"SLOW": an effective strategy for treating suspected gastroesophageal reux cough

Background Patients with gastroesophageal reux cough were always given drugs treatment to relieve symptoms. But most of these patients were found to have unhealty diatery habits. To develop a new strategy to assist drugs therapy, the study was conducted. Objective To explore the clinical signicance of “SLOW” strategy in the treatment of suspected gastroesophageal reux cough. Methods A prospective study was conducted to select 122 patients diagnosed with chronic cough and suspected with gastroesophageal reux cough who were admitted to Qilu hospital of Shandong University (Qingdao) from January 2015 to December 2017. Patients were randomly divided into experimental group (n=72) and control group (n=50). The experimental group was given omeprazole 20mg bid po + domperidone 10mg tid po + “SLOW” strategy, while the control group was only given omeprazole 20mg bid po + domperidone 10mg tid po. Hsu cough scoring system was used to analyze and evaluate the ecacy after 4 weeks of treatment. Results Among the 72 patients in the experimental group, 56 were effective (77.8 %), of which 44 cases were completely alleviated (61.1 %). Of the 50 control group patients, 27 were effective (54.0 %), of which 19 were in complete remission (38.0 %). The Hsu cough score showed a signicant decrease in the scores of the experimental group, which was statistically signicant compared with that of the control group (P<0.05). Conclusion The “SLOW” strategy, as a supplement to drug therapy, can increase the eciency of treatment and signicantly reduce the Hsu cough score. conducted to observe the effects of on the of


Introduction
Chronic cough is a common disease among respiratory outpatients, and the incidence rate among adults is as high as 10-40 %, among which gastroesophageal re ux cough accounts for about 20 % [1]. The members of this study found an obvious phenomenon in their daily work. Patients who experience chronic cough often have unhealthy eating habits, which include eating fast and much, preference for sugary desserts, liquid food, carbonated drinks and so on. These eating habits promote acid re ux of the stomach contents, which not only leads to gastroesophageal re ux cough (GERC), but also exacerbates chronic cough caused by other reasons. Currently, diagnosis of GERC requires 24-hour esophageal pH and multichannel impedance monitoring, which is rejected by many outpatients due to inconvenience and economic reasons. Clinical treatment of GERC mainly relies on drugs to inhibit gastric acid secretion and promote gastric peristalsis, while dietary guidance is relatively simple. Therefore, from the perspective of dietary habits, this study summarized the "SLOW" strategy, which means, to prevent chronic cough in patients with the above-mentioned dietary habits. For the "SLOW" strategy, "S" refers to slow and relaxed, which requires eating slowly and relaxedly. "L" speci es no liquid and sweet food. "O" indicates no overeating, especially during dinner, to ensure stomach is empty before going to bed. "W" means no water while eating which requires the participants to drink water at least 30 minutes before each meal or one to two hours after meals.

Subjects
Select patients diagnosed with chronic cough in Qilu Hospital of Shandong University (Qingdao) from January 2015 to December 2017, and the cause of chronic cough is suspected to be gastroesophageal re ux cough.
1.1 Inclusion criteria (1). The duration of cough was more than 8 weeks, and gastroesophageal re ux cough was suspected clinically; (2). Chest radiography showed no active or organic disease; (3). Cough SUPPRESSANTS and antibiotics were not effective; (4). Non-smokers or patients who have quit smoking for 2 or more years; (5). No history of dust exposure, no history of heart disease; (6). No history of upper respiratory tract infection within two months; (7). No application history of angiotensin converting enzyme inhibitors. In addition, participants need to have at least one of the following four eating habits: (1). Food needs to be consumed within 7 minutes, or less; (2). Preference for liquid foods, such as porridges, noodles, etc. or food containing more than 250ml liquid per meal, or having cooked rice soaked in water or soup, or have cookies soaked in milk before serving. (3). Participants with an inclination towards sweeter foods, such as desserts, sugar, sugary beverages, sweet potato, etc; (4). Overeating, especially at night, accounts for more than 50 % of daily intake. (1). Chest radiography suggests active or organic lesions; (2). New signs and symptoms of infection appeared during the study period; (3). The combination of cardiovascular and cerebrovascular emergencies; (4). Unable to cooperate with researchers for other reasons.

