Gastroesophageal reflux is a series of clinical syndromes caused by frequent reflux of gastric contents into the esophagus through the lower esophageal sphincter, while bronchial asthma is an inflammatory disease caused by a variety of causes, both diseases have long been known, but the relationship between the two has not attracted sufficient attention for many years. Only in recent years, with the advent of effective acid-suppressing drugs and portable pH testers, significant progress has been made in this area of research, and it has gradually been recognized that gastroesophageal reflux may be a triggering factor for asthma. We present a review of the current mechanisms, diagnosis and treatment of the link between asthma and gastroesophageal reflux. I. Mechanisms of gastroesophageal reflux leading to asthma 1. Vagally mediated reflexes: The tracheobronchial tree has the same embryonic origin as the esophagus, with the distal esophagus developing from the embryonic lung buds, that is, from the respiratory system, and both are autonomously innervated by the vagus nervel4]. In human studies, intraesophageal acid has been found to increase total respiratory resistance by 10%, especially during the onset of reflux symptoms, even up to 72%, and in experiments using dogs as a model, it was found that this increase in respiratory resistance caused by intraesophageal acid could be eliminated by bilateral vagal nerve dissection.Wright et al. evaluated 136 patients and found that intraesophageal acid increased 1 S Field et al. analyzed data from 312 asthmatics and found that FEV, peak expiratory flow (PEF), and airway resistance changes were 3%, 35%, and 42%, respectively, when gastroesophageal reflux symptoms were present, and that these changes were usually partially blocked by atropine and vagal nerve These changes are usually partially blocked by atropine and vagotomy. It is evident that vagally mediated reflexes play a major role in the process of GERD leading to asthma. Recent findings also suggest that asthma patients with GERD are often accompanied by autoregulatory impairment of vagal hyperresponsiveness, which leads to a decrease in lower esophageal sphincter pressure and frequent transient lower esophageal sphincter relaxation, a major mechanism for the development of reflux. 2, bronchial hyperresponsiveness: Intraesophageal acid can enhance bronchial hyperresponsiveness to other stimuli such as acetylcholine. wu et al. l6] performed intraesophageal perfusion with 0.1% hydrochloric acid and saline in 7 voluntarily tested asthmatic patients, and then evaluated airway responsiveness with acetylcholine-induced changes in respiratory function due to asthma. The acetylcholine concentration was significantly lower than that of the saline perfusion group. In contrast, Bagnato et al. performed acetylcholine provocation test on 30 patients with GERD without asthma symptoms and 30 normal patients at the same time, and used the acetylcholine concentration that caused a 20% decrease in FEV. as an index to evaluate airway responsiveness, and found that 11 of the 30 patients were equal to or less than this index, while only 2 of the control group were equal to or less than this index. Vincent et al. also demonstrated that in the number of esophageal refluxes and bronchial reactivity. There is an association between Although there is no data showing that anti-reflux treatment can improve airway hyperresponsiveness, these data do suggest that airway hyperresponsiveness due to esophageal reflux plays an important role in the development of asthma. 3. Microinhalation: Animal experiments have confirmed that the increase in airway resistance due to tracheal acidification is several times higher compared to esophageal acidification. Tuchman et al. observed in adult cats that 10 ml of acid in the esophagus can cause a 1.5-fold increase in total lung resistance, whereas 0.5 ml of acid in the trachea can cause a 5-fold increase in total lung resistance. Similarly, in asthmatic patients with simultaneous monitoring of tracheal and esophageal pH, Jack et al. demonstrated that intraesophageal acid caused an 8% decrease in PEF and an 84% decrease in PEF when intraesophageal acid caused a decrease in tracheal pH. The above study shows that if trace inhalation is present, it will significantly increase airway reactivity. 