imaging, and only a few patients had imaging findings of pulmonary alveoli, bronchiectasis, and pulmonary fibrosis [3]. Several studies in small samples have shown that GERD is also associated with advanced lung lesions, such as idiopathic pulmonary fibrosis, pulmonary cystic fibrosis, connective tissue disease, COPD and lung transplantation have detected a high prevalence of GERD, and signs of regurgitant (bile salts) aspiration have been found in the airways of patients with lung transplantation, but the inadequacy of the means of detection, sample size and experimental design has not yet allowed for more definitive Conclusions [17]. 2, clinical features GER-related respiratory symptoms can be divided into the following categories: ① pharyngeal symptoms: repeated throat clearing movements, pharyngeal foreign body sensation, hysteria, pharyngeal pain, dysphagia, etc.; ② upper respiratory tract and ear, nose, and throat symptoms: caused by the entry of regurgitant into the nasal cavity, middle ear, and nasolacrimal duct, mainly manifested as runny nose, postnasal drip, nasal congestion, sneezing, hoarseness, cough, lacrimation, tinnitus, sudden deafness, etc. Allergic rhinitis-like symptoms; (3) lower respiratory tract symptoms: persistent cough, coughing, wheezing and other asthma-like symptoms. This kind of cough and sputum caused by reflux is mostly non-seasonal, without clear allergens that cause attacks, and is mostly related to diet, body position and certain non-specific respiratory irritants such as cold air and oil and smoke, and some other patients are obviously related to reflux symptoms. It is obvious at night, mostly with nocturnal awakening or choking. (iv) Oral symptoms: prolonged retention of corrosive gastric contents in the oral cavity can cause oral-specific disorders such as dental erosion, oral odor, burning sensation, recurrent ulcers, and chronic gingivitis [18]. Due to the insidious nature of the relationship between extraesophageal symptoms and GER, the uncertainty of medical treatment and the lack of groundbreaking studies, it is easy to cause neglect and lack of awareness of this disease. The aforementioned respiratory symptoms such as episodic cough, wheezing, chest tightness and shortness of breath usually lead to the diagnosis of asthma. To visualize, diagnose and treat the disease Wang Chung-ho has proposed the concept of gastroesophageal laryngotracheal syndrome (GELTS) [19, 20], and through a summary of more than 2000 inpatients with reflux-related respiratory disease proposed that asthma symptoms caused by gastroesophageal reflux should be considered as a disease entity that can be controlled by anti-reflux treatment [21]. Gastroscopy can visualize esophageal lesions such as esophagitis and Barrett’s esophagus, and can also observe the relaxation of the cardia and esophageal hiatal hernia; 24-hour pH monitoring is the most widely used and the “gold standard” GER test, single or double channel, mainly reflecting the activity parameters of acidic reflux in the esophagus. The pH+impedance test can further measure the nature of acidic and non-acidic reflux (liquid or gaseous) and the height of reflux; high-resolution manometry can reflect abnormal esophageal function, showing the pressure in the upper and lower esophageal sphincter and the body of the esophagus and its ability to transmit and remove esophageal contents; upper gastrointestinal imaging can also reflect the function of the esophagus, reflux and esophageal hiatal hernia, but The examination time is short, influenced by the examiner and not very sensitive. The above tests can accurately reflect the function of the esophagus and the occurrence of GER and accurately diagnose GERD, but they cannot directly reflect the situation outside the esophagus affected by reflux, which to some extent restricts the diagnosis and treatment of extraesophageal symptoms and research, but the abnormal esophageal parameters they provide are an important basis for anti-reflux treatment of GER extraesophageal symptoms. 4. Anti-reflux treatment for GER-related respiratory disease Anti-reflux treatment should be given for reflux-related respiratory disease, and the improvement or even complete elimination of respiratory symptoms or lesions brought about by effective anti-reflux is a strong evidence of the interrelationship between the two. 4.1 Internal therapy: Most esophageal symptoms of GERD can be effectively controlled by internal therapy such as life conditioning, acid suppression, protection of the upper GI mucosa, and improvement of GI dynamics. Commonly used acid suppressants such as PPI can effectively control esophageal symptoms such as heartburn [22]. Therefore, PPIs are also used in the treatment of asthma patients with combined GERD, and studies have shown that asthma symptoms can be improved in some patients with the application of PPIs, and some indicators of lung function have improved in a small number of patients, however, PPIs have not shown a significant benefit on asthma control compared with placebo [23]. PPIs have shown a high rate of relief in chronic cough in uncontrolled studies, while in randomized double-blind studies PPI has shown improvement in cough symptom scores in only 35-75% of patients [15]. A recent study of patients with a clinical diagnosis of laryngeal reflux (LPR) treated with PPI for 12 weeks found a significant and sustained improvement in both the symptom index of