Therapeutic schedule
The enrolled patients were randomly divided into the experimental group (n = 72) and the control group (n = 50). The experimental group was given omeprazole 20mg bid po + doperidone 10mg tid po + "SLOW" strategy. The control group was only given omeprazole 20mg bid po + domperidone 10mg tid po. Weekly follow-up calls were conducted to observe the effects of treatment on the symptoms of the chronic cough. The study was approved by the ethics committee of Qilu Hospital of Shandong University (Qingdao) and we have obtained the consent from the patients.

Observation indicators
3.1 Hsu's 6-level scoring system was used for cough scoring [2], and 0-5 points were scored according to the frequency of cough. The details are shown in table 1.

E cacy criteria
The criteria for treatment effectiveness are classi ed into four categories: (1). complete remission: cough symptoms disappeared; (2). markedly improved: cough symptom scores decreased by at least two points; (3). improved: cough symptom scores decreased by 1 point; (4). invalid: no change in score, or cough symptoms aggravate. Cough scores were given at the time of rst visit, followed up weekly by telephone and cough scores were recorded.

Analysis of other interfering factors
In order to further verify that the treatment effect of patients in the experimental group is related to the treatment strategy rather than other factors, including age, gender, cough duration and cough symptom score, etc. We conducted a multi-factor analysis of patients in the experimental group, especially those with complete remission of symptoms.

Statistical methods
The effective rate and complete response rate were expressed as percentages. Age and course of disease were tested by t test while chi-square (χ2) test was used for sex. Non-parametric test (rank sum test) was used for the comparison between groups before and after treatment. Non-parametric test (two relevant samples) was used for intra-group comparison before and after treatment.

Case information
A total of 122 patients were selected, randomly divided into the experimental group (n = 72) and the control group (n = 50

Changes in Hsu cough score
Before treatment there was no signi cant difference in Hsu cough scores between the experimental group and the control group (P > 0.05). After 4 weeks of treatment, the Hsu cough scores decreased signi cantly both in the control and experimental group (P < 0.01). However, the difference in Hsu cough scores between the experimental group and the control group was also statistically signi cant (P<0.05), which was shown in table 4.

Factors in uencing turnaround time
The turnaround time is not related to various factors such as age, gender, cough duration time, and cough symptom scores.

Factors in uencing cure time
We checked the 44 patients whose cough was completely eliminated, and we revealed that the cure time is not related to age, gender, cough duration time and cough symptom score.