4, airway inflammation: Some studies have confirmed that in a guinea pig model, intraesophageal acid can activate the local axonal reflex, i.e., intraesophageal acid causes the release of inflammatory substances such as substance P in the bronchial mucosa through local nerve reflexes, resulting in airway edema. Inhalation of citric acid was also found to cause a dose-dependent increase in pulmonary resistance with sensory nerve activation and peripheral neurokinin release, and the increased total pulmonary resistance was eliminated by kinin NK-2 receptor antagonists.l8 J. The airway inflammatory response also plays an important role in the mechanism of asthma caused by GERD, which provides a rationale for the use of kinin and bradykinin antagonists in the treatment of asthma with GERD. This provides a rationale for the use of kinin and bradykinin antagonists in the treatment of asthma with GERD. 5. Ventilation changes: Although there have been many experiments in which intraesophageal acid caused bronchospasm, there have been reports of intraesophageal acid causing neither changes in FEV. nor bronchospasm. field et al. L5 J reviewed 18 sets of trials of 312 asthmatic patients with airway responses to intraesophageal acid from 1966 to 1997 and found that 35% of patients experienced changes in PEF and 42% experienced changes in airway resistance. Changes in airway resistance occurred in 42% of patients and no changes in FEV. in 90% of patients, and they concluded that bronchospasm does not play a major role in the development of asthma and is not present in all asthmatics. These findings led Field et al. to try to find other possible causes to explain asthma symptoms associated with GERD, and it turned out that intraesophageal acid could cause significant changes in microventilation and respiratory rate, so they postulated that this could be another explanation for GERD-related asthma symptoms. II. Mechanisms of asthma causing GERD Airway obstruction during the onset of asthma increases the negative pressure in the thoracic cavity, which increases the pressure gradient in the diaphragm and predisposes to esophageal reflux. In addition, airway obstruction flattens the diaphragm, weakening its anti-reflux capacity. The application of theophylline drugs in the treatment of asthmatic patients can increase gastric acid secretion and decrease lower esophageal sphincter pressure, inducing reflux or worsening reflux symptoms in patients. In an open-label trial, Eksiroh et al. found a 24% increase in reflux duration and a 3-fold increase in reflux symptoms after theophylline treatment. Similarly, systemic application of a monoadrenergic agonist reduced lower esophageal sphincter pressure, but did not show this effect in non-asthmatic patients Ruzkowski et al. found a 40% reduction in the incidence of GERD symptoms in patients treated with inhaled monoadrenergic agonists compared to theophylline in a small crossover trial. Third, obesity and gastroesophageal reflux and asthma relationship Obesity and adult exacerbation of asthma have a certain relationship _9 J. It is speculated that obesity may be by leading to reflux and aggravate asthma. In addition, it has been reported that the phenomenon of esophageal weakness in asthmatic patients with gastroesophageal reflux is as high as 53%, while in patients with gastroesophageal reflux and no asthma, this phenomenon is only 19% llo]. In conclusion, further observations are still needed regarding the association between the two. IV. Diagnosis Patients with asthma with typical GERD symptoms do not require any diagnostic tests. However, if asthmatic patients have mild or atypical reflux symptoms, diagnostic tests should be used. Since mucosal lesions are uncommon in these patients, endoscopy is not specific for the diagnosis of asthma with GERD. Intraesophageal 24-h pH is the most sensitive diagnostic method acceptable in patients with asthma, but a significant number of false negatives still exist because at least 1/4 of patients with typical gastroesophageal reflux have normal records. Harding et al l found a significant correlation between respiratory symptoms and intraesophageal acid contact time, but whether these findings can be used to diagnose patients with gastroesophageal reflux who have normal intraesophageal acid contact time in asthmatic patients, remains to be investigated. In the search for more rational diagnostic measures, O’Connor et al. l ] compared 11 different regimens and found that treatment with omeprazole 20 mg once daily for 3 months followed by 24-h pH monitoring in those patients who failed to respond