laryngeal reflux and the laryngoscopic pharyngeal lesion score [24]. Acid suppression therapy is an important aspect of anti-reflux therapy, but is not effective in reducing reflux, inhibiting non-acid reflux and altering anatomical and functional abnormalities of the anti-reflux barrier. And it is prone to recurrence and requires long-term or even lifelong medication after discontinuation in some patients [25], especially when combined with esophageal hiatal hernia [26]. Although anti-reflux drugs such as PPI have the above-mentioned shortcomings, they can also be effective for well-chosen patients, and therefore are still recommended for empirical or experimental treatment. The fact that respiratory symptoms do not respond well to anti-reflux drugs such as PPIs does not mean that their respiratory symptoms are not related to GER. Anti-asthmatic drugs can reduce the frequency and degree of symptoms in this group of patients, but the effect of drug treatment is poor and the disease tends to progress. 4.2 Anti-reflux surgical treatment: Surgery reduces the duration, frequency, amount and height of reflux by reconstructing the anti-reflux barrier at the gastroesophageal junction. As long as any one of these reflux parameters is improved, their corresponding reflux symptoms will be improved, thus eliminating reflux from the mechanism of GER. 4.2.1 Fundoplication: laparoscopic Nissen fundoplication is one of the most commonly used anti-reflux procedures for long-term effective control of esophageal symptoms of GER [27].Field summarized 24 articles from 1966 -1998 on the outcome after anti-reflux surgery in patients with asthma combined with GERD, with 417 cases, and the post-anti-reflux rates of GER symptoms, asthma symptoms, use of anti-asthma medications The improvement rates of GER symptoms, asthma symptoms, use of anti-asthma drugs and pulmonary function after anti-reflux surgery were 90%, 79%, 88% and 27%, respectively, and there were many “cured” patients with complete disappearance of clinical symptoms, indicating that anti-reflux surgery can not only effectively control GER and asthma for these patients [28]. Although the improvement in pulmonary function is not as pronounced as in symptoms, the improvement in symptoms significantly improves the quality of life of the patients. Another study showed that fundoplication in children with hormone-dependent refractory asthma combined with GERD significantly improved asthma symptoms and lung function and reduced or discontinued hormone use [29]. Wang Zhonghao’s team used laparoscopic fundoplication for GER-related respiratory disease in clinical practice and conducted studies in 2008, and has accumulated more than 1400 cases and reported surgical outcomes similar to those in the literature [21]: complete relief of respiratory symptoms and little or no medication discontinuation in 35.9% of patients, which can be considered clinically cured; 43.8% had significant relief and reduction of anti-asthma medication. 7.8% of patients had mild remission; another 12.5% had poor or ineffective outcomes [30]. Postoperative heartburn and reflux scores decreased from 4.92 ± 1.99 and 4.98 ± 1.81 to 1.62 ± 2.33, 0.64 ± 1.43, and cough, wheeze and shortness of breath scores decreased from 7.23 ± 1.87, 7.50 ± 1.88 and 5.83 ± 2.13 to 2.79 ± 2.82, 2.53 ± 2.9 and 1.37 ± 2.10, respectively [31]. Chandra summarized nine prospective studies of surgical treatment of GER-related chronic cough with a total of 689 cases and a mean surgical efficiency of 85% [15]. Lindstrom reported the results of surgical treatment of 29 patients with GERD presenting with respiratory and ear, nose, and throat symptoms, 25 of which showed almost complete disappearance of symptoms after surgery [32]. Tian Shurui et al. reported the improvement of Stretta treatment on 199 cases of reflux-related ENT symptoms with an efficiency rate of 67.3%, with significant rates ranging from 33.3% to 49.4% for different subsymptoms [33]. Linden et al. performed Nissen fundoplication in 14 patients with idiopathic pulmonary fibrosis combined with GERD who were prepared for lung transplantation and were followed up for a mean of 15 months. patients had a more pronounced early FEV1 decline and lower survival after lung transplantation [35].Hoppo studied the anti-reflux efficacy in 43 end-stage lung diseases with detectable GERD, 19 of which were pre-lung transplantation patients and 24 of which were 31±24 months post-lung transplantation, including 11 COPD, 14 idiopathic pulmonary fibrosis, 6 cystic fibrosis, 7 scleroderma and 5 other cases. One year after anti-reflux surgery, 91% of post-transplant patients and 85% of pre-transplant patients showed significant improvement in FEV1 compared to preoperative. Anti-reflux surgery was associated with a significant reduction in pneumonia and rejection in post-lung transplant patients and also stabilized pre-lung transplant patients [36]. The Nissen total fundoplication and Toupet with folding surgical procedures are comparable and commonly used for esophageal symptoms, while the incidence of dysphagia after Toupet is lower than that of Nissen [37]. A recent randomized controlled study found that the Nissen procedure appears to be more effective than Toupet for respiratory symptoms [38]. The author, on the other hand, believes that the procedure should be selected individually for patients with GER-related respiratory disease, with the Nissen procedure preferred, and the Toupet procedure may be chosen for patients with preoperative abnormal esophageal dynamics and significant dysphagia may reduce the incidence of postoperative dysphagia. For patients with significant acid reflux on esophageal pH test fundoplication with additional gastric highly selective vagotomy may reduce postoperative acidic gastric juice secretion and further improve the efficacy to reduce postoperative reflux and anti-reflux medication [39]. 