Discussion
Both esophagus and trachea originate from fetal foregut in the process of tissue development, and their autonomic nerves have homology. Re ux and acidic gas stimulate various mechanical and chemical receptors in the esophagus, and then affect the trachea through the vagus re ex [3]. When the esophageal mucosa is stimulated by gastric contents (acidic or non-acidic), the trachea will produce the re ex stimulation which is called "esophagus-bronchial re ex". The vagus nerve afferent pathway on the surface of the esophagus is also an important cough regulating nerve. When stimulated, it can directly lead to cough or increase cough excitability via the central nervous system.
Chronic cough patients with the abovementioned characteristics are prone re ux of gastric contents into the esophagus. Although no further de nite diagnosis has been made, they are the suspected GERC patients. Symptoms of chronic cough can be caused by inhalation of the gastric contents into the lung by mistake or indirect stimulation into the throat. Moreover, esophagobronchial re ex can also be caused by the re ux of gastric contents, resulting in long-term cough due to the high sensitivity of the esophageal mucosa to various irritations [4].
Currently, the routine treatment of GERC mainly involves the intervention of direct stimulation of gastric contents on the lungs and throat. Regimens generally include proton pump inhibitors (PPI), gastric motility agents, and gastric acid neutralizers, with few interventions targeting esophagobronchial re ex and esophageal hypersensitivity. Therefore, the treatment effect of some patients is not ideal, and refractory gastroesophageal re ux disease (RGERC) even occurs [5].
In untreated GREC, acid re ux and non-acid re ux accounted for 50 % respectively, while among GREC patients receiving PPI treatment, 4 % coughs were associated with acid re ux, 74 % with weak acid re ux, and 17 % with weak base re ux [6]. In adults, re ux of gastric acid into the throat and irritation of the cough is rare. However, 24-hour esophageal pH monitoring found that most GERC patients only had distal re ux, suggesting that some cough causes were signi cantly correlated with distal re ux. Meanwhile, through the MII multi-conductor impedance electrode, it can be known that non-acidic re ux is also closely correlated with GERC [7]. At this time, gastroscopy does not necessarily reveal abnormal esophageal mucosa, which is called gastroscopy-negative GERD or non-erosive re ux disease (NERD).
When we do gastroscopes, we don't necessarily nd abnormalities in the esophagus mucosa, called gastroscopy-negative GERD or non-corrosive re-disease NERD, and the current consensus holds that NERD is a subtype of GERD [8]. NERD is divided into three subtypes: (1) Abnormal acid exposure; (2) The esophageal mucosa is highly sensitive (the physiological amount of acid re ux can cause heartburn symptoms); (3) The production of symptoms has nothing to do with acid re ux [9].
So any stomach contents entering the esophagus, whether weak acid or even basic re ux, can also cause intractable cough, and stimulation of the esophageal mucosa leading to pain in the anterior chest or back. Preventing food re ux to the esophagus and reducing irritation to the esophagus may be effective in relieving the cough of such patients, rather than just reducing the acidity of the esophagus. To this end, we have developed a "SLOW" strategy based on the following considerations: "S" stands for slowly and relaxed, which is the focus of this strategy because eating fast could aggravate GERC in three aspects: (1) Food rst reaches the gastric fundus after eating. If food is eaten too fast for a long time, it will be swallowed in large lumps, which will not only cause the expansion of the esophagus, but also cause the expansion of the gastric fundus, stimulate the stretch receptors in the gastric fundus and stimulate the transient relaxation of the esophageal sphincter [10]. (2) Eating too fast, saliva cannot be secreted in time, and the decrease in saliva volume leads to the decrease in the concentration of epidermal growth factor, which can inhibit gastric secretion [11]. Therefore, the decrease of the amount of saliva, can lead to increased gastric acid secretion, easy to aggravate the stimulation of the esophagus.
(3) Eating too fast, the mood is often a state of tension and anxiety, and mood has a signi cant impact on the stomach. Psychosocial stimuli can aggravate acid re ux symptoms in patients with gastropathy, and the potential mechanisms may include: exacerbating the frequency and degree of esophageal acid exposure, inhibiting gastric acid drainage, or hypersensitivity of esophageal mucosa generated by stimulation [12]. "L" is for no liquid and sweat food. There are three possible reasons: (1) Liquid food contains much water, the required chewing frequency is low and chewing intensity is small, these can inhibit the secretion of saliva. Decreased levels of epidermal growth factor and amylase in saliva can increase gastric acid production. (2) Gastric emptying requires the muscles of the pylorus to wrap the food and deliver it downward. If the food is too thin, it will be di cult to wrap it tightly, resulting in up-down turbulence and delayed emptying, which will also increase the possibility of re ux. (3) Sparse foods tend to ow back into the esophagus, while irritant uids, such as coffee and carbonated drinks, can aggravate the incidence of gastroesophageal re ux [13].
"O" means no overeating. If you eat too much, the emptying will become slower, which will naturally increase the chances of re ux [14]. So we recommend that patients go on a diet and stop eating 3 hours before bedtime.
"W" means no water while eating correctly. This is the same as eating liquid food. Drinking a lot of water reduces the production of saliva and slows the emptying of the stomach. We recommend drinking water 1-2 hours after meals.
Kahrilas et al believe that acid-inhibiting therapy has a de nite therapeutic effect on chronic cough, but how to screen patients is the key [15]. This study can provide reference for screening patients who bene t. Dietary intervention is currently a weak link in the treatment of cough. This strategy requires no additional drugs, has no economic burden and no side effects, is easily understood and accepted by patients, and is easy to be promoted in medical institutions at all levels. Therefore, for chronic cough patients who have the habit of eating fast, preferring sweets and liquids, overeating and drinking water while eating, it is recommended to empirically apply the strategy of "SLOW", and try to supplement the current drug treatment of chronic cough, especially GERC.

Declarations CONSENT FOR PUBLICATION
Not applicable.

COMPETING INTERESTS
The authors declare that they have no competing interests.

AVAILABILITY OF DATA AND MATERIALS
The datasets used during the current study are available from the corresponding author on reasonable request.
14. Xu X, Yang Z, Chen Q, et al. Comparisom of clinical characteristics of chronic cough due to non-acid and acid gastroesophagel re ux . No cough (fully recovered) 1 One paroxysmal cough per day 2 At least two paroxysmal coughs per day, but no night cough 3 Frequent cough, but does not affect daily activities, or night cough and wake once 4 Frequent cough and affect daily activities, night cough and wake often 5 Most of the time cough, or cannot sleep at night