to pharmacological therapy was the most cost-effective approach. In conclusion, both proton pump inhibitor treatment trials and 24-h pH monitoring are feasible, but they are subject to false-negative results, so when one of them is negative, this diagnosis still cannot be ruled out. If fat-filled alveolar macrophages are detected in the patient’s sputum, this is evidence of aspiration of gastric contents into the lungs; this method is highly specific, but not easily accepted due to lack of clinical feasibility. Another method is to use nucleotide technetium labeling to perform scintigraphy to document pulmonary aspiration of gastric contents. Intraesophageal acid perfusion to stimulate vagal reflexes causing bronchospasm is also a method to diagnose asthma due to gastroesophageal reflux. V. Treatment 1. Pharmacological treatment: Many clinical observations of anti-reflux drugs for asthma have design flaws, such as: (i) lack of control groups; (ii) lack of objective asthma and GERD evaluation indexes before and after treatment; (iii) inadequate acid suppression treatment; and (iv) small sample size. Despite these shortcomings, some clinical observations suggest that anti-reflux therapy may improve asthma symptoms and pulmonary function in some patients.Field et al. In a double-blind, placebo-controlled, crossover trial of 20 mg omeprazole twice daily for 6 weeks in asthmatic patients with gastroesophageal reflux, Meier et al. found that 4 of 14 patients had an improvement in FEVl greater than 20% , and 6 of the 10 patients with no improvement in FEVl still exhibited esophagitis on examination after 6 weeks of treatment, and their acid reflux was 3-5 times higher than those with improvement, suggesting that it is important to prolong acid suppression therapy before determining the outcome. Studies by others have reached similar conclusions, such as Harding et al_l mari treated 30 patients with asthma with GERD with increasing doses of proton pump inhibitors, and a pre- and post-treatment outcome assessment found that at least 73% of patients had improved PEF and/or reduced asthma symptoms. Asthma symptoms improved over time, with 30% of patients showing improvement at 1 month, 43% at 2 months, and up to 57% at 3 months. Among those with improvement, FEVl, FEVl/FVC and PEF improved significantly in 25-75% of cases. F0rd et al. treated 11 patients with nocturnal asthma with GERD with omeprazole 20 mg daily for 4 weeks and found no change in asthma symptoms or PEF compared to the placebo group. In a randomized, placebo-controlled, crossover trial of 20 patients with nocturnal asthma with GERD treated with omeprazole 40 mg daily for 4 weeks, no significant changes were found in asthma symptoms, inhaled monoadrenergic agonist dose, morning PEF, or respiratory function. Moreover, these patients underwent intraesophageal acid testing and found no reduction in the duration of acid exposure. 2. Surgical treatment: Field et_l conducted a retrospective study of 24 trials of surgical treatment of acid reflux from 1966 to 1998, including 417 patients with asthma, and found that after surgical treatment with antacid, 90% of patients had improved GERD symptoms, 79% had improved asthma symptoms, 88% had reduced dosage of anti-asthma medication, and 27% had pulmonary function The trial’s design was flawed. Despite the design flaws of some trials, there is evidence that at least 70% of patients with asthma symptoms improved significantly after anti-reflux surgery. 3. Comparison of surgical versus pharmacological treatment: Larrain et al. compared the effects of cimetidine 300 nag four times daily with surgical treatment and found improvements in FEV, PEF and drug use in both the pharmacological and surgical groups compared with the placebo group after 6 months of treatment. Asthma symptoms improved by 36% in the control group, 74% in the drug group, and 77% in the surgical group, while Sontag et al. compared the effect of treatment with ranitidine 150 mg three times a day with surgical treatment in 72 asthma patients with GERD. In the surgical group, 75% of patients had reduced or improved asthma symptoms, compared to 9% and 4% in the ranitidine group and the control group. From this, Menes et al_l J concluded that anti-reflux surgical treatment was superior to H, receptor blockers, but there is insufficient information to compare the difference between surgical treatment and proton pump inhibitor treatment for the control of asthma symptoms.