4.2.1 Endoscopic treatment: The endoscopic surgical treatment developed in recent years is more minimally invasive, including lower esophageal Stretta radiofrequency, intraluminal suture and lower esophageal sphincter injection, etc. Among them, Stretta radiofrequency treatment is mostly used abroad to treat esophageal symptoms of GERD and has achieved certain efficacy [40]. The results of 505 cases at 1 year after Stretta treatment were recently reported, with the reflux and heartburn symptom scores decreasing from 5.02 and 5.31 to 1.64 and 1.79, respectively, and the cough, wheezing and hoarseness symptom scores decreasing from 6.77, 7.83 and 5.13 to 2.85, 3.07 and 1.81 (P < 0.01) [41]. Another two cases of childhood asthma were similarly cured after anti-reflux treatment [42].Stretta radiofrequency treatment is nearly noninvasive and is mostly used by the author in patients without hiatal hernia, with relatively normal cardia morphology and function, insignificant esophageal symptoms but significant respiratory symptoms, unwilling to undergo laparoscopic surgery.Reflux symptoms remain after Stretta radiofrequency can also be re-frequency or optional fundoplication, and It can also be used for those who have inadequate anti-reflux with fundoplication. 4.2.2 Postoperative management: In addition to effective anti-reflux therapy, an important factor in the exacerbation of asthma and other respiratory symptoms caused by reflux is the persistence of varying degrees of airway hyperresponsiveness. Therefore, postoperative lifestyle adjustments are still needed for patients who have shown results to reduce reflux and recurrence of reflux, avoid cold or noxious air for respiratory irritation and avoid infection, and some patients still need regular or on-demand anti-asthma and/or anti-reflux medications. In patients with partial or complete recurrence or even in patients with poor surgical results, re-evaluation for GER is still necessary. If GER remains abnormal and is associated with respiratory symptoms, re-operation is worthwhile but needs to be chosen very carefully. If GER is not related to GER, the search for the cause and symptomatic treatment should be continued. 4.3 Supraduodenal vascular compression syndrome and medically induced reflux: Lifestyle changes such as postural changes and small, frequent meals can be used to reduce duodenal stasis and reflux. After Billroth gastrectomy, significant duodenal fluid (bile) reflux can occur, causing severe damage to the gastroesophageal mucosa and symptoms, and even frequent vomiting and extraesophageal symptoms, and acid suppression and other medical treatments are often poor, and Roux-en-Y surgery is feasible to eliminate Duodenal fluid reflux. Patients who have lost their esophageal cardia to esophageal surgery with significant reflux and poor conservative treatment can also have Roux-en-Y surgery to control reflux [43]. 5, Summary In conclusion, GER may be an important endogenous risk factor for several chronic respiratory diseases and is somewhat prevalent. The relationship between GER and respiratory disease and the adoption of anti-reflux surgical treatment is still debated, and although most of the existing surgical treatment studies have yielded encouraging results, the reliability of surgical treatment clinical studies as clinical evidence is weakened by the lack of uniform selection criteria for surgical treatment, differences in postoperative outcomes, and the inability to perform randomized double-blind studies, in addition, the fear of surgical The risk of complications from surgery seems to leave physicians on thin ice and without evidence. Anti-reflux treatment for chronic respiratory disease is not a panacea, and it is important to consider whether the patient's GER and respiratory symptoms are only exacerbated or merely coexist, whether the long-term respiratory lesions and hypersensitivity are irreversible, and whether various anti-reflux treatments cannot be applied to every patient and achieve complete suppression of reflux, or whether there are still unknown causes. Therefore, a comprehensive examination and individualized treatment are needed. With the development of screening tools and the improvement of comfort, safety and efficacy of surgical treatment, aggressive anti-reflux treatment for refractory, disabling chronic respiratory disease with clinical manifestations and tests suggesting a clear association with GER can have unexpected results. In patients who are expected to develop end-stage lung disease requiring future lung resection or lung transplantation, it seems more important to actively evaluate and detect the association with GER at an early stage and to provide aggressive anti-reflux therapy if necessary. As research on GER and respiratory disease advances and becomes more focused, this multidisciplinary disease entity will gradually break through disciplinary boundaries to restore its original nature, thus benefiting more patients.